# projects

application_id: 8481535
project_number: 5R01DK048498-19
project_title: Surgical Studies of Functional Gene Expression
administering_ic: NIDDK
award_notice_date: 2013-07-16
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 048498
program_official: SERRANO, JOSE
project_start_date: 1996-03-15
project_end_date: 2015-05-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The mammalian intestinal mucosa is in a constant state of renewal that is characterized by active proliferation of stem cells localized in the crypts progression of these cells up the crypt villus axis with cessation of proliferation and subsequent differentiation. A delicate and precise balance of proliferation -> differentiation -> apoptosis must exist in the gut mucosa to maintain this normal intestinal homeostasis. Surgical resection of the small intestine results in an adaptive hyperplasia whereas the inability to provide enteral nutrients as occurs in certain post-operative or trauma patients results in atrophy. The major focus of our group has been the analysis of mechanisms regulating intestinal proliferation differentiation adaptation and apoptosis. With the support of this grant we have made great strides in our better understanding of the molecular mechanisms regulating intestinal homeostasis. We have shown that stimulation of PI3K/Akt increases normal intestinal proliferation. Our most recent findings have identified novel and differential roles for the mammalian target of rapamycin (mTOR) protein complex a major downstream effector of PI3K in intestinal proliferation and differentiation and intestinal cell survival. In preliminary findings we have shown that inhibition of mTORC2 but not mTORC1 enhances intestinal cell differentiation suggesting differential effects for these proteins in the gut. Also we have recently described the molecular mechanisms contributing to glutamine-mediated intestinal cell survival and proliferation; the PI3K/mTOR pathway plays an important protective role to limit apoptosis associated with cellular stress. Finally we have demonstrated a novel role for the mTOR pathway in intestinal cell autophagy following glutamine deprivation. Based on our recent published and preliminary findings we have refined our central hypothesis to state that intestinal cell proliferation and differentiation are regulated by signaling mechanisms involving the PI3K/mTOR pathway acting on critical downstream effector proteins; novel and differential effects of mTOR and Akt components exist that further add to the complex but highly regimented regulation of intestinal homeostasis. To examine this hypothesis we have planned experiments with the following Specific Aims: 1) to determine the differential effects of mTOR complexes on intestinal cell homeostasis 2) to delineate the signaling proteins that mediate the effects of mTOR in the intestine and 3) to define the role of mTOR/mTOR complexes in intestinal cell growth in vivo. The studies in the current proposal represent direct extensions of our previous findings and are designed to define in a systematic fashion the molecular mechanisms and signaling events regulating the processes of intestinal proliferation differentiation and adaptation. To achieve our goals we have assembled a multidisciplinary diverse and highly collaborative team of investigators who each bring unique expertise and background to the project.    PUBLIC HEALTH RELEVANCE: The intestinal mucosa is in a constant state of growth and renewal; the molecular pathways contributing to this critical function are poorly understood. Our recent findings have identified novel roles for components of the PI3K/Akt/mTOR signaling pathway in intestinal homeostasis. Delineating the cellular factors and signaling pathways regulating these processes is crucial to our understanding of not only normal gut development and maturation but also the effects of surgical resection and stress on intestinal adaptation and survival.

project_terms:
1-Phosphatidylinositol 3-Kinase;Alkaline Phosphatase;Apoptosis;Atrophic;Autophagocytosis;Brush Border;Cell Differentiation process;Cell Proliferation;Cell Survival;Cell physiology;Cells;Cellular Stress;Characteristics;Chemicals;Complex;Cyclin-Dependent Kinase Inhibitor;Development;Differentiated Gene;Enteral;Enterocytes;Enteroendocrine Cell;Enzymes;Epithelial Cells;Equilibrium;Event;Excision;Gene Expression;Glutamine;Glycogen Synthase Kinase 3;Goals;Goblet Cells;Grant;Growth;Homeostasis;Hyperplasia;Intestinal Mucosa;Intestinal Volvulus;Intestines;Ischemia;MAPK3 gene;MAPK8 gene;Mediating;Molecular;Mucous Membrane;Nutrient;Oligo-16-Glucosidase;Operative Surgical Procedures;PTEN gene;Paneth Cells;Pathway interactions;Patients;Pattern;Play;Postoperative Period;Process;Proliferating;Proteins;Publishing;Regulation;Research Personnel;Role;Signal Pathway;Signal Transduction;Signaling Protein;Small Intestines;Stem cells;Stress;Sucrase;Trauma;Tumor Suppressor Proteins;Villus;base;cell growth;cell type;deprivation;design;in vivo;inhibitor/antagonist;intestinal homeostasis;mTOR protein;multidisciplinary;novel;overexpression;protein complex;public health relevance;research study

public_health_relevance:
The intestinal mucosa is in a constant state of growth and renewal; the molecular pathways contributing to thiscritical function are poorly understood. Our recent findings have identified novel roles for components of thePI3K/Akt/mTOR signaling pathway in intestinal homeostasis. Delineating the cellular factors and signalingpathways regulating these processes is crucial to our understanding of not only normal gut development andmaturation but also the effects of surgical resection and stress on intestinal adaptation and survival.


application_id: 8479579
project_number: 1R01CA175003-01
project_title: Activating Bax as a therapeutic strategy for lung cancer
administering_ic: NCI
award_notice_date: 2013-06-28
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: CA
serial_number: 175003
program_official: SALNIKOW, KONSTANTIN
project_start_date: 2013-08-01
project_end_date: 2018-05-31
study_section: Basic Mechanisms of Cancer Therapeutics Study Section[BMCT]
contact_pi_person_id: 6950638
contact_pi: LI, CHI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Most human cancer cells are resistant to apoptosis. Among the major regulators of apoptosis are the Bcl-2 family of proteins. An emerging cancer therapeutic strategy is directly activating the apoptotic pathways by inhibiting the activity of ani-apoptotic Bcl-2 proteins or promoting the function of pro-apoptotic Bcl-2 proteins. However many of these strategies target the interaction among various Bcl-2 proteins particularly the interaction between pro- apoptotic and anti-apoptotic Bcl-2 proteins. Due to functional redundancy among Bcl-2 proteins these approaches are likely effective only on limited tumor types or display non-specific killing activities. As an important pro-apoptotic Bcl-2 protein Bax s involved in the development of tumors and Bax activation has been linked to apoptosis in lung tumors. Given that Bax alone is sufficient to initiate apoptosis in almost all apoptotic paradigms
direct activation of Bax by small molecule compounds could induce death of Bax-expressing tumor cells. Our preliminary studies using in silico screening of large chemical libraries identifid a small molecule predicted to bind to the Bax hydrophobic groove. This compound is able to activate Bax leading to Bax-dependent tumor cell apoptosis and inhibition of mouse tumor growth. The following specific aims are proposed: 1) Examine the mechanisms by which the Bax activator inhibits tumor growth in mice. We will test the ability of the Bax activator to inhibt the growth of transplanted human tumors in mice as well as spontaneous mouse lung tumors. Furthermore we will investigate whether the active compound acts synergistically with other therapeutic drugs to inhibit the growth of tumors. 2) Improve the ability of Bax activators to activate Bax induce apoptosis and inhibit tumor growth. Ligand-based analyses will be used to identify potential compounds with greater biological activities and the compounds will be experimentally examined. 3) Investigate the mechanism of Bax activation on biological membranes by the Bax activators. We will use a novel patch-clamp technique combined with biochemical and cell biology approaches to investigate how the Bax activators induce Bax permeation channels on native biological membranes in vitro. We will also study how Bax permeation pore formation is regulated by the anti-apoptotic Bcl-2 protein Bcl-XL. As dysregulation of Bax expression has been implicated in lung tumor development inducing apoptosis in tumor cells by directly activating Bax holds promise as a novel therapeutic strategy to treat lung cancer patients.

project_terms:
Address;Alleles;Anus;Apoptosis;Apoptosis Regulator;Apoptotic;BCL-2 Protein;BCL2 gene;Bax protein;Binding (Molecular Function);Biochemical;Biological;Cancer Patient;Carboplatin;Cell Death;Cells;Cellular biology;Cessation of life;Computer Simulation;Development;Generations;Growth;Human;In Situ;In Vitro;Inhibition of Apoptosis;Killings;Lead;Ligands;Link;Lung Neoplasms;Malignant Neoplasms;Malignant neoplasm of lung;Mediating;Membrane;Mus;Neoplasm Transplantation;Organelles;Patch-Clamp Techniques;Pathway interactions;Pharmaceutical Preparations;Process;Property;Protein Family;Relative (related person);Resistance;Role;Structure;Structure-Activity Relationship;Synthesis Chemistry;Testing;Therapeutic;Time;Toxic effect;Transplantation;Tumor Cell Line;Xenograft Model;base;cancer cell;cancer therapy;cytotoxic;cytotoxicity;design;improved;in vivo;inhibitor/antagonist;neoplastic;neoplastic cell;novel;novel therapeutics;pharmacophore;preclinical study;pro-apoptotic protein;public health relevance;research study;screening;small hairpin RNA;small molecule;small molecule libraries;tumor;tumor growth;tumor xenograft;virtual

public_health_relevance:
This project is designed to address the question of whether inducing apoptosis by direct activation of the pro- apoptotic protein Bax will be an effective chemotherapeutic treatment for cancer. By carrying out the experiments proposed in this study we hope to develop agents for the selective activation of Bax as a novel anti-neoplastic strategy.


application_id: 8478688
project_number: 1R01HL112788-01A1
project_title: BIOACTIVE LIPIDS IN STEM CELL HOMING AND MOBILIZATION
administering_ic: NHLBI
award_notice_date: 2013-05-25
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: HL
serial_number: 112788
suffix: A1
program_official: THOMAS, JOHN
project_start_date: 2013-06-01
project_end_date: 2017-03-31
study_section: Molecular and Cellular Hematology Study Section[MCH]
contact_pi_person_id: 2265592
contact_pi: RATAJCZAK, MARIUSZ Z
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
AMD3100;Address;Adult;Affect;Back;Blood;Blood Vessels;Bone Marrow;Bone Marrow Transplantation;CXCR4 Receptors;CXCR4 gene;Cell Adhesion Molecules;Cell surface;Cells;Chemotactic Factors;Clinical Research;Complement Activation;Data;Development;Engraftment;Erythrocytes;Exhibits;Fetal Liver;Fibroblasts;Genetic;Growth Factor;Hematopoietic;Hematopoietic Stem Cell Mobilization;Hematopoietic stem cells;Home environment;Homing;Human;Immunodeficient Mouse;Injection of therapeutic agent;Integrin alpha4beta1;Integrins;Laboratories;Life;Ligands;Lipids;Mediating;Modeling;Molecular;Mus;Osteoblasts;Patients;Peptide Hydrolases;Plasma;Play;Process;Publishing;Refractory;Research Personnel;Resistance;Role;Signal Transduction;Sphingolipids;Sphingosine-1-Phosphate Receptor;Stem cell transplant;Stem cells;Syndrome;Testing;Time;Transplantation Conditioning;Vascular Cell Adhesion Molecule-1;War;base;ceramide 1-phosphate;conditioning;improved;knock-down;mouse model;novel;peripheral blood;public health relevance;receptor;reconstitution;small molecule;sphingosine 1-phosphate;stem;trafficking

public_health_relevance:
With new data from our laboratory we have identified an important potential role for bioactive sphingolipids in trafficking of HSPCs. Bioactive sphingolipids are i) strong chemoattractants for HSPCs ii) resistant to proteolytic enzymes and iii) markedly increased in level in PB during mobilization and in BM after myeloablative conditioning for transplantation. Based on these findings we propose three interrelated aims to reappraise the role of SDF-1 in stem cell trafficking and address our central hypothesis that the bioactive lipids play an important and presently unappreciated role in homing and mobilization of HSPCs.


application_id: 8478550
project_number: 1R01HD075783-01
project_title: Evaluating the long-term effects of Green Dot on teen dating violence prevention
administering_ic: NICHD
award_notice_date: 2013-09-06
opportunity_number: PA-09-169
application_type: 1
activity_code: R01
ic: HD
serial_number: 075783
program_official: NEWCOMER, SUSAN
project_start_date: 2013-09-06
project_end_date: 2018-05-31
study_section: Community-Level Health Promotion Study Section[CLHP]
contact_pi_person_id: 1894149
contact_pi: COKER, ANN L
other_pis: FOLLINGSTAD, DIANE RUTH
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Accounting;Address;Adolescent;Adult;Binding (Molecular Function);Cohort Studies;Collection;Data;Data Analyses;Diffuse;Educational Status;Educational aspects;Elements;Equation;Evaluation;Exposure to;Family Violence;Frequencies (time pattern);Funding;Incidence;Individual;Intervention;Intervention Trial;Kentucky;Length;Life;Life Experience;Long-Term Effects;Measurement;Measures;Military Personnel;Outcome;Participant;Poa plant;Population;Pregnancy;Prevention program;Preventive Intervention;Primary Prevention;Randomized;Recruitment Activity;Relative (related person);Risk Estimate;Schools;Students;Substance abuse problem;Teen Dating Violence;Testing;Time;Training;Universities;Victimization;Violence;base;cohort;college;dating violence;dating violence prevention;design;emerging adult;experience;follow-up;high risk;high school;innovation;member;novel;partner violence;peer;peer violence;population based;programs;prospective;public health relevance;randomized trial;sexual violence;social norm;stressor;therapy design;twelfth grade;violence prevention;young adult

public_health_relevance:
Because teen dating and sexual violence rates remain high tests of promising primary prevention interventions with sufficient lengths of follow-up to detect changes in violence are needed. We propose a cohort study of high school seniors (n=7500) followed for up to 42 months who participated in a high school based randomized intervention trial of an active bystanding prevention program.


application_id: 8478095
project_number: 5R44DK089892-04
project_title: BIOMARKER FOR EARLY DETECTION OF CHRONIC KIDNEY DISEASE
administering_ic: NIDDK
award_notice_date: 2013-06-04
opportunity_number: PA-11-096
application_type: 5
activity_code: R44
ic: DK
serial_number: 089892
program_official: MOXEY-MIMS, MARVA M
project_start_date: 2010-09-20
project_end_date: 2015-05-31
study_section: Special Emphasis Panel[ZRG1-DKUS-L(11)B]
contact_pi_person_id: 1897474
contact_pi: CARRITHERS, STEPHEN L
other_pis: COUGHLIN, RICHARD THOMAS
congressional_district: 04
department: Unavailable
primary_duns: 189577070
primary_uei: DJ6WUEKKFBM8
duns_number: 189577070
uei: DJ6WUEKKFBM8
fips: US
organization_id: 10001287
organization_name: SEQUELA
organization_city: PEWEE VALLEY
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 400569116
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): There are an estimated 26 million Americans with early chronic kidney disease (CKD). Early diagnosis and treatment are the only cost-effective means to reverse this growing problem. NIH recognizes the challenge to diagnose CKD early during its initiation and development phases in order to prevent further renal damage reduce cardiovascular risk and minimize the economic impact of CKD. Current methods and biomarkers that are used to assess CKD are effective once the disease is well established but are not reliable for the detection of early disease. Further many patients initially determined tohave a mild decline in kidney function by the current methods may actually be misclassified and possibly under-diagnosed resulting in a patient having undiagnosed moderate to severe kidney damage. We will produce a new ELISA for CKD to be employed as a diagnostic test based upon the use of a novel biomarker that reflects early events in the pathophysiology of kidney disease. Detection of this biomarker for CKD will give laboratory results and clinical insight thatare complementary to creatinine-based glomerular filtration rate (GFR) estimates as well as tests for urine albumin. This should result is a more reliable and earlier identification of CKD.  n addition our CKD-Assay would give physicians the ability to evaluate patients that have been recently diagnosed with hypertension or diabetes. In Phase I we evaluated the feasibility and proof-of principal of this test and found that the prototype assay in both populations was highly sensitive and specific. In Phase II we will look for the influence of comorbid conditions and medications on assay performance compare our results to the gold standard assay of GFR and follow up patients over at least 3 years to evaluate the ability of this biomarker to follow progression of CKD. Lastly we will evaluate whether patient characteristics such as age gender BMI ethnicity and other factors impact on assay performance. We request Phase II support so that we can evaluate the prototype assay and further test its feasibility to help identiy at-risk patients for early kidney disease and monitor therapy with the ultimate goal of obtaining FDA approval and reducing the societal impact of under-diagnosed CKD.

project_terms:
Affect;Age;Albumins;American;Antibodies;Archives;Biological Assay;Biological Markers;Blood Circulation;Cardiovascular Diseases;Characteristics;Chronic Kidney Failure;Clinical;Clinical Trials;Complement;Creatinine;Detection;Development;Diabetes Mellitus;Diagnosis;Diagnostic tests;Disease;Early Diagnosis;Early identification;Early treatment;Enzyme-Linked Immunosorbent Assay;Ethnicity aspects;Event;Filtration;Functional disorder;Gender;Glomerular Filtration Rate;Goals;Gold;Health;Hemodialysis;Homeostasis;Hypertension;Impairment;Individual;Kidney;Kidney Diseases;Laboratories;Linear Models;Measures;Medical;Methods;Microalbuminuria;Monitor;NHANES;Patients;Performance;Pharmaceutical Preparations;Phase;Physicians;Play;Population;Prevalence;Race;Reagent;Renal function;Risk;Role;Sampling;Serum;Sodium Chloride;Specificity;Staging;Testing;United States;United States National Institutes of Health;Urine;Variant;Water;base;cardiovascular risk factor;case control;commercialization;cost effective;economic impact;follow-up;high risk;insight;novel;phase 1 study;post gamma-globulins;prevent;prohormone;prototype;prouroguanylin;research and development;research clinical testing;scale up

public_health_relevance:
Chronic Kidney Disease affects nearly 26 million people in the United States which places them at higher risk of cardiovascular disease and hemodialysis. We will develop an assay for the identification of people with advanced kidney disease that are under-diagnosed by current methods and to aid physicians in earlier treatment and better assessment of chronic kidney disease.


application_id: 8474756
project_number: 5R21ES021311-02
project_title: Effect of dietary fat on the hepatotoxicity of environmental arsenic
administering_ic: NIEHS
award_notice_date: 2013-05-17
opportunity_number: RFA-ES-11-002
application_type: 5
activity_code: R21
ic: ES
serial_number: 021311
program_official: SHREFFLER, CAROL A
project_start_date: 2012-05-25
project_end_date: 2015-04-30
study_section: ZES1-LWJ-J(DI)1
contact_pi_person_id: 1902836
contact_pi: WATSON, WALTER H
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): High intake of dietary fat and chronic exposure to environmental arsenic (As) are independent risk factors for liver disease but there have been no studies on how these two risk factors interact to damage the liver. The majority of obese people in the United States have steatosis (fatty liver) but less than 20% of people with steatosis progress to the much more serious condition of steatohepatitis (fatty liver with inflammation and liver injury) indicating that other environmental factors have an impact on inflammatory liver injury. The current proposal examines the role of environmental As in the progression from steatosis to steatohepatitis. A diet high in fat places a metabolic burden on the liver making it susceptible to injury by a second insult. In the studies proposed here the hypothesis to be tested is that chronic As exposure contributes to liver disease progression by altering metabolic pathways related to inflammation. Specifically this team will examine the basis for their recent observation that As exposure results in inflammatory liver injury in mice fe a high fat diet whereas the same concentration of As is not toxic in mice fed a low fat diet. The plan is to identify pathways altered by high fat As and the combination of the two by measuring changes in liver at the level of metabolomics and proteomics signatures. By constructing a model integrating both the enzymatic activities and metabolites one will be able to identify the pathways where these two stresses interact. These studies are expected to reveal metabolic signaling and regulatory pathways that are associated with inflammatory liver injury in a model of diet-environment interaction that is relevant to the United States population where high fat diets are common and As exposure levels are typically below the threshold for overt hepatotoxicity. This new information will be used as a basis for future studies examining the molecular targets of As that are responsible for increased sensitivity to inflammation. These studies may be applicable to other As- associated illnesses such as cardiovascular disease and cancer that are driven by chronic inflammation.

project_terms:
Address;Affect;Animal Model;Area;Arsenic;Benign;Biological Markers;Cardiovascular Diseases;Chronic;Consumption;Data;Development;Diet;Dietary Arsenic;Dietary Fats;Disease;Disease Progression;Environment;Environmental Risk Factor;Exposure to;Fat-Restricted Diet;Fatty Liver;Fatty acid glycerol esters;Figs - dietary;Future;Goals;Hepatotoxicity;Individual;Inflammation;Inflammatory;Inflammatory Response;Injury;Intake;Ions;Knowledge;Label;Liver;Liver diseases;Malignant Neoplasms;Manuscripts;Mass Fragmentography;Measures;Mediating;Meta-Analysis;Metabolic;Metabolic Pathway;Modeling;Molecular Target;Mus;Obesity;Organ;Pathogenesis;Pathway Analysis;Pathway interactions;Peptides;Population;Predisposing Factor;Proteins;Proteome;Proteomics;Regulatory Pathway;Risk;Risk Factors;Role;Sampling;Signal Pathway;Signal Transduction;Steatohepatitis;Stimulus;Stress;Techniques;Testing;Toxic effect;United States;base;cell injury;clinically relevant;cytokine;drinking water;feeding;improved;lipid metabolism;liquid chromatography mass spectrometry;liver injury;metabolomics;mouse model;novel;protein expression;research study;response;sodium arsenite;two-dimensional

public_health_relevance:
Most obese people have fatty liver disease to at least some extent. The proposed studies will examine how environmental As contributes to progression to more serious forms of liver disease.


application_id: 8472090
project_number: 1R01NR014189-01
project_title: Early Detection and Prevention of Mild Cognitive Impairment due to cerebrovascula
administering_ic: NINR
award_notice_date: 2012-09-26
opportunity_number: RFA-NR-12-010
application_type: 1
activity_code: R01
ic: NR
serial_number: 014189
program_official: TULLY, LOIS
project_start_date: 2012-09-26
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZNR1 REV-T (13)]
contact_pi_person_id: 1900844
contact_pi: JICHA, GREGORY A
other_pis: MOSER, DEBRA KAY
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): There is a great unmet need to distinguish clinically between the different causes of cognitive impairment in elderly individuals for the sake of early diagnosis and therapeutic intervention designed to improve outcomes for patients. The University of Kentucky Alzheimer's Disease Center (UK-ADC) has been at the forefront of studying the most prevalent causes of Non-AD MCI demonstrating that over two-thirds of elderly patients have non-AD brain conditions that deleteriously affect cognition. We have chosen to focus on MCI due to cerebrovascular disease (MCI-CVD). This application focuses on defining the pathological underpinnings and relationships of specific risk factors to MCI-CVD developing clinical diagnostic criteria for MCI-CVD using imaging serum and CSF biomarkers that will also allow longitudinal evaluation and assessment of therapeutic interventions in MCI-CVD. As such the current application represents a comprehensive bench-to-bedside translational program designed to directly increase our understanding of and impact the major cause of cognitive decline in the elderly population today. The multidisciplinary team represents leaders in the field with proven track histories of scientific accomplishments and collaborative enterprise in the area of MCI. Successful completion of project aims will allow an integrated understanding of MCI-CVD with the potential for tremendous impact on one of the major healthcare crises facing the nation today.   
   
PUBLIC HEALTH RELEVANCE: Mild cognitive impairment (MCI) is often conflated with early Alzheimer's disease (AD) although a large proportion of individuals with MCI lack AD pathology. Especially among individuals beyond 85 years of age the prevalence of non-AD brain diseases such as cerebrovascular disease (CVD) surpasses that of advanced AD. We have chosen to focus on MCI due to cerebrovascular disease (MCI-CVD). The current application represents a comprehensive bench-to-bedside translational program designed to directly increase our understanding of and impact the major cause of cognitive decline in the elderly population today. The multidisciplinary team represents leaders in the field with proven track histories of scientific accomplishments and collaborative enterprise in the area of MCI. Successful completion of project aims will allow an integrated understanding of MCI-CVD with the potential for tremendous impact on one of the major healthcare crises facing the nation today.

project_terms:
Affect;Age-Years;Alzheimer's Disease;Area;Autopsy;Biological;Blood;Brain;Brain Diseases;Brain Pathology;Cardiovascular Diseases;Cerebrospinal Fluid;Cerebrovascular Disorders;Clinical;Clinical Trials;Cognition;Cognitive;Data;Dementia;Diagnostic;Diagnostic Imaging;Disease;Doctor of Philosophy;Early Diagnosis;Elderly;Ensure;Etiology;Evaluation;Healthcare;Image;Impaired cognition;Individual;Intervention;Kentucky;Medical;Modification;Natural History;Neuropsychological Tests;Outcome;Pathology;Patients;Persons;Placebo Control;Population;Prevalence;Prevention;Randomized;Recording of previous events;Research Personnel;Risk Factors;Scientific Advances and Accomplishments;Serum;Staging;Statistical Models;Testing;Therapeutic Intervention;Universities;bench to bedside;biomarker;cohort;design;digital;disorder risk;improved;mild cognitive impairment;multidisciplinary;older patient;programs;standard of care;success;therapy design


application_id: 8470628
project_number: 5R01DK071349-09
project_title: Mechanisms Underlying Metabolic Syndrome in Obesity
administering_ic: NIDDK
award_notice_date: 2013-03-20
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DK
serial_number: 071349
program_official: ABRAHAM, KRISTIN M
project_start_date: 2005-06-01
project_end_date: 2015-03-31
study_section: Clinical and Integrative Diabetes and Obesity Study Section[CIDO]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: KERN, PHILIP A
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Resident macrophages in adipose tissue account for much of the cytokine expression with obesity. We described the expression of thrombospondin (TSP1) a pleiotropic adipokine in insulin resistant subjects. Through its anti-angiogenic properties and its ability to activate TGF2 TSP1 may be an important part of the adipocyte/macrophage interaction that results in simultaneous impairment of angiogenesis and increased TGF- 2-mediated fibrosis and inflammation. We recently demonstrated that macrophages also infiltrate skeletal muscle with obesity that is strongly correlated with insulin resistance. Furthermore the presence of macrophages in co-culture with muscle cells in the presence of palmitic acid to mimic an obese environment results in a synergistic increase in the expression and secretion of inflammatory cytokines from muscle cells all of which impair insulin action. We hypothesize that macrophages in both muscle and adipose tissues promote the development of metabolic syndrome during obesity. To test this hypothesis adipose (Aim 1) and muscle tissue (Aim 2) from obese insulin resistant compared to normal human subjects will be characterized. Macrophage number the proportion of macrophages that are classically versus alternatively activated and the proportion of macrophages in crown-like structures (in adipose) will be quantified along with markers of the TGF2 pathway fibrosis hypoxia tissue remodeling and vascularity. To specifically determine the role of TSP1 and the TGF2 pathway in insulin resistance adipose and muscle tissue fibrosis hypoxia and macrophage function will be analyzed in high fat fed TSP1 null mice in Aim 3. A peptide that specifically blocks TSP1- mediated TGF2 activation will also be used in wild type high fat fed mice to test the hypothesis that macrophage infiltration and fibrosis in adipose and muscle will be ameliorated in the absence of TSP1 resulting in improved insulin sensitivity. Aim 4 is the intervention aim in which the mechanisms underlying the beneficial effects of aerobic exercise training on insulin sensitivity will be determined. Following 12 weeks of training in obese and lean subjects changes in muscle and adipose macrophage number activation state the TSP1/TGF2 pathway and inflammation in response to a single bout of eccentric exercise will be quantified relative to insulin sensitivity. Finally in Aim 5 the effects of different macrophage populations on adipocytes and muscle cells will be studied in vitro. The expression of genes involved in adipogenesis extracellular matrix and the TGF2 pathway will be monitored in adipocytes following macrophage co-culture. These will also be quantified in muscle cells as well as the response to insulin. We will determine whether mechanical stimulation of myotubes to mimic exercise will alter the muscle cell response to macrophages.

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

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


application_id: 8470220
project_number: 5F30HL099272-04
project_title: Regulation of Lysolipid Signaling by Autotaxin-Integrin Interactions on Platelets
administering_ic: NHLBI
award_notice_date: 2013-04-29
opportunity_number: PA-08-021
application_type: 5
activity_code: F30
ic: HL
serial_number: 099272
program_official: SARKAR, RITA
project_start_date: 2010-05-01
project_end_date: 2013-05-12
study_section: Special Emphasis Panel[ZRG1-F10A-S(20)L]
contact_pi_person_id: 9792683
contact_pi: FULKERSON, ZACHARY
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) is an extracellular signaling molecule with a broad range of physiologic effects. LPA may be rapidly produced at sites of inflammation thrombosis and vascular injury and has been proposed as a mediator of cardiovascular disease. LPA elicits effects by binding to a class of G protein- coupled receptors. In the vasculature it may regulate smooth muscle function and cause activation of endothelial cells and platelets. The production of LPA in circulation is dependent tipon autotaxin (ATX) an enzyme with lysophospholipase D activity. ATX contains a somatomedin B-like (SMB) domain with an RGD sequence homologous to the integrin-binding region of vitronectin. This suggests that ATX may bind to integrin receptors thus localizing production of LPA in vicinity of membrane LPA receptors. My preliminary data indicates that activated platelets bind ATX in a 3 integrin-dependent manner. I hypothesize that the binding of ATX to activated platelet 3 integrins serves to increase LPA production by bringing ATX in proximity to its substrate lysophosphatidylcholine. To test this hypothesis I propose two aims. First I will define the mechanism by which ATX binds to activated platelets (Specific Aim 1). I propose that binding occurs via interaction of the RGD sequence on ATX with activated aVp3 and/or allbp3 on the platelet surface. To test this hypothesis I will use genetic pharmacologic and immunologic approaches. Second I will evaluate the role of this interaction on ATX activity (Specific Aim 2). I will accomplish this by using tools established in my preliminary studies and in Specific Aim 1 to disrupt ATX binding and evaluate the effect of binding on lysophospholipase D activity both in vitro and in vivo. Our laboratory is uniquely well-prepared for such study as we have a great deal of experience in lysophospholipid signaling and metabolism. This work will provide novel insights into lysophospholipid signaling as it presents a mechanism of generating LPA directly at the surface of the targeted cell. Furthermore this will also provide a new therapeutic target for cardiovascular and other diseases in which LPA signaling has been implicated. The formation of a platelet clot is typically the final event leading to heart attacks and strokes and anti-platelet drugs such as aspirin and Plavix have been a mainstay in treatment of cardiovascular disease. However these medications are not effective in all people and oftentimes cause unnecessary bleeding. It is therefore important to study further mechanisms by which platelets are regulated so that safer and more effective therapeutics might be developed.

project_terms:
Address;Adhesions;Animals;Aspirin;Binding (Molecular Function);Biological Assay;Blocking Antibodies;Blood Circulation;Blood Platelets;Blood Vessels;Cardiovascular Diseases;Cardiovascular Physiology;Cardiovascular system;Catalysis;Cell Adhesion;Cell physiology;Cells;Coagulation Process;Coupled;Data;Disease;Endothelial Cells;Enzymes;Event;Family;G-Protein-Coupled Receptors;GTP-Binding Proteins;Generations;Genetic;Glycerophospholipids;Hemorrhage;Hydrolysis;Immunologics;In Vitro;Inflammation;Injury;Integrin Binding;Integrins;Laboratories;Lipids;Lymphocyte;Lysophosphatidic Acid Receptors;Lysophosphatidylcholines;Lysophospholipids;Measures;Mediator of activation protein;Membrane;Metabolism;Molecular;Molecular Conformation;Muscle Cells;Muscle function;Mutation;Myocardial Infarction;Names;Pharmaceutical Preparations;Physiological;Plavix;Production;Protocols documentation;RGD (sequence);Regulation;Role;Signal Transduction;Signaling Molecule;Site;Smooth muscle (tissue);Surface;System;Testing;Therapeutic;Thrombosis;Variant;Vitronectin;Work;alkylglycerophosphoethanolamine phosphodiesterase;base;experience;extracellular;in vivo;inhibitor/antagonist;insight;lysophosphatidic acid;migration;new therapeutic target;novel;nuclease;phosphoric diester hydrolase;receptor;small molecule;somatomedin B;stroke;therapeutic development;tool


application_id: 8469566
project_number: 5R01HL106173-03
project_title: Resolution of inflammation in obesity and diabetes: Role of lipid mediators
administering_ic: NHLBI
award_notice_date: 2013-05-31
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 106173
program_official: TOLUNAY, ESER
project_start_date: 2011-08-01
project_end_date: 2016-05-31
study_section: Atherosclerosis and Inflammation of the Cardiovascular System Study Section[AICS]
contact_pi_person_id: 8656605
contact_pi: SPITE, MATTHEW R
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Type 2 diabetes (T2D) and obesity have emerged as major public health crises. These conditions increase the risk of cardiovascular diseases and cause microvascular dysfunction. Patients with T2D also show deficits in wound healing and tissue repair. Although the mechanisms leading to T2D are not well understood recent work has shown that the states of diabetes and obesity are associated with low-grade chronic inflammation which triggers and sustains insulin resistance in target tissues. This project is to test the hypothesis that chronic inflammation in obesity and diabetes is sustained in part due to the failure of pro-resolving pathways. This hypothesis predicts that innate immune responses activated in obesity and diabetes fail to resolve leading to chronic inflammation and insulin resistance. It also predicts that restoration of endogenous pro-resolving mediators should extinguish inflammation and restore insulin sensitivity. The specific aims of this project are to: (1) Define changes in resolution of inflammation during diabetes and obesity; (2) Determine whether restoring resolution will diminish inflammation and insulin resistance; and (3) Identify the mechanism by which promotion of resolution affects insulin resistance. To accomplish these aims we will examine the time course of the development and the resolution of acute inflammation. We will measure changes in pro-resolving lipid mediators by a mass-spectrometry-based lipidomic approach establish the temporal relationship between changes in lipid mediator synthesis and insulin resistance and identify the mechanisms by which diabetes and obesity affect the biosynthesis of pro-resolution mediators. To assess the functional significance of the changes in resolution in diabetes and obesity we will test whether treatment with resolvin D1 (RvD1) will correct the resolution defect and improve glucose tolerance systemic insulin resistance and wound healing in high-fat fed and db/db mice. We will determine how RvD1 affects vascular inflammation and adipose-tissue macrophage phenotype. To delineate the mechanism of action we will examine whether obesity and diabetes affects the expression and function of the RvD1-receptor Frp2 in macrophages and adipose tissue and whether Frp2 deletion will abolish the pro-resolving effects of RvD1 as well as its ability to diminish chronic inflammation insulin resistance and promote wound healing. To distinguish between the effect of RvD1 on macrophages and adipocytes and as a gain-of-function test of our hypothesis we will test whether myeloid- specific overexpression of human FPR2 will enhance resolution of inflammation in diabetes and promote the pro-resolving actions of RvD1. We will identify the mechanisms by which binding of RvD1 to Fpr2 promotes macrophage phagocytosis. Results of this project will provide new knowledge about the processes that sustain chronic adipose tissue inflammation and promote insulin resistance in diabetes and obesity and could lead to the development of an entirely new approach for the treatment of insulin resistance and wound healing in diabetes and obesity.

project_terms:
Acute;Adipocytes;Adipose tissue;Affect;Anabolism;Animal Model;Anti-Inflammatory Agents;Anti-inflammatory;Apoptotic;Binding (Molecular Function);Cells;Chronic;Defect;Development;Diabetes Mellitus;Diet;Disease;Dopamine D1 Receptor;Excision;Failure (biologic function);Fatty acid glycerol esters;Functional disorder;Health;Homeostasis;Human;Immune;Immune response;Infection;Inflammation;Inflammatory;Injury;Insulin;Insulin Resistance;Interruption;Invaded;Kidney Diseases;Knowledge;Lead;Mass Spectrum Analysis;Measures;Mediating;Mediator of activation protein;Metabolic;Mus;Myelogenous;Natural immunosuppression;Neuropathy;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Pathway interactions;Patients;Phagocytes;Phagocytosis;Phenotype;Process;Recurrence;Resolution;Retinal Diseases;Risk;Role;Signal Transduction;Stimulus;Testing;Therapeutic;Time;Tissue Expansion;Tissues;Work;Wound Healing;base;cardiovascular disorder risk;db/db mouse;diabetic;feeding;gain of function;glucose tolerance;improved;insulin sensitivity;lipid mediator;macrophage;mouse model;novel strategies;novel therapeutic intervention;overexpression;pathogen;prevent;programs;public health medicine (field);response;restoration;tissue repair;vascular inflammation

public_health_relevance:
This project will provide a new understanding of the mechanisms that contribute to chronic inflammation in diabetes and obesity and will provide new avenues for treating insulin resistance in diabetes and obesity. These results could also be developed as an adjunct treatment for promoting resolution of inflammation and wound healing in diabetics.


application_id: 8469519
project_number: 5R01GM089684-04
project_title: DNA repair mechanisms in trinucleotide repeat instability
administering_ic: NIGMS
award_notice_date: 2013-05-21
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: GM
serial_number: 089684
program_official: KRASNEWICH, DONNA M
project_start_date: 2010-06-01
project_end_date: 2015-07-31
study_section: Molecular Genetics A Study Section[MGA]
contact_pi_person_id: 7875365
contact_pi: LI, GUO-MIN
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 the project is to understand the mechanisms by which cells maintain trinucleotide repeat (TNR) stability. Expansions of TNR sequences e.g. (CAG)n and (CTG)n are tightly associated with progression of certain human neurological and neurodegenerative diseases including Huntington's disease (HD) and myotonic dystrophy. However the mechanisms and factors that promote/prevent TNR expansions are unknown. Because CAG and CTG repeats form thermo- stable hairpins with multiple A-A and T-T mispairs in the hairpin stem respectively DNA mismatch repair (MMR) and TNR hairpin repair have been proposed to play major roles in TNR maintenance. Surprisingly previous studies in transgenic mice suggest that mismatch recognition protein MSH2- MSH3 heterodimer (also called MutS2) promotes (CAG)n expansions by binding to (CAG)n-formed hairpins and inhibiting their repair. Our recent studies have shown that human cells catalyze error-free repair of (CAG)25 and (CTG)25 hairpins in a nick-directed PCNA-dependent manner. The repair targets the nicked strand for incisions at the repeat sequences followed by repair DNA synthesis using the continuous strand as a template thereby ensuring TNR stability. However MutS2 does not inhibit stimulates (CAG)25 or (CTG)25 hairpin repair. Interestingly our preliminary studies have shown that cell lines derived from HD patients are defective in (CAG)n hairpin repair hinting possible pathogenesis for HD. In this application Specific Aim 1 is to evaluate the model that the MMR system promotes (CAG)n expansion. Human and animal cell lines with or without MutS2 overexpression will be examined for their ability to repair (CAG)n hairpins in vitro and to replicate CAG repeats in vivo. Determination of TNR hairpin repair activity and (CAG)n stability in these cells will clarify if the MMR system is responsible for (CAG)n expansions in human cells. Specific Aim 2 is to further test the hypothesis that hairpin repair defects are associated with TNR diseases by screening hairpin repair proficiency in cell lines derived from HD patients. Specific Aim 3 is to purify and characterize a protein required for (CAG)n hairpin repair but defective in an HD cell line. A successful completion of the proposed work will provide significant insight into the mechanisms of TNR expansions and the etiology of TNR expansion-associated diseases.

project_terms:
Animals;Binding (Molecular Function);Biochemical;Biological Assay;CAG repeat;Cell Line;Cells;DNA;DNA Repair;DNA biosynthesis;Defect;Disease;Ensure;Etiology;Fragile X Syndrome;Friedreich Ataxia;Generations;Genes;Genetic;Genome;Goals;Hela Cells;Human;Huntington Disease;In Vitro;Lead;Length;Link;MSH2 gene;MSH3 gene;Maintenance;Mismatch Repair;Modeling;Myotonic Dystrophy;Neurodegenerative Disorders;Neuromuscular Diseases;Nuclear Extract;Nucleotides;Pathogenesis;Pathway interactions;Patients;Play;Population;Protein Binding;Proteins;RNA Interference;Role;Site;Surgical incisions;System;Testing;Transgenic Mice;Trinucleotide Repeat Expansion;Trinucleotide Repeats;Work;base;effective therapy;in vivo;insight;nervous system disorder;overexpression;prevent;public health relevance;repaired;research study;screening;stem

public_health_relevance:
Expansion of simple nucleotide repeats in DNA is the genetic basis for more than 40 human familial neurological neurodegenerative and neuromuscular disorders including Huntington's disease myotonic dystrophy Friedreich ataxia and fragile X syndrome. The repeat expansion can occur in any part of a gene and leads to a defective gene product. However how the repeat units expand and what cellular mechanism(s) prevent such an expansion in normal population are not fully understood. This application is to identify protein components that promote or prevent repeat expansions. A successful completion of the proposed work will provide significant insight into the pathogenesis underlying diseases associated with repeat expansions and approaches to develop effective treatments for the diseases.


application_id: 8469331
project_number: 5R01HL074091-09
project_title: Mechanisms of Long-term Cardiac Ion Channel Regulation
administering_ic: NHLBI
award_notice_date: 2013-06-01
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 074091
program_official: LATHROP, DAVID A
project_start_date: 2009-06-01
project_end_date: 2016-05-31
study_section: Electrical Signaling, Ion Transport, and Arrhythmias Study Section[ESTA]
contact_pi_person_id: 7875430
contact_pi: SATIN, JONATHAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Ca dysregulation in cardiac myocytes contributes to heart development defects and diseases of theaging heart. The long-term objective of this proposal is to provide a molecular mechanism that explains howcardiac L-type Ca channels (LTCC) sense and transduce signals that homeostatically regulate cardiacmyocytes. Cardiac myocytes present a conundrum with respect to Ca signaling to the nucleus. Cytosolic Caamplitude varies >10-fold during each cardiac cycle yet alterations of Ca somehow are differentially decodedfor longer-term transcriptional signaling. In this funding period we will test whether Ca channel activity and thecardiac L-type Ca channel itself encodes Ca signaling for long-term regulation. In the past funding period wediscovered that RGK chronically inhibited ICaL (LTCC current) and this RGK inhibition of ICaL resulted in acompensatory up-regulation of CaV1.2 mRNA. This suggests that ICaL block may signal transcriptional eventsin the nucleus. In new studies we confirmed and extended this notion by showing that LTCC-pharmacological-block but not internal Ca in general is responsible for perturbing heart development. Along the same lines inmature heart long-term blockade of LTCC also causes a compensatory up-regulation of LTCC and ICaL. Ourdriving hypothesis is that signaling is not simply determined by Ca but by active Ca channels. The discoverythat mobile segment of LTCC is localized to the nucleus or t-tubules coupled with the recent report that thispeptide is a transcription factor drives the exciting new hypothesis that this segment of the LTCC regulatesLTCC expression. We will study this aspect of long-term channel regulation in three aims: 1. We will assessnuclear translocation of a domain of the LTCC and determine the interaction between LTCC activity and sub-cellular localization; 2. We will determine the ability of LTCC to auto-regulate itself transcriptionally; and 3. Wewill determine the compensatory changes of SL Ca handling proteins in response to LTCC blockade. This workmay provide a missing molecular link between LTCC function and downstream signaling events.

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

public_health_relevance:
These studies show that widely used clinically-relevant drugs that are used to block LTCC mayinadvertently exacerbate heart dysfunction by paradoxically increasing LTCC function. This proposal will leadto understanding of a new mechanism whereby ion channels that control cardiac electrical activity also maycontrol long-term signaling pathways that are critical for maintenance of cardiac structure and function.


application_id: 8468132
project_number: 5R01CA153132-04
project_title: Oncopigs as a better model for human cancer
administering_ic: NCI
award_notice_date: 2013-06-11
opportunity_number: RFA-GM-10-009
application_type: 5
activity_code: R01
ic: CA
serial_number: 153132
program_official: MIETZ, JUDY
project_start_date: 2010-08-05
project_end_date: 2017-05-31
study_section: ZCA1-SRLB-R(M1)R
contact_pi_person_id: 8801334
contact_pi: CLARK, GEOFFREY J.
other_pis: RUND, LAURETTA ;SCHOOK, LAWRENCE B.
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 driven by the hypothesis that current in vivo models for evaluating cancer therapies are too non-predictive of the human condition for efficient use. This may become a major impediment to the translation of new potential drugs into effective therapies for patients. The project proposes to determine if transgenic pigs may serve as a novel and more human-like model for cancer. Although pigs have been used extensively in biomedical research to date there is no reported transgenic swine model for cancer. Like humans pigs can live for decades and have a very low rate of spontaneous cancer. This is in contrast to common rodent-based cancer models where life span is limited to a few years and the spontaneous development of cancer is quite high. We now know that 5-6 to six genetic defects are required to convert a normal pig cell into a tumor cell. This is the same as in humans. However mouse cells can be transformed into tumor cells by as little as two genetic lesions. These simple yet profound genetic observations point to pigs as a far superior model system for the human condition.  We propose to use state of the art technology to generate transgenic pigs that can be induced to lose the expression of three major tumor suppressors simultaneously in the breast. These alterations will be coupled with an up-regulation of a growth hormone receptor. These genetic defects are often found in breast cancer and particularly in Triple Negative (TN) breast cancer. TN breast cancer is an especially aggressive and difficult to treat form of breast cancer with a high morbidity rate. We will include a far red fluorescent protein in the system which will allow non-invasive imaging of the status of the induced breast cells.  The project will involve the collaboration of laboratories with extensive experience in the molecular and cellular biology of human breast cancer and laboratories with world renown in the production and husbandry of transgenic pigs.  Animals will be tested to determine if these lesions are sufficient to provoke breast cancer and whether any such cancers have the characteristics of TN breast cancer. We will also use the population to test the effectiveness of cancer chemopreventative agents and whether the pigs respond to front line therapy for TN breast cancer in a similar manner to humans.

project_terms:
African American;Animal Model;Animals;Arteriosclerosis;BRCA1 gene;Biological Assay;Biological Factors;Biological Models;Biomedical Research;Breast;Cancer Model;Cells;Characteristics;Clinical Trials;Collaborations;Controlled Study;Coupled;Development;Diabetes Mellitus;Disease;Disease model;Effectiveness;Epidermal Growth Factor Receptor;Failure (biologic function);Family suidae;Genetic;Growth Hormone Receptor;Hand;Human;Image;Laboratories;Lesion;Life;Lipids;Lipoproteins;Longevity;Malignant Neoplasms;Metabolism;Metastatic malignant neoplasm to brain;MicroRNAs;Modeling;Molecular;Molecular and Cellular Biology;Monitor;Morbidity - disease rate;Mus;Mutation;Neoplasm Metastasis;Patients;Pharmaceutical Preparations;Pilot Projects;Population;Production;Proteins;Reporting;Rodent;Series;Staging;Study models;System;Technology;Testing;Therapeutic;Time;Tissues;Transgenic Organisms;Translations;Tumor Suppressor Proteins;United States;Up-Regulation (Physiology);Variant;Woman;Work;arterial lesion;base;cancer genetics;cancer prevention;cancer therapy;design;effective therapy;experience;expression vector;genome sequencing;human disease;in vivo;in vivo Model;inhibitor/antagonist;interest;loss of function;malignant breast neoplasm;model development;mouse model;neoplastic cell;novel;novel therapeutic intervention;novel therapeutics;predictive modeling;public health relevance;red fluorescent protein;research study;success;triple-negative invasive breast carcinoma;tumor;tumorigenesis;tumorigenic;vector

public_health_relevance:
This project will establish a novel model system for evaluating new therapeutic approaches to cancer. The system should be much more predictive for the human condition thus enhancing the ability to identify and characterize effective novel therapeutics. It may also establish a unique model for the study of cancer preventative strategies that cannot be realistically modeled at present. The model is targeted towards breast cancer as over 40 thousand women are expected to die in the United states each year from this disease due to lack of sufficiently effective therapies.


application_id: 8468035
project_number: 5R01DC007176-09
project_title: Neurotrophin Regulation of Taste System Development
administering_ic: NIDCD
award_notice_date: 2013-05-16
opportunity_number: PA-10-067
application_type: 5
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)M]
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_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;public health relevance;research study;response


application_id: 8467742
project_number: 5R44HL102981-03
project_title: Counterpulsation Device with Integrated EKG System for Chronic Partial Circulator
administering_ic: NHLBI
award_notice_date: 2013-03-08
opportunity_number: PA-11-096
application_type: 5
activity_code: R44
ic: HL
serial_number: 102981
program_official: ADHIKARI, BISHOW B
project_start_date: 2010-06-01
project_end_date: 2015-02-28
study_section: Special Emphasis Panel[ZRG1-SBIB-V(12)B]
contact_pi_person_id: 8385495
contact_pi: SPENCE, PAUL A
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 610420817
duns_number: 610420817
fips: US
organization_id: 10006385
organization_name: SCR, INC.
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402022445
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2013-03-01
budget_end_date: 2015-02-28
project_abstract:
DESCRIPTION (provided by applicant): Heart failure (HF) remains one of the largest unsolved problems in health care today and continues to increase in incidence and cost ($34.8 billion in US in 2008). Prognosis remains limited especially in patients with advanced heart failure. Transplantation is often the best option for patients with advanced HF whose hearts are not recoverable but is limited by many factors primarily the small number of available donor hearts (<2500/yr in US). Use of current mechanical circulatory support (MCS) devices though increasing has also been limited due to the need for a major operation restriction to Class IV patients prolonged convalescence and cost (over $100000 US for the device itself). We have developed a novel MCS device (Symphony) that works synchronously with the heart can be placed with a minor operation and takes advantage of the proven benefits of counterpulsation. Symphony provides partial circulatory support to augment (not replace) native heart function. Recent clinical studies have provided strong evidence for the benefits of partial support. Also experimental data strongly supports the benefits of partial support rather than complete unloading of the heart to promote myocardial recovery. The Symphony device is placed through an 8-cm infraclavicular incision similar to that used for placement of a permanent pacemaker. A short graft is sewn to the subclavian artery connected to the pump and then positioned superficial to the pectoralis muscle. Symphony is timed with the EKG to fill during systole and eject during diastole. Recent work in a Phase 1 study demonstrated subcutaneous EKG leads were as effective as epicardial leads for QRS detection and triggering. In this phase II study we will complete development of the subcutaneous EKG lead system with integration to the Symphony device and lightweight portable driver and demonstrate efficacy safety and reliability of all system components. The development of a device that works synchronously with the heart provides partial support (thereby promoting recovery) and can be placed with a "pacemaker pocket" operative approach may have a significant impact in expanding the role of circulatory support in the treatment of HF patients. The additional advantage of low cost (due to simplicity of design and a limited operative approach) may further expand the use of mechanical support with this device to currently large unrealized global markets.

project_terms:
Adoption;Blood Circulation;Bypass;Cardiovascular system;Caring;Cattle;Chest;China;Chronic;Clinical;Clinical Research;Clinical Trials;Convalescence;Counterpulsation;Data;Detection;Development;Device Designs;Devices;Diastole;Early treatment;Electrocardiogram;Engineering;Exercise;Failure (biologic function);Fatigue;Fracture;Goals;Government Agencies;Healthcare;Heart;Heart Transplantation;Heart failure;Implant;Implantation procedure;Incidence;India;Infection;Infraclavicular region structure;Institutes;Intra-Aortic Balloon Pumping;Lead;Legal patent;Lung;Marketing;Mechanics;Medical;Methods;Metric;Mind;Minor;Modeling;Morphologic artifacts;Motion;Myocardial;Operative Surgical Procedures;Organ Donor;Outcome;Pacemakers;Patients;Pectoralis Muscles;Perfusion;Phase;Positioning Attribute;Predictive Value;Pump;Quality of life;Recovery;Research Personnel;Resources;Role;Safety;Sensitivity and Specificity;Signal Transduction;Staging;Sternotomy;Stroke Volume;Structure of subclavian artery;Study models;Support System;Surface;Surgical incisions;System;Systole;Testing;Therapeutic;Time;Transplantation;Ventricular;Work;Workload;biomaterial compatibility;clinical practice;commercialization;computerized data processing;conditioning;cost;design;heart function;hemodynamics;improved;industry partner;innovation;interest;migration;miniaturize;novel;operation;outcome forecast;patient population;phase 1 study;phase 2 study;product development;programs;prototype;research study;subcutaneous

public_health_relevance:
Heart failure is a major and growing health care concern for which there are limited treatment options in advanced stages. A novel circulatory support device is being developed that works synchronously with the heart (thereby promoting recovery) can be placed without a major operation and uses a proven mechanism of circulatory support (counterpulsation). This device may significantly increase the use of circulatory support for patients with advanced heart failure and possibly lead to earlier use in less ill patients with thepotential for myocardial recovery.


application_id: 8464187
project_number: 5R01HL072936-08
project_title: Regulation of Calcium Channel Function by the Rem GTPase
administering_ic: NHLBI
award_notice_date: 2013-06-18
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 072936
program_official: LATHROP, DAVID A
project_start_date: 2003-04-15
project_end_date: 2016-04-30
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:
DESCRIPTION (provided by applicant): 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 I(Ca). It was originally thought that Rem association with CaVbeta- subunits chronically regulated I(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 I(Ca) are PKA-modulation and calmodulin (CaM)-modulation. Our most recent studies suggest that Rem modulates I(Ca) responses to each of these signaling pathways. Thus Rem appears to contribute to both beta-adrenergic and Ca-CaM control of I(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 I(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 I(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 I(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:
Voltage-activated calcium channels serve two critical functions: the regulation of calcium entry and the control of heart contraction. Changes in the number or function of L-type calcium channels are implicated in a variety of cardiovascular disease including atrial fibrillation heart failure and ischemic heart disease. Thus understanding the basic mechanisms that regulate calcium cannels is important in 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: 8463781
project_number: 1R41AG044187-01
project_title: Development of a Novel Therapeutic for Alzheimer' Disease
administering_ic: NIA
award_notice_date: 2012-09-21
opportunity_number: RFA-OD-12-004
application_type: 1
activity_code: R41
ic: AG
serial_number: 044187
program_official: REFOLO, LORENZO
project_start_date: 2012-09-30
project_end_date: 2013-08-31
study_section: Special Emphasis Panel[ZRG1 ETTN-A (50)]
contact_pi_person_id: 2276639
contact_pi: LOVELL, MARK ANTHONY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 841834083
primary_uei: JK7PN2MFXEU2
duns_number: 841834083
uei: JK7PN2MFXEU2
fips: US
organization_id: 10022006
organization_name: COPLEX THERAPEUTICS, LLC
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405060001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Traditional approaches to drug development for Alzheimer's disease are becoming increasingly expensive and in many cases disappointingly unsuccessful. Based on preliminary in vitro and in vivo studies we have identified a novel lactam derivative of the commonly prescribed 14 dihydropyridine calcium channel blocker nifedipine (1-acetyl-24- dimethylbenzo[c][27]naphthyridin-5(6H)-one; NFD-L) that lacks calcium channel blocking capacity but significantly decreases Ass1-42 production by increasing levels of alpha-secretase (ADAM-10) and decreasing levels of presenilin-1 and nicastrin (components of the gamma secretase complex). Based on our preliminary data the hypothesis to be tested in this proposal is that NFD-L lacks calcium channel blocking capacity and potential adverse cardiovascular side effects effectively diminishes generation of A?1-42 by increasing levels of alpha-secretase (ADAM-10) processing of APP and by decreasing levels of proteins involved in A?1-42 processing (presenilin-1 and nicastrin) and improves spatial learning in a mouse model of amyloid deposition. In addition we hypothesize that NFD-L does not lead to microhemorrhages or edema (amyloid related imaging abnormalities; ARIA) that are associated with immunotherapy mediated A? clearance. If successful the data obtained in this proposal would further clarify the effects of NFD-L on A? processing and confirm whether or not it induces ARIA which would address FDA concerns and potentially increase the likelihood of successful commercialization of NFD-L.   
   
PUBLIC HEALTH RELEVANCE: Currently two classes of medications are FDA approved for use by Alzheimer's disease (AD) patients including cholinesterase inhibitors (Aricept) and an N-methyl-D-aspartate (NMDA) antagonist (Memantine). Although these therapeutics show clinical benefit in some patients many do not respond. Additionally these drugs do not significantly modify disease progression and perhaps more importantly are not approved for patients at earlier stages of the disease (mild cognitive impairment; MCI). For these reasons there is a critical need to identify additional therapeutics that can be initiated early in the disease progression to alter the pathogenesis of the disease. Preliminary and future studies described in this proposal aim to test the efficacy of a novel derivative of a commonly prescribed calcium channel blocker in a mouse model of amyloid beta (A1-42) deposition (APP/PS1 mice) and to determine if the novel therapeutic leads to microhemorrhages or edema as has been observed in studies using A immunotherapy. If successful the results of the proposed studies would address concerns that have been raised by the FDA regarding amyloid lowering agents and further support testing of the compound in clinical trials.

project_terms:
APP-PS1;Active Immunization;Address;Adverse effects;Adverse event;Age;Age-Months;Alzheimer's Disease;Amyloid;Amyloid beta-Protein;Amyloid deposition;Animals;Antibodies;Aricept;Attenuated;Behavior;Behavioral;Brain;Calcium Channel;Calcium Channel Blockers;Cardiovascular system;Cell Culture Techniques;Cholinesterase Inhibitors;Cleaved cell;Clinical;Clinical Research;Clinical Trials;Cognitive;Data;Deposition;Development;Diet;Diffusion Magnetic Resonance Imaging;Dihydropyridines;Disease;Disease Progression;Edema;Evaluation;Formic Acids;Future;Generations;Human;Image;Immunohistochemistry;Immunotherapy;In Vitro;Kentucky;Lactams;Lead;Learning;Liquid substance;Magnetic Resonance Imaging;Measures;Mediating;Memantine;Mus;N-Methylaspartate;Nifedipine;Passive Immunization;Pathogenesis;Patients;Pharmaceutical Preparations;Process;Production;Proteins;Recovery;Rodent;Side;Specimen;Staging;Testing;Therapeutic;Therapeutic Studies;Time;Tissues;Transgenic Mice;United States Food and Drug Administration;Universities;Weight;alpha secretase;amyloid precursor protein processing;base;behavior test;beta-site APP cleaving enzyme 1;cerebrovascular;commercialization;dihydropyridine;drug candidate;drug development;efficacy testing;gamma secretase;human subject;improved;in vivo;mild cognitive impairment;morris water maze;mouse model;nicastrin protein;notch protein;novel;novel therapeutics;presenilin-1;response

public_health_relevance:
Currently two classes of medications are FDA approved for use by Alzheimer's disease (AD) patients including cholinesterase inhibitors (Aricept) and an N-methyl-D-aspartate (NMDA) antagonist (Memantine). Although these therapeutics show clinical benefit in some patients many do not respond. Additionally these drugs do not significantly modify disease progression and perhaps more importantly are not approved for patients at earlier stages of the disease (mild cognitive impairment; MCI). For these reasons there is a critical need to identify additional therapeutics that can be initiated early in the disease progression to alter the pathogenesis of the disease. Preliminary and future studies described in this proposal aim to test the efficacy of a novel derivative of a commonly prescribed calcium channel blocker in a mouse model of amyloid beta (A1-42) deposition (APP/PS1 mice) and to determine if the novel therapeutic leads to microhemorrhages or edema as has been observed in studies using A immunotherapy. If successful the results of the proposed studies would address concerns that have been raised by the FDA regarding amyloid lowering agents and further support testing of the compound in clinical trials.


application_id: 8462809
project_number: 1R41ES022893-01
project_title: Development of a Plasma Biomarker of Alzheimer's Disease
administering_ic: NIEHS
award_notice_date: 2012-09-26
opportunity_number: RFA-OD-12-004
application_type: 1
activity_code: R41
ic: ES
serial_number: 022893
program_official: SHAUGHNESSY, DANIEL
project_start_date: 2012-09-26
project_end_date: 2013-09-25
study_section: Special Emphasis Panel[ZRG1 ETTN-A (50)]
contact_pi_person_id: 2276639
contact_pi: LOVELL, MARK ANTHONY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 614763006
duns_number: 614763006
fips: US
organization_id: 10010025
organization_name: SCOUT DIAGNOSTICS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402431805
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2012-09-26
budget_end_date: 2013-09-25
project_abstract:
DESCRIPTION (provided by applicant): The major barriers to preventing or treating Alzheimer's disease (AD) are its unknown pathogenesis/etiology and the lack of an objective sensitive and specific biomarker of the disease particularly at the early stages when therapeutic interventions would likely have the greatest efficacy. The basic hypothesis of this application is that plasma levels of a novel aberrant protein/protein complex consisting or lipocalin (brain-specific) prostaglandin-d- synthase (PDS) and transthyretin (TTR) are decreased early in disease progression and that baseline (pre-conversion) PDS/TTR levels are significantly lower in subjects who transition to mild cognitive impairment (MCI) or AD compared to normal control (NC) subjects or subjects with non-AD neurodegenerative disorders. As such plasma PDS/TTR concentrations can be used to preferentially identify subjects who are likely to transition to MCI or AD. Preliminary analysis of antemortem plasma samples from 76 NC and 45 MCI subjects showed a statistically significant decrease of PDS/TTR levels in MCI. In addition analysis of plasma PDS/TTR concentrations in normal subjects who later converted to MCI showed PDS/TTR concentrations before conversion were significantly (32 percent) lower than levels in plasma from NC subjects who remained cognitively normal during a comparable follow-up period. Although our preliminary data are promising and suggest PDS/TTR concentrations may be used to identify and predict subjects who will convert to dementia further study is needed. To further test our hypothesis we will analyze plasma samples from additional 80 - 100 samples from each group (NC MCI and probable AD). We will also test whether plasma PDS/TTR complex concentrations decrease in the same person following conversion to MCI or AD by analyzing pre- and post-conversion specimens from NC subjects who transitioned from normal to MCI (n = 83) or AD (n = 32) compared to results obtained for plasma samples from control subjects who remained cognitively normal (n = 360) after a comparable follow-up period. Plasma specimens will also be analyzed from subjects with non-AD neurodegenerative diseases including frontotemporal dementia and diffuse Lewy body disease. In addition we will test whether pre-conversion PDS/TTR concentrations alone or in combination with A1-42 A1- 40 measures correlate with or enhance identification of MCI/AD patients based on Mini Mental State Examination (MMSE) and specific memory scores (Animal fluency Trials A Trials B and logical memory (logmemL)). Overall the proposed studies if successful will identify and validate a novel blood based biomarker of AD that can be used to identify subjects early in disease progression when pharmacologic interventions likely have the greatest efficacy.   
   
PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the sixth leading cause of death in the United States and currently affects 4.5 million Americans. Two major barriers to treating and eventually preventing AD are: 1) the lack of understanding about the process of neuron degeneration and loss and 2) the lack of a sensitive and specific biomarker of the disease. Preliminary and future studies described in this application show that a novel protein-protein complex present in serum can be quantified using an enzyme linked immunoassay (ELISA). This protein-protein complex is a sensitive and specific biomarker of AD including early stages of AD when therapeutic interventions are most likely to have beneficial effects.

project_terms:
Affect;Alzheimer's Disease;American;Animals;Autopsy;Biological Assay;Blood;Brain;Cause of Death;Cerebrospinal Fluid;Clinical;Complex;Data;Dementia;Development;Diagnostic;Disease;Disease Progression;Enzymes;Etiology;Frontotemporal Dementia;Future;Immunoassay;Intervention;Left;Legal patent;Lewy Body Disease;Link;Measures;Memory;Nerve Degeneration;Neurodegenerative Disorders;Pathogenesis;Patients;Persons;Plasma;Prealbumin;Process;Prostaglandins;Protein Fragment;Proteins;Sampling;Sensitivity and Specificity;Serum;Specimen;Staging;Symptoms;Testing;Therapeutic Intervention;United States;Validation;base;biomarker;crosslink;dimer;follow-up;hyperphosphorylated tau;mental state;mild cognitive impairment;nervous system disorder;neuroinflammation;neuron loss;novel;prevent;protein complex

public_health_relevance:
Alzheimer's disease (AD) is the sixth leading cause of death in the United States and currently affects 4.5 million Americans. Two major barriers to treating and eventually preventing AD are: 1) the lack of understanding about the process of neuron degeneration and loss and 2) the lack of a sensitive and specific biomarker of the disease. Preliminary and future studies described in this application show that a novel protein-protein complex present in serum can be quantified using an enzyme linked immunoassay (ELISA). This protein-protein complex is a sensitive and specific biomarker of AD including early stages of AD when therapeutic interventions are most likely to have beneficial effects.


application_id: 8462570
project_number: 5R01CA140991-05
project_title: Targeting Glucose Metabolism in Cancer
administering_ic: NCI
award_notice_date: 2013-05-03
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 140991
program_official: SPALHOLZ, BARBARA A
project_start_date: 2009-07-01
project_end_date: 2015-04-30
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 9475582
contact_pi: TELANG, SUCHETA
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): A high rate of glycolytic flux even in the presence of oxygen is a central metabolic hallmark of neoplastic tumors. Cancer cells preferentially utilize glycolysis in order to satisfy their increased energetic and biosynthetic requirements. This metabolic phenotype is confirmed by positron emission tomography (PET) with 2-[18F]-fluoro-2-deoxy-glucose which demonstrates that tumors take up 10-fold more glucose than adjacent normal tissues in vivo. Over-expression of HIF-1a and myc ras activation and loss of p53 function stimulate glycolysis by activating a family of four bifunctional 6-phosphofructo-2-kinase/fructose-26-bisphosphatases (PFKFB) which synthesize fructose-26-bisphosphate (F26BP) an allosteric activator of 6-phosphofructo-1- kinase (PFK-1) which is an essential control point in the glycolytic pathway. The PFKFB enzymes are encoded by four genes (PFKFB1-4) reportedly expressed in distinct tissues: liver/skeletal muscle (PFKFB1) heart (PFKFB2) placenta (PFKFB3) and testis (PFKFB4). Previous studies have focused on the PFKFB3 isozyme as the dominant source of F26BP in neoplastic cells due to its high kinase:phosphatase ratio (~740:1) and overexpression in multiple tumors. The identification of the specific PFKFB isozyme responsible for the high rate of glycolysis in cancer cells may allow for the development of novel agents that suppress tumor growth through inhibition of glycolysis. In preliminary studies we measured mRNA expression of the four PFKFB isozymes in 20 tumor tissues by multiplex RT-PCR and found that PFKFB4 mRNA (and not PFKFB3) was markedly increased in 17/20 tumors relative to adjacent normal tissues. We speculated that the high PFKFB4 expression may be caused by disparate oncogenic pathways converging to enhance glycolytic flux. We found that hypoxic exposure of K-rasG12S+ A549 lung adenocarcinoma cells and introduction of H-rasG12V into immortalized human bronchial epithelial cells increased PFKFB4 mRNA and protein expression. Further cell fractionation revealed that the PFKFB4 protein and not PFKFB3 localized to the cytoplasm the cellular compartment of both PFK-1 and glycolysis. Last transient siRNA silencing of PFKFB4 mRNA expression in K- rasG12S+ A549 cells decreased steady-state concentration of F26BP glycolytic flux and anchorage- independent tumor growth in mice. Taken together these preliminary studies provide rationale for further investigation of the PFKFB4 isozyme as a possible novel target for the development of anti-neoplastic agents. We hypothesize that the PFKFB4 isozyme is required for the high glycolytic flux survival growth and spread of transformed cells. We plan to test this hypothesis by pursuing the following specific aims: 1. To examine the requirement for F26BP synthesized by PFKFB4 for glycolytic and mitochondrial metabolism. 2. To determine the requirement for F26BP synthesized by PFKFB4 for growth invasiveness and survival of normal immortalized and ras-transformed epithelial cells. 3. To examine the effect of PFKFB4 genomic deletion on growth and metabolism of ras-dependent tumors in vivo using a Cre-lox inducible mouse knockout of PFKFB4.

project_terms:
6-Phosphofructo-2-kinase;6-Phosphofructokinase;A549;Actins;Adenocarcinoma Cell;Age-Months;Anchorage-Independent Growth;Apoptosis;Attenuated;Basement membrane;Binding (Molecular Function);Brain;Breast;Carbon;Cell Fractionation;Cells;Chickens;Citric Acid Cycle;Colon;Cytoplasm;Data;Development;Enzymes;Epithelial Cells;Exons;Family;Freezing;Fructose;Gel;Genes;Genomics;Glucose;Glycolysis;Glycolysis Inhibition;Growth;Heart;Human;Hypoxia;Immunohistochemistry;In Situ;In Situ Nick-End Labeling;In Vitro;Investigation;Isoenzymes;Knockout Mice;Label;Lactic acid;Lamins;Large T Antigen;Liver;Lung;Lung Adenocarcinoma;Lung Neoplasms;Malignant Neoplasms;Mammary Neoplasms;Mammary gland;Measures;Messenger RNA;Metabolic;Metabolism;Mitochondria;Modeling;Mortality Vital Statistics;Mouse Mammary Tumor Virus;Mus;Mutation;NADH;Normal tissue morphology;Nude Mice;Oncogenic;Open Reading Frames;Organ;Ovary;Oxygen;Oxygen Consumption;Pathway interactions;Phenotype;Phosphoric Monoester Hydrolases;Phosphotransferases;Placenta;Positron-Emission Tomography;Production;Promotor (Genetics);Protein p53;Proteins;Regulation;Relative (related person);Reporting;Resistance;Reverse Transcriptase Polymerase Chain Reaction;Site;Skeletal muscle structure;Small Interfering RNA;Source;Specimen;Subfamily lentivirinae;TOCSY;Tamoxifen;Telomerase;Testing;Testis;Tissues;Transgenes;Tumor Tissue;Vascularization;Western Blotting;base;cancer cell;cancer type;cell transformation;cellular transduction;design;glucose metabolism;glucose uptake;in vivo;inhibitor/antagonist;mRNA Expression;neoplastic;neoplastic cell;neurotensin mimic 1;novel;overexpression;protein expression;public health relevance;recombinase;screening;shunt pathway;small hairpin RNA;small molecule;tumor;tumor growth;vector

public_health_relevance:
We anticipate that shRNA silencing or genomic deletion of the PFKFB4 isozyme will attenuate the neoplastic potential of transformed epithelial cells and conversely that increased F26BP (from overexpression of PFKFB4) will enhance glycolytic flux and augment tumor growth. These findings may validate PFKFB4 as a new target for the inhibition of glycolysis. Accordingly suppression of glycolytic flux in cancer via the development of small molecule inhibitors of PFKFB4 through computational screening for competitive inhibitors of the PFKFB4 substrate-binding domain may reduce the high mortality that is associated with cancer.


application_id: 8462405
project_number: 3R01DA016718-08S1
project_title: Licit & Illicit Opioids: Comparative Studies in Humans
administering_ic: NIDA
award_notice_date: 2012-06-08
opportunity_number: PA-08-127
application_type: 3
activity_code: R01
ic: DA
serial_number: 016718
suffix: S1
program_official: HAMPSON, AIDAN
project_start_date: 2004-07-10
project_end_date: 2015-04-30
study_section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE]
contact_pi_person_id: 1877426
contact_pi: WALSH, SHARON L.
other_pis: Not Applicable
congressional_district: 06
department: MISCELLANEOUS
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): While rates of heroin dependence have been fairly stable over the last several years rates of prescription opioid abuse dependence and diversion have risen significantly. The initial 5-year award focused on the emerging prescription opioid abuse epidemic by conducting a series of studies on the clinical pharmacology of the most widely abused opioids (hydrocodone oxycodone and Oxycontin(R)). These studies investigated relative abuse potential estimates relative potency effects of pain on abuse liability and pharmacokinetics and pharmacodynamics of these drugs when misused by the oral intranasal and intravenous routes. The present application extends these findings by conducting a series of studies to collect new data on opioids purported to have low abuse liability but based upon surveillance studies are emerging as new drugs of abuse including tramadol buprenorphine (Subutex(R)) and buprenorphine/naloxone (Suboxone(R)). Three studies will be conducted enrolling both sporadic opioid abusers and opioid dependent individuals to examine the relative abuse potential and reinforcing efficacy of tramadol buprenorphine and buprenorphine/naloxone when misused by various routes of administration. These studies include careful double-blind randomized placebo- controlled crossover designs and incorporate innovative methodological additions to the standard abuse liability approach including 1) concurrent evaluation of the direct reinforcing efficacy of these compounds using human self-administration procedures to assess the concordance of findings between the "gold standard" approach to a model that examines drug-taking behavior directly 2) multiple relevant comparator agents and 3) multi-dimensional outcomes of safety subjective reports observer-rating and psychomotor performance along. The three proposed inpatient studies will examine the comparative abuse liability and reinforcing efficacy of 1) oral tramadol over a range of doses in comparison to oxycodone (a high efficacy agonist) codeine (an intermediate efficacy agonist) and placebo in non-dependent opioid abusers 2) intranasal buprenorphine and buprenorphine/naloxone over a range of doses in comparison to one another and to oxycodone codeine and placebo in non-dependent opioid abusers and 3) intranasal buprenorphine and buprenorphine/naloxone over a range of doses in comparison to one another and to oxycodone naloxone and placebo in opioid-dependent subjects maintained on a short-acting pharmaceutical opioid. These studies will provide important new information on two emerging drugs of abuse- tramadol and buprenorphine- both drugs at risk for being rescheduled to more restrictive status in the U.S. It is critical that availability of these drugs be preserved for their target patient groups (i.e. pain patients and opioid dependent individuals seeking office- based treatment for drug dependence respectively) while protecting the public safety. These studies will provide empirical data on the relative abuse liability of these drugs in a relevant population and can inform and support evidence-based regulatory decision-making.    PUBLIC HEALTH RELEVANCE: Prescription opioid abuse has increased dramatically in the United States and is a significant public health problem. It is important to understand the pharmacological effects of prescribed opioids in order to predict and control their abuse and other negative health consequences. These studies will provide new information on the abuse-related features of tramadol (used for pain) and buprenorphine alone and in combination with naloxone (used for treatment of opioid dependence).

project_terms:
Abuse Reporting;Adolescent;Agonist;Arkansas;Award;Behavior;Buprenorphine;Case Study;Clinical Pharmacology;Codeine;Comparative Study;Crossover Design;Data;Decision Making;Dependence;Dose;Double-Blind Method;Drug Addiction;Drug Kinetics;Enrollment;Epidemic;Epidemiology;Evaluation;Gold;Health;Heroin;Heroin Dependence;Human;Hydrocodone;Individual;Inpatients;Intravenous;Kentucky;Learning;Marketing;Methadone;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Naloxone;Opiate Addiction;Opioid;Oral;Outcome;Oxycodone;Pain;Patients;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Placebo Control;Placebos;Population;Procedures;Psychomotor Performance;Randomized;Relative (related person);Reporting;Research Design;Risk;Route;Rural;Safety;Schedule;Self Administration;Series;Solid;Subutex;System;Tramadol;United States;base;comparative;drug of abuse;evidence base;indexing;innovation;opioid abuse;overdose death;prescription opioid abuse;public health medicine (field);public health relevance;surveillance study;tramadol abuse;young adult

public_health_relevance:
PROJECT NARRATIVEPrescription opioid abuse has increased dramatically in the United States and is a significant public healthproblem. It is important to understand the pharmacological effects of prescribed opioids in order to predict andcontrol their abuse and other negative health consequences. These studies will provide new information onthe abuse-related features of tramadol (used for pain) and buprenorphine alone and in combination withnaloxone (used for treatment of opioid dependence).


application_id: 8462255
project_number: 5R01ES017244-03
project_title: Prevention of UV-induced carcinogenesis by cyanidin-3-glucoside
administering_ic: NIEHS
award_notice_date: 2013-03-26
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: ES
serial_number: 017244
program_official: QUINN, ASHLINN KO
project_start_date: 2011-08-01
project_end_date: 2016-03-31
study_section: Special Emphasis Panel[ZRG1-OTC-N(03)M]
contact_pi_person_id: 2107851
contact_pi: SHI, XIANGLIN
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Epidemiological clinical and laboratory studies have implicated that ultraviolet radiation (UV) is a complete environmental carcinogen and that repeated exposures can lead to the development of melanoma and nonmelanoma skin cancers. In addition to sunscreens chemoprevention of skin cancer by natural non-toxic compounds is suggested as an effective strategy to prevent the incidence of skin cancer. Our in vitro and in vivo studies on cyanidin-3-glucoside (C3G) a compound found in blackberries and other foods show that this compound is able to inhibit NF-:B AP-1 COX2 and TNF1 activation/expression neoplastic transformation cancer cell migration and invasion and induction of apoptosis in HL60 cells. C3G also functions as an antioxidant by inhibiting the generation of reactive oxygen species and inducing antioxidant-regulative transcription factors. These preliminary studies indicate that C3G may function as a potential chemopreventive and chemotherapeutic agent. The overall hypothesis of this application is that C3G functions as an antioxidant and inhibits oxidative stress activation of transcription factors and inflammatory signaling proteins leading to protection against UVB-induced carcinogenesis. Specific Aim 1. In vitro and in vivo investigation of antioxidant properties of C3G. Electron spin resonance (ESR) spin trapping will be used to determine the reaction rates of C3G toward hydroxyl (7OH) and superoxide (O27-) radicals using Fenton reaction (Fe(II) + H2O2) and xanthine/xanthine oxidase as sources of these free radicals in a non-cellular system and to investigate antioxidant activities against UVB-induced 7OH and O27- radicals in a cellular system. Low frequency (in vivo) ESR will be also used to study antioxidant activities of C3G against UVB-generated O27- and 7OH radicals in the skin of SKH-1 hairless mice. Specific Aim 2. In vivo investigation of the effects of C3G on UVB-induced oxidative stress and activation of oxidative stress sensitive transcription factors. We will investigate the effects of C3G on UVB-induced lipid peroxidation protein oxidation and oxidative DNA damage in KSH mice. We will also study the effects of C3G on UVB-induced activation of activation protein (AP)-1 nuclear factor (NF)-:B and nuclear factor of activated T cells (NAFT) in transgenic mice. Specific Aim 3. Investigate the effects of C3G on UVB-induced inflammatory mediators. These inflammatory mediators include infiltrating leukocytes and myeloperoxidase (MPO) COX-2 PGE2 and several pro-inflammatory cytokines TNF-1 IL-2 and IL-6. Specific Aim 4. Investigation of the effects of C3G on UVB-induced tumorigenesis and early biomarkers. These markers include changes in thymine-positive cells proliferative cell nuclear antigen terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and apoptotic cells together with a change in p53 and p21/cip1- positive cell population in epidermis. These studies will provide a mechanistic rationale for an early on C3G efficacy in skin cancer prevention.

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

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


application_id: 8462226
project_number: 5R01CA138688-05
project_title: Convergence of MicroRNAs and p53 Signaling in Multiple Myeloma: Environmental Co
administering_ic: NCI
award_notice_date: 2013-05-03
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 138688
program_official: JOHNSON, RONALD L
project_start_date: 2009-07-01
project_end_date: 2014-08-31
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)S]
contact_pi_person_id: 8146758
contact_pi: LI, YONG
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Multiple myeloma (MM) is one of the most common hematological neoplasms. It constitutes about 1% of human cancers and 2% of all cancer deaths. Polycylic aromatic hydrocarbons such as 2378- tetrachlorodibenzo--dioxin (TCDD) have been closely correlated to MM by epidemiologic studies yet the biologic mechanisms of a causal relationship between TCDD exposure and MM have not been well understood. One of the unique features of MM compared to other cancers is the extremely low genetic mutation rate of the tumor protein p53 (TP53) gene. TP53 encodes the p53 tumor suppressor guardian of the human genome. Genomic instability (chromosome translocation aneuploidy and gene mutation) is widely observed in MM and reveals that the function of p53 as the guardian of the human genome is compromised in MM. We explored the molecular mechanisms of p53 inactivation in MM by a new class of noncoding small RNAs microRNAs (miRNAs) as recent reports have demonstrated that some miRNAs such as miR-34 are important players in the p53 tumor suppressor network. We hypothesize that miRNAs negatively regulate the human TP53 gene in MM. We propose three aims for this project: first we will identify miRNAs that target the human TP53 gene by a combination of mutagenesis reporter expression and immunoblotting analyses; second we will assess the pathological significance of miRNA:TP53 interactions in MM cell lines and primary MM cells by expression profiling and miRNA inhibition assays; third we will determine whether dioxin modulates p53 signaling by upregulating miRNA expression. A novel p53 inactivation mechanism by an miRNA that is upregulated by dioxin will lead to unique targets for diagnostic markers and therapeutic interventions in MM patients as well as provide a better understanding of the biological interactions between dioxin exposure and MM tumorigenesis.

project_terms:
101 Mouse;ARNT gene;Aneuploidy;Antisense RNA;Apoptosis;Apoptotic;Aromatic Hydrocarbons;Aromatic Polycyclic Hydrocarbons;Aryl Hydrocarbon Receptor;Benzo(a)pyrene;Binding Sites;Biological;Biological Assay;Biological Process;Bone Marrow;CDKN2A gene;Cell Aging;Cell Cycle Arrest;Cell Death;Cell Line;Cells;Cellular Assay;Cessation of life;Characteristics;Chromosomal translocation;Clinical;Code;Collaborations;Computing Methodologies;Cytoplasm;Development;Diagnosis;Diagnostic;Diagnostic Neoplasm Staging;Dioxins;Disease Progression;Double Minutes;Drug Targeting;Elements;Environmental Pollution;Environmental Risk Factor;Epidemiologic Studies;Epigenetic Process;Etiology;Event;Exposure to;FDA approved;Gene Expression;Gene Library;Gene Mutation;Gene Targeting;Genes;Genome;Genomic Instability;Hematologic Neoplasms;Human;Human Genome;Immunoblotting;Immunoglobulins;Incidence;Infiltration;Laboratories;Lead;Little's Disease;MDM2 Gene Amplification;Malignant Neoplasms;Mediating;Messenger RNA;Methods;MicroRNAs;Molecular;Molecular Profiling;Monitor;Multiple Myeloma;Mus;Mutagenesis;Mutate;Mutation;Neoplasms;Neoplastic Plasma Cell;Nucleotides;Oncogene Activation;Onset of illness;Pathogenesis;Patients;Pattern;Pharmaceutical Preparations;Physiological;Plasma Cells;Process;Prognostic Marker;Promotor (Genetics);Protein p53;Proteins;RNA;Regulation;Reporter;Reporting;Research;Role;Sampling;Signal Transduction;Small RNA;Specimen;TP53 gene;Testing;Therapeutic Intervention;Time;Tumor stage;Tumor-Suppressor Gene Inactivation;Universities;Untranslated RNA;Untranslated Regions;Viral Proteins;Wisconsin;antiangiogenesis therapy;base;clinically significant;mutant;novel;overexpression;p14ARF Protein;prevent;public health relevance;research study;response;stressor;tool;tumor;tumorigenesis;vector

public_health_relevance:
TP53 gene alterations are rare and late events in multiple myeloma (MM) the second most common hematological malignancy constituting about 1% of all human cancers. It is critical to explore whether there are unique mechanisms that inactivate wild-type TP53 function as an early and original molecular event in MM development. The proposed research plan is to test the hypothesis that TP53 is negatively regulated by microRNAs (miRNAs) a class of newly discovered small noncoding RNAs to define whether miRNA dysregulation contributes to tumorigenesis prior to TP53 gene alterations and to determine whether dioxin modulates p53 signaling through upregulating miRNA expression.


application_id: 8461125
project_number: 5R43HL114235-02
project_title: A NEW TECHNIQUE FOR TREATING HEMORRHAGIC SHOCK
administering_ic: NHLBI
award_notice_date: 2013-04-24
opportunity_number: PA-10-122
application_type: 5
activity_code: R43
ic: HL
serial_number: 114235
program_official: WARREN, RONALD Q
project_start_date: 2012-04-19
project_end_date: 2015-03-31
study_section: Special Emphasis Panel[ZRG1-SBIB-V(12)B]
contact_pi_person_id: 1885914
contact_pi: CHIEN, SUFAN
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 968792007
primary_uei: DHTASEX58M16
duns_number: 968792007
uei: DHTASEX58M16
fips: US
organization_id: 10029830
organization_name: NOVERATECH, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 402021959
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The specific aims of this proposal are to use a newly developed intracellular energy delivery technique to enhance resuscitation and to study the relationship between tissue high-energy phosphate supplementation and tissue necrosis and apoptosis during hemorrhagic shock.  In most western countries trauma/hemorrhage is the leading cause of death up to the age of 40. The most common consequence of severe trauma and hemorrhage is shock which is a hypovolemic condition in which oxygen delivery to the body is inadequate for the generation of the adenosine triphosphate (ATP) and adenosine diphosphate (ADP) necessary to maintain the function and structural integrity of tissues. Treatment strategies for shock have changed very little in the past half century and the incidence of mortality and morbidity remains very high. Depletion of high-energy phosphates during hemorrhagic shock was described decades ago and direct administration of free Mg-ATP was reported to increase tissue ATP concentrations tissue and mitochondrial Mg levels and cellular functions by some authors. However this approach is controversial not only because the protective effects cannot always be duplicated by other scientists but also because the half life of ATP is very short in the blood circulation-less than 40 seconds. Furthermore it i well known that highly charged molecules like ATP do not normally cross the cell membrane. We have developed a technique for intracellular Mg-ATP delivery (named ATP- vesicles or VitaSolTM). Preliminary results have indicated a very promising effect in several models of tissue hypoxia and ischemia including shock. Our hypothesis is that the replenishment of intracellular ATP levels alleviates or eliminates many of the detrimental effects caused by hemorrhagic shock thereby increasing survival time.  This Phase I proposal has two aims: 1) To establish the effect of VitaSolTM treatment on hemorrhagic shock; and 2) To investigate the relationship between tissue high- energy phosphate contents and necrosis and apoptosis during hemorrhagic shock and the effect of VitaSolTM treatment on these changes. These studies have not been performed in the past. The success of this project will likely provide a totally new therapeutic approach for treatment of severe trauma and shock. Further study of this new energy delivery technique may also benefit various clinical conditions such as coronary heart disease stroke spinal cord injury cardiopulmonary bypass organ transplant chronic wounds and many other conditions where ischemia is involved. The potential impact on medicine is high.

project_terms:
Adenosine Diphosphate;Adenosine Triphosphate;Age;Apoptosis;Blood Circulation;Blood Substitutes;Blood Transfusion;Brain Hypoxia-Ischemia;Cardiopulmonary Bypass;Cause of Death;Cell membrane;Cell physiology;Charge;Chronic;Clinical;Colloids;Coronary heart disease;Country;Generations;Half-Life;Hemorrhage;Hemorrhagic Shock;Hypovolemics;Incidence;Intervention;Ischemia;Medicine;Mitochondria;Morbidity - disease rate;Mortality Vital Statistics;Names;Necrosis;Organ Transplantation;Outcome;Oxygen;Patients;Phase;Reporting;Resuscitation;Scientist;Shock;Solutions;Spinal cord injury;Supplementation;Techniques;Time;Tissue Model;Tissues;Trauma;Vesicle;base;crystalloid;effective therapy;inorganic phosphate;novel therapeutic intervention;protective effect;restoration;stroke;success;treatment strategy

public_health_relevance:
Trauma/hemorrhage is the leading cause of death up to the age of 40 in most western countries but no effective treatment has been developed and mortality remains very high. This proposal is to use our newly developed intracellular energy delivery technique to enhance resuscitation in hemorrhagic shock. The success of this project will likely have a major impact on medicine.


application_id: 8461124
project_number: 5R13CA168316-02
project_title: Advancing Health Communication Research through the KCHC-DCHC Conference Series
administering_ic: NCI
award_notice_date: 2012-12-20
opportunity_number: PA-10-071
application_type: 5
activity_code: R13
ic: CA
serial_number: 168316
program_official: BLAKE, KELLY D
project_start_date: 2012-04-19
project_end_date: 2016-12-31
study_section: ZCA1-PCRB-G(F2)
contact_pi_person_id: 1974135
contact_pi: HARRINGTON, NANCY GRANT
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_terms:
AIDS/HIV problem;Address;Area;Behavioral;Behavioral Genetics;Behavioral Sciences;Communication;Communication Research;Communities;Diabetes Mellitus;Discipline;Discipline of Nursing;Disease;District of Columbia;Effectiveness of Interventions;Ensure;Event;Faculty;Goals;Government;Growth;Health;Health Communication;Health Personnel;Health Promotion;Health Sciences;Healthy People 2020;Human Resources;Interdisciplinary Study;International;Internet;Kentucky;Knowledge;Life;Malignant Neoplasms;Medical Informatics;Medicine;Mission;Participant;Personal Satisfaction;Persuasive Communication;Process;Psychology;Publications;Publishing;Request for Applications;Research;Research Personnel;Risk;Risk Reduction Behavior;Scholarship;Science;Scientist;Series;Sister;Social Sciences;Sociology;Students;Substance abuse problem;Technology;Translational Research;Travel;United States National Institutes of Health;Work;behavioral/social science;burden of illness;career;career development;design;disability;disorder prevention;drug abuse prevention;graduate student;health information technology;health literacy;interest;meetings;member;prevent;public health medicine (field);public health relevance;skills;social;social science research;substance abuse prevention;symposium;therapy design

public_health_relevance:
The Kentucky Conference on Health Communication (KCHC)-District of Columbia Health Communication (DCHC) conference series will advance health communication research and practice in order to reduce the burden of pressing public health problems such as cancer diabetes substance abuse and HIV/AIDS. The conference will promote career development in the social and behavioral sciences through support of early career researchers and graduate students increasing the number of professionals with expertise in health communication.


application_id: 8461005
project_number: 2R01EY012716-14
project_title: Functional State of Developing Retinogeniculate Synapse
administering_ic: NEI
award_notice_date: 2013-02-18
opportunity_number: PA-11-260
application_type: 2
activity_code: R01
ic: EY
serial_number: 012716
program_official: STEINMETZ, MICHAEL A
project_start_date: 2001-05-01
project_end_date: 2018-02-28
study_section: Special Emphasis Panel[ZRG1 IFCN-Q (02)]
contact_pi_person_id: 1864719
contact_pi: GUIDO, WILLIAM
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): We have developed a powerful mouse model to study visual circuit development in the dorsal lateral geniculate nucleus (dLGN) the thalamic relay of retinal information to the visual cortex. To date studies have focused largely on the retinogeniculate pathway and the refinement of connections between retinal ganglion cells and dLGN neurons. While many of the changes in retinogeniculate axon patterning and connectivity have been delineated information about two fundamental aspects of organization is still lacking. One relates to the cell- class specificity of connections between RGCs and dLGN cells and the other pertains to the source of connections to dLGN cells namely the wealth of input that arises from nonretinal projections. Both aspects are critical for a contemporary understanding of thalamic function which is to provide a faithful relay of retinal signals but at the same time to modulate the gain of transmission based on changes in behavioral state. The goals of this proposal are to assess how retinogeniculate refinement relates to class specific connections whether retinogeniculate refinement proceeds in a way that establishes separable parallel visual channels to determine when nonretinal projections develop in dLGN and to assess how such input coordinates with the innervation and refinement of the retinogeniculate pathway. To address these issues we will conduct anatomical electrophysiological and optogenetic experiments in transgenic mice that allow for the visualization and experimental isolation of specific cell types arising from the retina or from such nonretinal sources as layer VI of visual cortex the thalamic reticular nucleus and cholinergic nuclei of the brainstem. These studies will
provide valuable information about how the developing brain forms precise patterns of connections and offer further insight into the study and treatment of developmental and neurological disorders that result from the formation of abnormal patterns of connectivity.

project_terms:
3-Dimensional;Address;Adopted;Age;Architecture;Axon;Behavioral;Biological Models;Brain;Brain Stem;Cell Nucleus;Cells;Cholera Toxin Protomer B;Deafferentation procedure;Development;Disease;Dorsal;Event;Exhibits;Eye;Felis catus;Genetic;Goals;Imagery;In Vitro;Injection of therapeutic agent;Injury;Interneurons;Knowledge;Label;Lateral Geniculate Body;Life;Light;Mus;Neurons;Optic Nerve;Pathway interactions;Pattern;Preparation;Retina;Retinal;Retinal Ganglion Cells;Rhodopsin;Signal Transduction;Slice;Source;Specificity;Synapses;Testing;Thalamic structure;Time;Transgenic Mice;Transgenic Organisms;Trees;Variant;Viral;Visual;Visual Cortex;base;biocytin;cell type;cholinergic;developmental disease/disorder;insight;loss of function;monocular;mouse model;mutant;nerve supply;nervous system disorder;optogenetics;postnatal;preference;public health relevance;reconstruction;research study;response;retinal axon;retinal progenitor cell;retinogeniculate;synaptogenesis;transcription factor;transmission process

public_health_relevance:
These studies will provide valuable information about how the developing brain forms precise patterns of connections and offer further insight into the study and treatment of developmental and neurological disorders that result from the formation of abnormal patterns of connectivity. Knowledge gained from these studies will also have important implications for understanding and predicting how thalamic circuits involving retinal and nonretinal projections respond to disease or injury.


application_id: 8460774
project_number: 5R01MD004598-05
project_title: Does Violence Against Women result in disparities in cancer care for women with b
administering_ic: NIMHD
award_notice_date: 2013-04-19
opportunity_number: RFA-MD-09-004
application_type: 5
activity_code: R01
ic: MD
serial_number: 004598
program_official: ALVIDREZ, JENNIFER L
project_start_date: 2009-09-25
project_end_date: 2015-04-30
study_section: ZMD1-PA(R4)S
contact_pi_person_id: 1894149
contact_pi: COKER, ANN L
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Background: Violence against women (VAW) is defined by the United Nations as "any act of gender based violence thatresults in physical sexual or psychological harm or suffering to women." In Kentucky almost 40% of women hadexperienced some form of VAW in their lifetime. The frequency of VAW poses a serious public health challenge not onlydue to the prevalence but also the long term impact on women's health documented in an impressive body of literature.However very little research has explored the effect of lifetime VAW on cancer prevention and control. Kentucky has ahigh cancer burden with the highest cancer mortality rate of all US states. Incidence rates of cancer and the proportion ofwomen diagnosed at a later stage are higher in the Appalachian region of Kentucky. VAW frequently co-occurs withsocial factors leading to health disparities including unemployment less education and minority race. Overall objectivesof this project are to determine the extent to which VAW may explain noted disparities in cancer care based on women'srace/ethnicity socioeconomic status access to health insurance or residence in high poverty and rural areas of Kentucky.Specific aims: To determine whether VAW is associated with disparities in breast cancer (aim 1) colorectal cancer (aim2) and cervical cancer (aim 3) care outcomes to include not receiving cancer screening at recommended intervals beingdiagnosed with cancer at a later stage not receiving recommended cancer treatment including supportive/palliative careand poorer cancer specific survival among women diagnosed with these cancers in Kentucky and adjusting for relevantconfounders including race socioeconomic status having health insurance rural residence and specific regions of highpoverty (e.g. living in the Appalachian region of eastern Kentucky or the Delta region of western Kentucky). Methods:We propose a prospective cohort using the Kentucky Cancer Registry (KCR) as the source of 3150 breast cancer cases1575 colorectal cancer cases and 525 cervical cancer cases. These 5250 women will be interviewed by phone to determinetheir lifetime exposure to VAW and comorbid conditions. These data will be linked with state level Medicare claims datafor women completing phone surveys who are 65 or older. The Medicare claims data administered by the Center forMedicare and Medicaid Services include comprehensive coverage of medical services regardless of where the patientsseek care in the nation which would allow the detailed examination of the proposed cancer care continuum: cancerscreening stage at diagnosis treatment supportive or palliative care and survivorship. Both logistic regression and Coxproportional hazards modeling will be used to determine the role of VAW (by frequency duration severity recency andtype) and socioeconomic attributes influencing disparities in cancer care. These associations will be investigated for eachof the hypothesized five cancer care outcomes and by specific cancer. The mediating or moderating role of socioeconomicfactors will also be explored using structural equation modeling. Relevance: This will be the first population-based cohortof the influence of VAW on the life course of cancer care in a state with high cancer burden and regions of extremepoverty. Findings will have significant public health impact in reducing disparities and improving cancer prevention andcontrol in women.

project_terms:
Adult;Affect;Appalachian Region;Breast;Breast Cancer Treatment;Cancer Burden;Cancer Control;Cancer Patient;Caring;Censuses;Cervical;Child;Choices and Control;Clinic;Colonoscopy;Colorectal;Colorectal Cancer;Consent;Cox Proportional Hazards Models;Data;Data Analyses;Data Set;Diagnosis;Diagnostic Neoplasm Staging;Divorce;Educational aspects;Ensure;Epidemiologic Studies;Equation;Ethnicity aspects;Event;Exposure to;Family member;Fecal occult blood;Frequencies (time pattern);Funding;Gender;Geographic state;Grant;Health;Health Insurance;Healthcare;Human Papillomavirus;Incidence;Individual;Insurance Coverage;Intervention;Interview;Kentucky;Life;Life Cycle Stages;Link;Literature;Logistic Regressions;Low income;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Mammography;Measures;Mediating;Medical;Medical Surveillance;Medicare;Medicare claim;Medicare/Medicaid;Mental Health;Methods;Minority;Modeling;Mortality Vital Statistics;Neighborhoods;Occult blood screen;Outcome;Outcomes Research;Palliative Care;Pap smear;Parents;Pathway interactions;Patient Self-Report;Patients;Pattern;Physicians;Positioning Attribute;Poverty;Poverty Areas;Prevalence;Race;Recruitment Activity;Registries;Research;Research Personnel;Risk;Role;Rural;Schools;Screening for cancer;Services;Severities;Smoke;Smoking Status;Socioeconomic Factors;Socioeconomic Status;Solutions;Source;Stage at Diagnosis;Staging;Supportive care;Surveys;Survivors;Telephone;Telephone Interviews;Texas;Time;Tumor stage;Unemployment;Uninsured;United Nations;United States Centers for Medicare and Medicaid Services;Violence;Woman;Women's Health;Work;base;cancer care;cancer diagnosis;cancer health disparity;cancer prevention;cancer therapy;care seeking;cohort;emotional abuse;experience;health disparity;improved;low socioeconomic status;malignant breast neoplasm;men;neoplasm registry;physical conditioning;population based;programs;prospective;psychologic;public health medicine (field);residence;rural area;screening;social;socioeconomics;survivorship;tool;violence against women

public_health_relevance:
Determining whether violence against women influences the life course of cancer prevention andcontrol for women with breast cervical or colorectal cancer can result in an important opportunity tounderstand reasons for and potential solutions to cancer care disparities. If VAW does influence cancercare interventions can be developed to identify VAW in women with cancer and provide appropriatesupport to ensure receipt of recommended care.


application_id: 8459016
project_number: 5R01DE017921-04
project_title: Role of JAK2 in Innate Immunity
administering_ic: NIDCR
award_notice_date: 2013-05-20
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DE
serial_number: 017921
program_official: MELILLO, AMANDA A
project_start_date: 2010-06-23
project_end_date: 2014-12-31
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.

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:
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.


application_id: 8458101
project_number: 5T32AG000242-20
project_title: Cellular and Molecular Basis of Brain Aging
project_terms: Aging;Base of the Brain;Molecular
administering_ic: NIA
award_notice_date: 2013-05-07
opportunity_number: PA-06-468
application_type: 5
activity_code: T32
ic: AG
serial_number: 000242
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 1994-09-30
project_end_date: 2014-09-30
study_section: ZAG1-ZIJ-7(J4)
contact_pi_person_id: 8383539
contact_pi: GERHARDT, GREG A.
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The goal of this Training Program is to prepare promising graduate students and postdoctoral fellows for successful careers in the neurobiology of aging. We will provide broad-based training in modern concepts in the neurobiology of aging with an emphasis on cellular and molecular mechanisms underlying aging processes and possible therapeutic interventions. The unifying focus of the training faculty is our interest in understanding both normal and pathological mechanisms by which the nervous system responds to changes that occur with age and emerging concepts in therapeutic intervention. This Training Program provides the formal framework for faculty in different departments who share a common interest in the molecular- cellular basis of brain aging and translational research to provide in-depth training in aging. The emphasis of the Training Faculty complement each other: some focus on processes that occur in the brain during normal aging others emphasize the neuropathological processes of diseases and injuries that predominate in the aging brain and there is a combined interest in applying this knowledge to treating neural disorders of aging. Thus trainees will learn from faculty who utilize a broad spectrum of state-of-the-art methodological approaches to probe critical questions in aging research. Our successes attest to our abilityto identify attract train and place promising young investigators in the area of the neurobiology of aging. Now more than ever before we are particularly qualified to train graduate students and postdoctoral fellows. The national need for training new investigators in the area of aging is clear due to our changing demography and the increasing average lifespan. Normal aging or pathology of the nervous system underlies much age-associated morbidity. Only if we better understand the basic mechanisms that regulate the aging of the brain and apply this to the treatment ofthe elderly can we hope to improve the qualityof life during the latter half ofthe lifespan. Our ability to attract and train graduate students and postdoctoral fellows to meet the challenges in the area of the neurobiology of aging will be greatly enhanced by this Training Program.     RELEVANCE: This Program will train the next generation of scientists to carryout research on the neurobilogy of aging. Dramatic improvements in the treatment of age-related illnesses such as Alzheimer's disease Parkinson's disease stroke epilepsy and others are need for the aging world population. Only through training of such research areas can we hope to make strides in new treatments for illnesses that cost us billions.


application_id: 8457709
project_number: 1F32HL116186-01A1
project_title: Nutrient excess alters resolution of inflammation in diabetes and obesity
administering_ic: NHLBI
award_notice_date: 2013-01-25
opportunity_number: PA-11-113
application_type: 1
activity_code: F32
ic: HL
serial_number: 116186
suffix: A1
program_official: MEADOWS, TAWANNA
project_start_date: 2013-03-01
project_end_date: 2016-02-29
study_section: Special Emphasis Panel[ZRG1 F06-T (20)]
contact_pi_person_id: 11169883
contact_pi: HELLMANN, JASON L
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The overall objective of this study is to determine whether systemic inflammation in diabetes and obesity persists because of a failure of endogenous pathways that normally resolve inflammation. Our working hypothesis is that chronic inflammation in T2D and obesity is sustained in part due to a deficiency in specialized pro-resolving lipid mediator (SPM)-stimulated resolution which impairs wound healing. To test this hypothesis we will assess the development and resolution of acute inflammation in wild type and obese-diabetic mice and determine how SPM pathways are affected by nutrient excess. We will also perform a targeted lipidomic analysis of adipose tissue and plasma obtained from obese diabetic and non-diabetic humans undergoing bariatric surgery to elucidate whether SPM biosynthesis is associated with inflammation and metabolic parameters. Utilizing these approaches we will be able to elucidate how diabetes impacts resolution of inflammation and determine how SPM pathways are modulated in obese and diabetic humans. Lastly to test the efficacy of SPM in treating clinically-relevant manifestations of diabetes we will determine whether promoting resolution will decrease inflammation and enhance wound healing in a rodent model of cutaneous wound healing. We expect that this project will generate new knowledge regarding the mechanisms that sustain chronic inflammation in T2D and move the field forward by testing the efficacy of SPM in preventing not just systemic insulin resistance bu also specific clinical manifestations of diabetes such as impaired wound healing. In addition these studies will determine the association between insulin resistance and SPM pathways in obese humans which has not been previously assessed. Completion of these translational studies will lead to a better understanding of the mechanisms that sustain chronic inflammation in obesity and diabetes; an understanding that will open up new avenues for exploring a novel set of therapies for attenuating inflammation and promoting wound healing in diabetic patients.

project_terms:
Acute;Adipose tissue;Affect;Anabolism;Animal Model;Anti-Inflammatory Agents;Anti-inflammatory;Apoptotic;Atherosclerosis;Attenuated;Blood Vessels;Cells;Centers for Disease Control and Prevention (U.S.);Chronic;Clinical;Cutaneous;Defect;Development;Diabetes Mellitus;Diabetic mouse;Diet;Epidemic;Event;Explosion;Failure (biologic function);Fibrosis;Healed;Homeostasis;Human;Hyperglycemia;Immune response;Impaired wound healing;Infection;Infiltration;Inflammation;Inflammatory;Injury;Insulin Resistance;Interruption;Intervention;Knowledge;Lead;Leukocytes;Liquid Chromatography;Measures;Mediating;Mediator of activation protein;Metabolic;Microbe;Molecular;Natural immunosuppression;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;Obesity;Omega-3 Fatty Acids;Pathway interactions;Patients;Peritoneal;Phagocytes;Phagocytosis;Phase;Physiological;Plasma;Population;Process;Recurrence;Resolution;Retinal Diseases;Risk;Rodent Model;Testing;Time;Tissue Expansion;Tissues;Work;Wound Healing;Zymosan;bariatric surgery;base;clinical application;clinically relevant;db/db mouse;diabetic;diabetic patient;efficacy testing;healing;improved;insulin sensitivity;lipid mediator;liquid chromatography mass spectrometry;macrophage;microbial;non-diabetic;novel;novel therapeutics;peripheral blood;prevent;public health medicine (field);public health relevance;response;tandem mass spectrometry;tissue regeneration;tissue repair;translational study

public_health_relevance:
Results of this project will provide a new understanding of the mechanistic basis whereby diabetics suffer from delayed wound healing and chronic inflammation. These studies could lead to the development of new therapeutics aimed at resolving inflammation.


application_id: 8457019
project_number: 5K99DA033373-02
project_title: Tonic and Phasic Glutamate Release in Incentive Salience and Cocaine Reinforcemen
administering_ic: NIDA
award_notice_date: 2013-04-19
opportunity_number: PA-11-197
application_type: 5
activity_code: K99
ic: DA
serial_number: 033373
program_official: SORENSEN, ROGER
project_start_date: 2012-05-01
project_end_date: 2014-09-14
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 9713925
contact_pi: BECKMANN, JOSHUA
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): The proposed career development plan is designed to provide the PI with a unique skill set and experience to meet the short-term goal of becoming a productive independent researcher and long-term goal of becoming a significant contributor to the understanding and treatment of substance abuse disorders. The plan will be carried out at the University of Kentucky an institution with a rich history of interdisciplinary substance abuseresearch. The PI will be mentored by Dr. Michael Bardo and co-mentored by Dr. Greg Gerhardt established experts in neuropsychopharmacology and neurochemistry respectively. The plan proposes to use enzyme based microelectrode arrays to uncover the role of sub-second tonic/physic mesocorticolimbic glutamate release in individual differences in incentive salience/value attribution to reward-related cues and cocaine reinforcement in a preclinical rat model. When a stimulus reliably predicts reward some animals attribute incentive value to the stimulus and thus will approach and contact it (sign-trackers); other animals use the stimulus as a simple signal of forthcoming reward and thus will approach the receptacle into which reward will be delivered (goal-trackers). Recently it has been demonstrated that differences in sign and goal tracking are related to novelty seeking impulsivity initial vulnerability to cocaine reinforcement and relapse vulnerability. In addition to mesocorticolimbic dopamine stimulus-reward learning and drugs of abuse are known to alter mesocorticolimbic glutamate signaling. The overall proposed hypothesis is that differences in incentive value attribution are mediated by differential mesocorticolimbic glutamate release upon cue exposure; this differential release is then exacerbated by repeated cocaine self-administration giving rise to differential substance abuse vulnerability and relapse. Specific Aim 1 will determine if second-by-second tonic/physic glutamate signaling is differentially affected by food-associated cues in sign- vs. goal-tracking animals. Specific Aim 2 will determine the role of dopaminergic receptor function on the expression of sign-/goal tracking and underlying tonic/physic glutamate signaling. Specific Aim 3 will determine if second-by-second tonic and physic glutamatergic signaling in sign- and goal-tracking animals changes differentially with repeated cocaine self-administration. Specific Aim 4 will then determine the role of dopaminergic receptor function on cocaine self-administration and tonic/physic glutamate signaling in sign- and goal-trackers. Collectively these results will provide insight into the role of tonic/physic glutamate signaling in stimulus reward learning incentive value attribution to reward-associated stimuli and cocaine reinforcement while providing the PI with unique training in neuropsychopharmacology and neurochemistry by experts in both fields.

project_terms:
Abstinence;Addictive Behavior;Affect;Animals;Behavior;Cell Nucleus;Chronic;Cocaine;Control Animal;Cues;Development;Development Plans;Disease;Dopamine;Dopamine Antagonists;Dopamine Receptor;Enzymes;Exhibits;Food;Glutamates;Goals;Impulsivity;Incentives;Individual;Individual Differences;Institution;Kentucky;Learning;Maintenance;Mediating;Mentors;Microdialysis;Microelectrodes;Modeling;Neurons;Pharmaceutical Preparations;Pharmacotherapy;Phase;Physics;Play;Psychological reinforcement;Rattus;Receptor Inhibition;Recording of previous events;Relapse;Relative (related person);Research;Research Personnel;Resolution;Rewards;Role;Schedule;Self Administration;Self-Administered;Signal Transduction;Stimulus;Substance Use Disorder;Substance abuse problem;Technology;Time;Training;Universities;awake;base;career development;classical conditioning;cocaine exposure;design;drug of abuse;experience;insight;meetings;neurochemistry;novel;pre-clinical;prevent;receptor function;research study;response;skills;substance abuse treatment

public_health_relevance:
The proposed studies will provide insight into the underlying mechanisms that accompany individual differences in substance abuse disorders that may aid in the development of novel therapies for abuse disorders involving stimulants.  Although many people may experiment with drugs of abuse few come to develop a substance use disorder. These individual differences suggest that some people may be more or less prone to develop such disorders. These individual differences may be related to differential attribution of incentiv value to reward-related stimuli; the broad goal of this research is to identify the underlying neurochemical basis for individual differences in substance abuse vulnerability and will be beneficial in identifying novel pharmacological targets for the development of substance abuse pharmacotherapies.


application_id: 8457011
project_number: 5K01DA031764-02
project_title: Community Intervention Research on Prescription Drug Safety in Older Rural Adults
administering_ic: NIDA
award_notice_date: 2013-03-13
opportunity_number: PA-11-190
application_type: 5
activity_code: K01
ic: DA
serial_number: 031764
program_official: KAHANA, SHOSHANA Y
project_start_date: 2012-04-15
project_end_date: 2013-10-24
study_section: Career Development Education and Training Study Section[NIDA-K]
contact_pi_person_id: 8705215
contact_pi: ZANJANI, FAIKA
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  My training objectives for this K01 Career Development Award are to enhance my knowledge and experience in a) prescription drug and alcohol interactions among older adults; b) alcohol and substance abuse; and c) developing implementing and examining a community-based health intervention program. These training goals will support me in reaching my long-term career objective to become an expert in interventions for health behavior change among older adults to reduce inadvertent prescription drug use adversities. This will be accomplished through randomized community-based behavioral trials and designing and implementing awareness and motivational interventions. The ultimate goal of this K01 Career Development Award project is to support my development as an independent scientist capable of conducting community-based behavioral health intervention that will reduce alcohol-prescription drug interactions in rural older patients who regularly take prescription medications. The impetus behind this K01 Career Development Award application is the need for effective interventions to address the devastating health effects of prescription drug and alcohol interactions. Prescription overdoses that require medical attention in older adults are commonly associated with alcohol. In combination alcohol and prescription drug misuse can seriously undermine the medical condition that is being treated by the prescription drug medication lead to potential alcohol drug interactions increase the risk fo alcohol and illicit drug use and ultimately increase health costs. In the training component of th proposed program I will gain a more thorough understanding of principles surrounding prescription drug safety (PDS) alcohol interactions and community-based health interventions. Specifically my efforts will focus on understanding PDS by targeting the reduction of prescription drug and alcohol interactions in rural pharmacy settings. The proposed project will focus on older adults in rural settings because they are at high risk for prescription misuse in addition to having limited resources for managing PDS issues. The proposed research will involve the development implementation and evaluation of an intervention in a community setting designed to improve PDS through a) raising awareness about alcohol use and prescription drug interactions and b) using motivational interviewing to reduce alcohol consumption among at-risk alcohol consumers (consuming above recommended age-defined limits (>1 alcoholic drink a day in combination with prescription drugs). Prescription drug safety is characterized by consuming correct quantities and avoiding prescriptions in combination with adverse substances (e.g. alcohol) to prevent negative health outcomes. This K award will be a platform for the development of expertise but also a novel promising and wide reaching approach to prevent prescription drug interactions through community-based prevention methods targeting modifiable behaviors in community pharmacies. Promoting moderate alcohol use patterns to encourage safer use of prescription drugs is significant since approximately 50% of older adults consume alcohol of whom 25% consume more than the recommended age-defined limits. Additionally older adults use prescription drugs more than any other age group. Risky alcohol consumption (the age-defined definition involves consuming more than 1 drink/day on average) can have negative interactions with many medications commonly used by older adults and consequently can have detrimental impacts on health. These health effects include medication and disease-management non-adherence and increased likelihood of falls cognitive impairment medical adversities and fatality. The proposed study will involve the implementation of an intervention in community settings with the aid of local pharmacists and will include an awareness and motivational interviewing component to promote PDS. Specific Aims of the research proposal are to 1) Obtain community insights about PDS to examine rural resources/barriers which will inform the development of the PDS intervention program; 2) Create PDS intervention material for the awareness and motivational interviewing components 3) Implement and evaluate intervention components (Awareness and Motivational Interviewing) to promote PDS in rural regions and 4) Disseminate findings and develop an R01 NIH grant to examine the proposed intervention on a larger scale. Achieving the proposed aims will lead to an innovative approach to promote PDS within other rural communities. Establishing an effective PDS intervention will reduce adversities related to prescription drug and alcohol interactions for older adults and consequently improve their quality of life.

project_terms:
Accidental Injury;Address;Adult;Age;Aging;Alcohol abuse;Alcohol consumption;Alcohols;Area;Awareness;Behavior;Behavioral;Cessation of life;Clinical Trials Design;Cognition;Communities;Community Pharmacy;Community based prevention;County;Data;Development;Disease;Disease Management;Drug Interactions;Drug Prescriptions;Drug usage;Drug user;Educational aspects;Effectiveness;Elderly;Evaluation;Focus Groups;Future Generations;Goals;Grant;Guidelines;Health;Health Care Costs;Health behavior change;Illicit Drugs;Impaired cognition;Individual;Intervention;Intervention Studies;K-Series Research Career Programs;Knowledge;Lead;Manuals;Manuscripts;Medical;Medication Errors;Methods;Morbidity - disease rate;Mortality Vital Statistics;Myocardial Infarction;Outcome;Overdose;Pamphlets;Pattern;Pharmaceutical Preparations;Pharmacists;Pharmacy facility;Physiology;Psyche structure;Quality of life;Randomized;Randomized Controlled Trials;Research;Research Proposals;Resources;Risk;Risk Factors;Rural;Rural Community;Safety;Scientist;Substance abuse problem;Telephone;Testing;Training;United States National Institutes of Health;age group;alcohol risk;base;behavioral health;career;community setting;design;drinking;drug metabolism;effective intervention;experience;falls;follow-up;high risk;high risk drinking;improved;innovation;insight;intervention program;medical attention;meetings;misuse of prescription only drugs;motivational enhancement therapy;motivational intervention;novel;older patient;prevent;problem drinker;programs;public health medicine (field);research study;rural area

public_health_relevance:
This research will aid in reducing the rates and consequences of prescription drug and alcohol interactions among older adults residing in rural US areas. Reducing prescription drug and alcohol interactions can ultimately reduce individual and societal health burden and improve life quality through improved cognition and mental and physical capabilities.


application_id: 8456537
project_number: 2U10NS053368-06
project_title: NEUROPROTECTION EXPLORATORY TRIALS IN PD (NET-PD)
administering_ic: NINDS
award_notice_date: 2012-12-27
opportunity_number: RFA-NS-13-002
application_type: 2
activity_code: U10
ic: NS
serial_number: 053368
program_official: MOY, CLAUDIA S
project_start_date: 2006-05-17
project_end_date: 2015-11-30
study_section: Special Emphasis Panel[ZNS1 SRB-B (34)]
contact_pi_person_id: 1868189
contact_pi: CAMBI, FRANCA
other_pis: Not Applicable
congressional_district: 06
department: NEUROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): A major goal of the neuroscience community is to develop treatment strategies that will slow or forestall the progression of chronic neurodegenerative diseases. Parkinson's disease (PD) is one of the most common adult neurodegenerative disorders affecting over 1 million people in North America and the European Union. As a first step in identifying such therapies the NINDS Exploratory Trials in Parkinson's disease (NET-PD) network successfully completed futility studies which identified creatine as a potential agent to slow clinical decline in PD. The NET-PD network is now conducting a large long-term Phase 3 trial (known as LS1) comparing creatine to placebo. Our site #172 is one of the 50 NET-PD centers conducting the LS1 trial. In this renewal we plan on continuing the execution of the trial at our center enhance retention of enrolled subjects and complete the evaluations of all subjects enrolled at our site. All subjects are enrolled and the major effort isto enhance retention in order to test the primary hypothesis that daily administration of creatine (10
gm/day) is more effective than placebo in slowing clinical decline in PD between baseline and the 5 year follow-up visit against the background of dopaminergic therapy and best PD care. In addition secondary measures of efficacy of creatine on individual PD measures will be assessed. We have implemented measures to enhance retention following uniform guidelines from the Clinical Coordinating Center. In addition we have developed strategies that target the population at our site. These measures have been so far successful in retaining subjects past the 5 years of the trial.

project_terms:
Activities of Daily Living;Address;Adult;Affect;Caring;Chronic;Clinical;Communities;Creatine;Digit structure;Disease;Disease Progression;Dopamine Agonists;Dose;England;Enrollment;European Union;Evaluation;Futility;Goals;Guidelines;Health;Ice;Individual;Levodopa;Measures;Mental Depression;Modality;Monoamine Oxidase B;Movement Disorders;National Institute of Neurological Disorders and Stroke;Nerve Degeneration;Neurodegenerative Disorders;Neurosciences;Newly Diagnosed;North America;Outcome Measure;Parkinson Disease;Participant;Patients;Phase;Phase III Clinical Trials;Pioglitazone;Placebos;Quality of life;Safety;Selegiline;Site;Symptoms;Target Populations;Testing;Therapeutic Equivalency;Visit;cognitive function;disability;double-blind placebo controlled trial;efficacy testing;follow-up;inhibitor/antagonist;neuroprotection;primary outcome;programs;rasagiline;treatment strategy

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is the most common neurodegenerative movement disorder. Current therapies treat the symptoms however do not modify the course of the disease. Disease modifying treatment are an unmet need for PD patients. The NET-PD program addresses this need. LS1 will help to determine if creatine can slow clinical decline and provide better information on the course of early PD than is currently available.


application_id: 8455424
project_number: 1R43GM101810-01A1
project_title: Biological Methods for Enhancing Wound Healing Properties
administering_ic: NIGMS
award_notice_date: 2013-09-19
opportunity_number: PA-12-088
application_type: 1
activity_code: R43
ic: GM
serial_number: 101810
suffix: A1
program_official: SOMERS, SCOTT D
project_start_date: 2013-09-20
project_end_date: 2015-09-19
study_section: Special Emphasis Panel[ZRG1 MOSS-T (12)]
contact_pi_person_id: 9710810
contact_pi: FATH-GOODIN, ANGELIKA
other_pis: WEBB, BRUCE A
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Chronic wounds and ulcers are increasing with the growing incidence of diabetes and associated illnesses and have annual costs exceeding $20 billion. These non-healing wounds result in chronic disease limb amputations and death and are complicated by antibiotic resistant bacteria infection. This proposal seeks to improve and develop new capabilities of a biological treatment of such wounds maggot debridement therapy (MDT) that is effective but underutilized. Some maggot species have evolved to digest fluids dead tissues and bacteria in wounds and have been recognized for over 200 years for this improved wound healing behavior. For approximately a century Lucilia sericata maggots have been produced for MDT. This proposal seeks to create transgenic flies with properties that will support increased use of MDT. The goals of the proposal are 1) to produce flightless flies with limited dispersal capability 2) to engineer fluorescent flies that are more readily observed in wounds 3) to engineer flies that facilitate analgesic and therapeutic peptide expression to improve patient comfort and wound healing. These mutants will facilitate fly production and also impede genetically engineered insect escape. The objectives of this proposal will support greater use of MDT thereby reducing treatment costs improving wound healing and limiting the persistent use of antibiotics for treating chronic wounds.

project_terms:
Affect;Amputation;Analgesics;Anti-Bacterial Agents;Antibiotic Resistance;Antibiotic Therapy;Antibiotics;Bacteria;Bacterial Infections;Behavior;Binding (Molecular Function);Biological;Breeding;Cessation of life;Chemicals;Chronic;Chronic Disease;Containment;Debridement;Development;Devices;Diabetes Mellitus;Disease;Dynorphins;Endorphins;Engineering;Enkephalins;Europe;Excision;Exudate;Facility Construction;Funding;Gene Proteins;Genes;Genetic Engineering;Genome;Goals;Growth Factor;Healed;Human;Immune system;Incidence;Individual;Infection;Injection of therapeutic agent;Insecta;Kentucky;Knowledge;Label;Larva;Liquid substance;Lower Extremity;Lucilia (blowfly);Maggots;Mediating;Medical Device;Methods;Microbial Biofilms;Molecular;Monitor;Movement;Mutagenesis;Necrosis;Opioid Receptor;Outcome;Patients;Peptides;Phase;Production;Promotor (Genetics);Property;Proteins;Renaissance;Salivary Glands;Salivary Proteins;Site;Small Business Innovation Research Grant;Sterility;Technology;Testing;Therapeutic;Tissues;Transgenes;Transgenic Organisms;Treatment Cost;Ulcer;United States;United States National Institutes of Health;Universities;War;Wound Healing;commercialization;conventional therapy;cost;cost effective;diabetic patient;egg;erythritol anhydride;experience;feeding;fitness;fly;green bottle fly;healing;improved;interest;limb amputation;mutant;novel strategies;phase 2 study;professor;public health relevance;research study;targeted delivery;therapeutic transgene;therapy development;trait;transgene expression;wound

public_health_relevance:
Chronic wounds and ulcers are increasing with the growing incidence of diabetes and associated illnesses and have annual costs exceeding $20 billion. Concurrently treatment of bacterial infections that are common complications of chronic wounds and ulcers is becoming more difficult with the rapid emergence of antibiotic resistant bacteria. This proposal seeks to expand the use and improve the efficacy of a biological method for treatment of chronic wounds and their associated diseases. )


application_id: 8454713
project_number: 2R44GM093411-02
project_title: Enhancing mammalian glycoprotein production in the baculovirus expression vector
administering_ic: NIGMS
award_notice_date: 2012-09-24
opportunity_number: PA-12-088
application_type: 2
activity_code: R44
ic: GM
serial_number: 093411
program_official: MARINO, PAMELA
project_start_date: 2010-05-01
project_end_date: 2014-08-31
study_section: Special Emphasis Panel[ZRG1 IMST-J (15)]
contact_pi_person_id: 9710810
contact_pi: FATH-GOODIN, ANGELIKA
other_pis: GEISLER, CHRISTOPH
congressional_district: 06
department: Unavailable
primary_duns: 178801671
primary_uei: X99BTLBLJSK5
duns_number: 178801671
uei: X99BTLBLJSK5
fips: US
organization_id: 10009196
organization_name: PARATECHS CORP.
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405053322
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The baculovirus expression vector system (BEVS) is a proven powerful and versatile method of eukaryotic protein expression. It is used to produce vaccines diagnostics and biologically active proteins for a multitude of research projects. Like all expression systems however BEVS has its disadvantages. One is the fact that expression is short-lived due to virus-induced cell death and lysis. ParaTechs has already commercialized a product that addresses this shortcoming. Cell lines that express a viral ankyrin gene show delayed death and lysis of baculovirus-infected cells thereby significantly enhancing recombinant protein production. This activity referred to as vankyrin-enhanced BEVS (VE-BEVSTM) boosts target protein expression up to 22-fold. A second limitation of baculovirus expression is that insect cells lack the ability to produce terminally sialylated complex N-glycans which limits the usefulness of BEVS for the expression of human therapeutic proteins. GlycoBac LLC has developed a transgenic insect cell line (SfSWT4) that expresses six mammalian glycosylation enzymes allowing synthesis of terminally sialyated proteins. This Phase II proposal combines ParaTechs' VE technology with GlycoBac's cell line to optimize expression of "humanized" N-glycans. In Phase I the transgenic cell line SfSWT4 was transformed with several vankyrin genes under the control of different promoters. Polyclonal cells were screened for enhanced glycoprotein expression. Data demonstrating that infected cells lived longer and produced more authentically sialylated protein confirmed our hypothesis. Phase II will extend these studies by (1) cloning and characterization of VE-SWTTM cells according to FDA guidelines for cells used to produce vaccines and biological; (2) examining synergistic effects between VE virus vectors and VE-SWT cell lines to provide greater levels of enhancement; and (3) demonstrating enhanced expression of medically relevant glycoproteins in VE-SWTTM cells. These Phase II studies will significantly expand the applications of ParaTechs' VE-BEVS technology and GlycoBac's glycoengineered cell lines. Personnel at both companies have experience with the techniques to be used. Preliminary studies indicate that this technology has a significant chance of performing as envisioned. Furthermore prior marketing experience with transformed cell lines previously released from the two companies suggests a significant demand for the expanded technology. This new technology should be relatively easy to commercialize based on the established reputations of ParaTechs Inc. and GlycoBac LLC and the growing demand for improved cell lines to express recombinant humanized glycoproteins.   
   
PUBLIC HEALTH RELEVANCE: The inability of insect cells to produce terminally sialylated complex N-glycans limits the usefulness of the baculovirus expression system for the production of human therapeutic proteins. This proposal addresses that deficiency and aims to develop new cell lines that produce authentic "humanized" N-glycans in the context of ParaTechs' vankyrin-enhanced baculovirus technology. Successful completion of these objectives will produce cells that provide the highest levels of accurately processed secreted and transmembrane proteins and will be marketed to individual researchers and pharmaceutical companies engaged in structure-function studies of the human secretome and development of protein therapeutics.

project_terms:
Address;Alteplase;Ankyrins;Baculovirus Expression System;Baculoviruses;Biological;Cell Death;Cell Line;Cells;Cessation of life;Cloning;Complex;Cytolysis;Data;Development;Diagnostic;Disadvantaged;Engineering;Enzymes;Funding;Genes;Glycoproteins;Goals;Guidelines;Human;Human Resources;Individual;Influenza Virus Hemagglutinin Glycoproteins;Insecta;Integral Membrane Protein;Life;Marketing;Methods;Modeling;Pharmacologic Substance;Phase;Polysaccharides;Positioning Attribute;Process;Production;Promotor (Genetics);Property;Proteins;Recombinant Proteins;Recombinants;Research Personnel;Research Project Grants;Serum-Free Culture Media;Site;Structure;System;Techniques;Technology;Testing;Transformed Cell Line;Transgenic Organisms;United States National Institutes of Health;Vaccines;Viral;Virus;alpha 1-Antitrypsin;base;efficacy testing;experience;expression vector;glycosylation;improved;new technology;phase 2 study;protein expression;therapeutic protein;vector

public_health_relevance:
The inability of insect cells to produce terminally sialylated complex N-glycans limits the usefulness of the baculovirus expression system for the production of human therapeutic proteins. This proposal addresses that deficiency and aims to develop new cell lines that produce authentic "humanized" N-glycans in the context of ParaTechs' vankyrin-enhanced baculovirus technology. Successful completion of these objectives will produce cells that provide the highest levels of accurately processed secreted and transmembrane proteins and will be marketed to individual researchers and pharmaceutical companies engaged in structure-function studies of the human secretome and development of protein therapeutics.


application_id: 8454519
project_number: 5R01CA137052-05
project_title: Identifying candidate modifier elements of a breast cancer risk associated allele
administering_ic: NCI
award_notice_date: 2013-05-01
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 137052
program_official: SHARMAN, ANU
project_start_date: 2009-05-08
project_end_date: 2014-04-30
study_section: Cancer Genetics Study Section[CG]
contact_pi_person_id: 6825342
contact_pi: SAMUELSON, DAVID J
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Identifying candidate modifier elements of a breast cancer risk associated allele Project Summary/Abstract: A woman's risk of developing breast cancer is influenced by genetic epigenetic and environmental factors. Up to 30-40% of the risk of developing breast cancer is likely to be inherited. Breast cancer genetics is complex. The factors controlling disease risk are high penetrant genes with risk alleles that are low in population frequency and low penetrant modifier genes with risk associated alleles that are common in the population. Most of the genetic variation in breast cancer risk is unaccounted and the majority of the genes influencing susceptibility to breast cancer are likely controlled by common genetic variation. The common single nucleotide polymorphism (SNP) rs889312 marks a low penetrant breast cancer risk associated allele on human chromosome 5 (Nature 447 2007). The breast cancer risk associate gene and causal polymorphisms at this locus have not been identified. The human region is orthologous to rat mammary carcinoma susceptibility QTL Mcs1b. The rat Mcs1b locus has been narrowed to 1.2 Mb using congenics. These experiments used the Wistar Furth (WF) strain which is highly susceptible to 712- dimethylbenz[a]anthracene (DMBA)-induced mammary carcinomas as the genetic background. The Mcs1b Copenhagen (COP) allele on a WF background conferred a 60% reduction in DMBA-induced mammary carcinoma development to WF.COP congenics that were COP-homozygous and a 30% reduction to congenics that were COP/WF-heterozygous at Mcs1b. The objective of the proposed work is to use systems genetics in a model organism to identify quality candidate breast cancer risk genetic elements. This will be accomplished through the following specific aims: aim 1: fine map rat Mcs1b to a genomic interval less than 0.5 Mb by testing additional congenic lines carrying shorter segments of the Mcs1b locus as currently defined; aim 2: determine if the Mcs1b COP allele acts in an autonomous manner within the mammary gland by conducting rat mammary gland transplant experiments; and aim 3: identify and evaluate breast cancer candidate genes/genetic elements within rat Mcs1b by determining potential candidates and testing each to identify quality candidates. The final aim will be completed in stages that will incorporate comparative genomics genetic and expression analyses resequencing and in vitro and in vivo validation of candidates.

project_terms:
910-Dimethyl-12-benzanthracene;Alleles;Animal Model;Anthracenes;Area;Automobile Driving;BRCA1 gene;BRCA2 gene;Basic Research Breast Cancer;Biological Assay;Biological Models;Breast Cancer Genetics;Breast Cancer Model;Breast Cancer Prevention;Breast Carcinoma;Candidate Disease Gene;Cause of Death;Chromosomes Human Pair 2;Chromosomes Human Pair 5;Complex;DNA Resequencing;Development;Disease;Elements;Environmental Risk Factor;Epigenetic Process;Frequencies (time pattern);Functional RNA;Genes;Genetic;Genetic Markers;Genetic Models;Genetic Polymorphism;Genetic Predisposition to Disease;Genomics;Goals;Health;Human;Human Chromosomes;In Vitro;Inbred Strains Rats;Inbreeding;Incidence;Individual;Inherited;Intercistronic Region;Knowledge;Lead;Location;Malignant Neoplasms;Mammary Tumorigenesis;Mammary gland;Maps;Modeling;Molecular Genetics;Molecular Target;Mortality Vital Statistics;Nature;PTPRJ gene;Phenotype;Population;Predisposition;Principal Investigator;Quantitative Trait Loci;Rat-1;Rattus;Recombinants;Research;Research Project Grants;Risk;STAT5a Transcription Factor;Single Nucleotide Polymorphism;Staging;Susceptibility Gene;System;Testing;Transgenic Model;Translating;Transplantation;Variant;Variation (Genetics);Woman;Work;abstracting;aged;anticancer research;cancer prevention;cancer risk;candidate validation;comparative;comparative genomics;congenic;disorder risk;genetic analysis;genetic element;genome wide association study;in vivo;knockout gene;malignant breast neoplasm;novel;novel strategies;rat genome;research study

public_health_relevance:
Breast cancer is a complex disease and the leading cause of death by cancer in US women aged 20- 59 years. Most common susceptibility genes and molecular genetic mechanisms contributing to breast cancer susceptibility are unknown. To work toward decreasing the incidence and mortality due to breast cancer basic research toward better understanding of the genetic etiology of this complex disease is warranted. The proposed research uses a comparative genetic approach to accomplish this and may also identify novel potential targets for breast cancer prevention.


application_id: 8452236
project_number: 5F31DA032496-02
project_title: Prolonged activation of endogenous opioid analgesia after inflammation
administering_ic: NIDA
award_notice_date: 2013-02-19
opportunity_number: PA-11-112
application_type: 5
activity_code: F31
ic: DA
serial_number: 032496
program_official: BABECKI, BETH
project_start_date: 2012-03-01
project_end_date: 2013-08-04
study_section: Special Emphasis Panel[ZRG1-F02B-M(20)L]
contact_pi_person_id: 10742197
contact_pi: CORDER, GREGORY
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): Peripheral tissue inflammation can lead to maladaptive plasticity in the spinal cord and brain which contributes to persistent pain. The intensity and quality of pain is determined by the net balance between the activities of pronociceptive systems with compensatory endogenous inhibitory systems namely spinal opioid signaling. Interestingly a small set of studies indicate that endogenous opioid inhibition f acute nociception persists even after the initial signs of hyperalgesia have subsided. For example opioid receptor antagonists reinstate allodynia. This raises two intriguing questions. First opioid receptor subtypes and neural circuits remain unclear. Second does a latent nociceptive sensitization persist in the absence of overt behavioral signs of hypersensitivity? My preliminary data show that naltrexone when intrathecally administered weeks to months after intraplantar CFA reinstated behavioral signs of hypersensitivity and induced dorsal horn ERK phosphorylation. Both were blocked by spinal antagonism of NMDA receptors. My central hypothesis is that peripheral inflammation induces prolonged signaling of CNS opioidergic-circuits (Aim 1) that mask pronociceptive NMDA and AMPA signaling (Aim 2). This F31 proposal attempts to better characterize the mechanisms that underlie the latent sensitization that is masked by endogenous opioid activity. Aim 1 tests the hypothesis that spinal opioidergic signaling tonically masks nociceptive sensitization. Aim 1A investigates - - and ?-opioid receptor subtypes with the use of selective antagonists. Aim 1B and 1C test mechanisms of constitutive receptor signaling and tonic opioid release with the use of ex vivo spinal cord slice GTP ?S35 binding assay and intrathecal sequestering opioid peptide antiserum respectively. Aim 1D tests the hypothesis that opioid receptor blockade disinhibits tonic afferent nociception. In Aim 2 I will test the idea that glutamatergic signaling drives the hypersensitivity that follows spinal opioid receptor blockade with a focus on spinal NMDA (Aim 2A) and AMPA/kainate-receptors (Aim 2B). By better understanding long-lasting opioid antinociception this project could pave the way for future strategies to enhance endogenous opioid analgesia in humans with chronic pain and thus has the long-term potential to reveal novel targets to prevent the transition for acute to chronic pain. This F31 award will help me achieve my goals that will enable me to successfully compete for strong post-doctoral positions and ultimately a successful career in research science and teaching beginning with a tenure-track position in a strong medical research university environment:

project_terms:
6-Cyano-7-nitroquinoxaline-23-dione;Absence of pain sensation;Acute;Afferent Neurons;Agonist;Animal Model;Animals;Antibodies;Attenuated;Behavior;Behavioral;Binding (Molecular Function);Biological Assay;Brain;CTOP;Coupling;Cutaneous;Data;Dose;Dynorphins;Educational process of instructing;Endogenous Opiates;Enkephalins;Environment;Equilibrium;Female;Freund's Adjuvant;Future;GTP-Binding Proteins;Glutamates;Goals;Guanosine Triphosphate;Heating;Human;Hyperalgesia;Hypersensitivity;Immune Sera;Inflammation;Inflammatory;Injection of therapeutic agent;Injury;Intrathecal Injections;Kainic Acid Receptors;Lead;Light;Local anesthesia;Masks;Mechanics;Mediating;Medical Research;Mus;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;NMDA receptor antagonist;Naltrexone;Neurons;Neurotransmitters;Nociception;Opioid;Opioid Peptide;Opioid Receptor;Pain;Pain quality;Pathway interactions;Peptides;Peripheral;Persistent pain;Phosphorylation;Positioning Attribute;Postdoctoral Fellow;Predoctoral Individual National Research Service Award;Presynaptic Terminals;Receptor Signaling;Research;Resolution;Science;Sensory Thresholds;Signal Transduction;Slice;Spinal;Spinal Anesthesia;Spinal Cord;Stimulus;Synapses;System;Testing;Therapeutic;Tissues;Touch sensation;Universities;allodynia;attenuation;career;central sensitization;chronic pain;design;dorsal horn;endomorphin 1;inflammatory pain;injured;kainate;male;meetings;naltrindole;neural circuit;neuronal excitability;norbinaltorphimine;novel;prevent;receptor;response;sciatic nerve;stressor;transmission process

public_health_relevance:
Sensitization of pain pathways in the setting of tissue inflammation leads to a state of hypersensitivity that is counteracted by compensatory endogenous inhibitory systems. This project aims to understand the mechanisms by which the spinal opioid system masks long-lasting glutamatergic sensitization. Therapeutic strategies designed to enhance this endogenous opioid signaling may reduce the occurrence of persistent pain.


application_id: 8452094
project_number: 5T32HL072743-10
project_title: Interdisciplinary Cardiovascular Training Program
project_terms: Cardiovascular system;Training Programs
administering_ic: NHLBI
award_notice_date: 2013-05-13
opportunity_number: PA-08-226
application_type: 5
activity_code: T32
ic: HL
serial_number: 072743
program_official: SCOTT, JANE
project_start_date: 2004-04-01
project_end_date: 2014-06-30
study_section: NHLBI Institutional Training Mechanism Study Section[NITM]
contact_pi_person_id: 1887495
contact_pi: RANDALL, DAVID C
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
This training program offers pre-doctoral trainees a breadth of exposure and a depth of expertise to acquirethe essential aptitudes and tools to thrive in an aggressive cardiovascular research environment. Ourspecific goals are to:(a) provide rigorous state-of-the-art education in basic sciences of the cardiovascularsystem; (b) provide training in ethical conduct of research; (c) facilitate translational science by providing ourtrainees with the requisite tools and experience to compete in this arena; and (d) create future "citizens ofscience" by fostering an environment that promotes advocacy of research with highest ethical standards. Wepropose to train 5 pre-doctoral fellows and 4 Summer Minority Scholars. Our training faculty composed of30 scientists are all extramurally funded with laboratories well suited to train young scientists and withexcellent training records. The highly collaborative training faculty will implement a structured programcovering the areas of cardiac hypertrophy and heart failure arrhythmogenesis central nervous control ofcardiovascular function and vascular biology with a focus on mechanisms of atherosclerosis abdominalaortic aneurysms and thrombosis. This breadth of cardiovascular research opportunities for fellows issupported and enhanced by strong links to the Cardiovascular Research Center and the Gill Heart Institute.A multidisciplinary training faculty represent the combined resources of 11 academic departments in 3Colleges and 3 Centers providing both faculty and students a rich environment within which to work andinteract and opportunities for translational research. The curriculum exposes students to essentialknowledge ranging from molecules to the integrated physiology of the whole organism with numerousopportunities for in-depth study of focused areas of cardiovascular function. An important feature of ourprogram is the development of new vehicles to train fellows in techniques of translational research.Moreover our successful minority recruitment program will continue to promote diversity within our trainingprogram. Finally the University of Kentucky strategic plan targets the cardiovascular sciences for focuseddevelopment optimizing the environment for the training of superbly-equipped young scientists.RELEVANCE (See instmctions):The ultimate basis for this training program is the continuing dearth of well-trained investigators in thecardiovascular sciences relative to the needs of American society for improved cardiovascular disease(CVD) prevention and treatment. Research by well-trained scientists and clinicians such as we will trainshows continued promise for improvement of the cardiovascular health of Americans.


application_id: 8452093
project_number: 5R01AI048850-10
project_title: Fatty Acid Binding Proteins in Macrophage Function
administering_ic: NIAID
award_notice_date: 2013-04-04
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AI
serial_number: 048850
program_official: PEYMAN, JOHN A
project_start_date: 2003-04-01
project_end_date: 2015-04-30
study_section: Innate Immunity and Inflammation Study Section[III]
contact_pi_person_id: 1882106
contact_pi: SUTTLES, JILL
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Fatty acid binding proteins FABPs have been identified as central regulators of both metabolic and inflammatory pathways.  FABPs act as intracellular receptors for a variety of hydrophobic compounds enabling their diffusion within the cytoplasmic compartment.  We have shown that adipocyte FABP (A-FABP) and epithelial FABP (E-FABP) regulate macrophage cholesterol trafficking and inflammatory function in part via regulation of the activity of the peroxisome proliferator-activated receptor (PPAR-?).  Macrophages and dendritic cells (DC) from FABP- deficient mice are defective in expression of proinflammatory cytokines and are inefficient in the promotion of proinflammatory T cells responses during antigen presentation.  FABP-deficient mice are protected from development of experimental autoimmune encephalomyelitis (EAE). Overall the results of our research suggest that FABPs regulate a molecular switch between metabolic and inflammatory pathways in macrophages and DC and as a consequence regulate both innate and adaptive immune responses.  We will continue our studies of these proteins through the pursuit of the following specific aims: Specific Aim 1 is to identify the molecular mechanism(s) by which FABPs affect inflammatory cytokine gene expression in macrophages and DC.  We have found that FABP-deficiency is accompanied by elevated activity of AMP- activated protein kinase (AMPK) and that AMPK is a negative regulator of macrophage inflammatory function.  Experiments will be performed to determine the link between FABPs AMPK and PPAR-? testing the hypothesis that FABP regulation of energy stores regulates AMPK activity which in turn modulates inflammatory activity.  Specific Aim 2 is to further delineate the impact of FABP-deficiency on autoimmune disease using EAE as a model.  This aim will include an evaluation of the specific contributions of T cell priming and of the tissue environment towards the protection from EAE displayed by FABP-deficient mice.  In this aim we will also test the in vivo efficacy of inhibitors of FABPs as an anti-inflammatory therapy using the EAE model.  Specific Aim 3 is to test the hypothesis that the expression of FABPs links dietary fat intake with exacerbated inflammatory disease. We will evaluate the effects of fat intake on FABP expression in leukocyte populations and the association of diet-induced FABP expression with inflammatory responsiveness.  The completion of these studies will provide a more comprehensive understanding of how FABPs regulate immune and inflammatory responses.

project_terms:
5'-AMP-activated protein kinase;AMP-activated protein kinase kinase;Adipocytes;Adipose tissue;Affect;Anti-Inflammatory Agents;Anti-inflammatory;Antigen Presentation;Autoimmune Diseases;Autoimmune Process;Automobile Driving;Brain;Cells;Chronic;Cytokine Gene;Data;Dendritic Cells;Development;Diet;Dietary Fats;Diffusion;Disease;Environment;Epithelial;Evaluation;Exhibits;Experimental Autoimmune Encephalomyelitis;Fatty acid glycerol esters;Gene Expression;Genes;Glycogen Synthase Kinases;Goals;Health;Human;Hydroxymethylglutaryl-CoA reductase;IL2RA gene;Immune response;Infiltration;Inflammation;Inflammatory;Inflammatory Response;Intake;Interferons;Interleukin-17;Leukocytes;Link;Lipids;Metabolic;Modeling;Molecular;Mus;Non-Insulin-Dependent Diabetes Mellitus;Nuclear;Obesity;Pathway interactions;Peroxisome Proliferator-Activated Receptors;Play;Population;Production;Protein Deficiency;Proteins;Regulation;Research;Role;Spinal Cord;T cell response;T-Lymphocyte;Testing;Tissues;Transcriptional Activation;Wild Type Mouse;Work;base;cholesterol trafficking;cytokine;disorder risk;fatty acid-binding proteins;feeding;in vivo;inhibitor/antagonist;mTOR protein;macrophage;protein expression;protein function;public health relevance;receptor;research study;response;small molecule;transcription factor

public_health_relevance:
Project NarrativeFatty acid-binding proteins (FABPs) have been shown to play a role in obesity and Type 2diabetes.  This proposal is based on studies demonstrating that FABPs also strongly promoteinflammation and contribute to autoimmune inflammatory disease.  The goals of the project areto determine the mechanisms by which FABPs regulate inflammatory function in leukocytes andto test the hypothesis that FABPs constitute an accessible and effective target for treatment ofinflammatory disease.  Given the recent identification of small molecule inhibitors of FABPfunction this project has direct relevance to human health.


application_id: 8452036
project_number: 1R43HL114204-01A1
project_title: Crosslink augmentation to resist snoring and obstructive sleep apnea syndrome
administering_ic: NHLBI
award_notice_date: 2013-06-04
opportunity_number: PA-12-088
application_type: 1
activity_code: R43
ic: HL
serial_number: 114204
suffix: A1
program_official: TWERY, MICHAEL
project_start_date: 2013-06-05
project_end_date: 2015-01-31
study_section: Special Emphasis Panel[ZRG1 CVRS-H (11)]
contact_pi_person_id: 6575299
contact_pi: HEDMAN, THOMAS P
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 602492451
duns_number: 602492451
fips: US
organization_id: 10009769
organization_name: ORTHOPEUTICS, LP
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 405111285
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2013-06-05
project_abstract:
DESCRIPTION (provided by applicant):  Snoring is a condition that affects people of all ages with a reported prevalence of up to 48% of men and 34% of women. Snoring poses not only an inconvenience with regard to sleep-cycle disruption of the sufferer's bed partner and family but it can also lead to sleep-deprivation in the sufferer and to a more serious and sometimes life-threatening condition obstructive sleep apnea syndrome (OSAS) where breathing is interrupted during sleep by physical obstruction of the airway. Prevalence of OSAS in the United States has been estimated at 4.2% for those aged 16 and older or approximately 10 million individuals. Both snoring and OSAS are in most cases the result of obstructed airflow due to abnormalities in the geometry of the air passages and the propensity for aberrant deformation of the soft palate. Repeated trauma to the soft palate due to snoring can be expected to increase its passive deformability and damage muscle fibers and peripheral nerve fibers increasing the tendency for obstruction. Thus treatment of snoring can play an important role in reducing the incidence of OSAS. Current treatments include surgery the use of oral appliances and more recently minimally invasive procedures targeted at stiffening the soft palate. All of the newer procedures rely to some extent on the formation of fibrotic scar tissue to stiffen the soft palate.
This fibrotic tissue can be expected to exhibit inferior mechanical properties and loss of structural integrity leading to the eventual loss of some initial treatment-related benefits. This
Phase I study aims to determine feasibility of injecting non-toxic protein crosslinking agents to stiffen the soft palate without producing scar tissue. Previous testing suggests that this technique can augment the soft palate's mechanical properties reduce vibration and concomitantly increase resistance to mechanical degradation. The overall aim of this program will be to commercialize a less expensive faster (same-day benefit) and superior injectable treatment for the reduction of snoring prevention of OSAS and reduction of airway collapse. Feasibility will be evaluated in four parts: 1) the ability of crosslinking agents to improve the mechanical properties and increase the resistance to mechanical degradation of soft palate tissue will be tested; 2) a wind tunnel test system will be developed to measure the vibration magnitude and oscillation frequency of horse soft palates; 3) the wind tunnel will be used to quantify reduction of vibration in horse soft palates following preferred crosslinker injections; ad 4) safety and treatment effect will be evaluated in pilot studies involving treatment of soft palats in normal horses and horses diagnosed with dorsal displacement of the soft palate (DDSP) which involves a form of awake snoring and apnea.

project_terms:
Address;Affect;Age;Air;Airway Obstruction;Animals;Apnea;Architecture;Beds;Biomechanics;Breathing;Cicatrix;Connective Tissue;Crosslinker;Data;Diagnosis;Dorsal;Environmental Wind;Equus caballus;Euthanasia;Exhibits;Failure (biologic function);Family;Fatigue;Feasibility Studies;Fibrosis;Flaccid Muscle Tone;Frequencies (time pattern);Human;In Vitro;Incidence;Individual;Inferior;Injectable;Injection of therapeutic agent;Investigation;Lead;Life;Measures;Mechanics;Modeling;Muscle Fibers;Nerve Fibers;Obstruction;Obstructive Sleep Apnea;Operative Surgical Procedures;Oral;Palate;Peripheral Nerves;Phase;Physiological;Pilot Projects;Plastics;Play;Prevalence;Prevention;Procedures;Property;Reporting;Resistance;Role;Safety;Schedule;Severities;Sleep;Sleep Deprivation;Small Business Innovation Research Grant;Snoring;Soft Palate;Specimen;System;Techniques;Technology;Testing;Tissues;Trauma;United States;Woman;aged;awake;base;crosslink;improved;in vivo;men;minimally invasive;phase 1 study;phase 2 study;programs;protein crosslink;public health relevance;resilience;success;treatment effect;vibration

public_health_relevance:
Snoring is a highly prevalent condition that can lead to sleep-deprivation in the sufferer and to a more serious and sometimes life-threatening condition obstructive sleep apnea syndrome (OSAS) where breathing is interrupted during sleep by physical obstruction of the airway. Current treatments for snoring and OSAS include surgery the use of oral appliances and more recently minimally invasive procedures directed at stiffening the soft palate all of which rely on the formation of mechanically inferior scar tissue We propose to investigate a less expensive injectable agent which we believe based on previous studies can improve the soft palate's mechanical properties reduce vibration and concomitantly increase resistance to mechanical degradation for the reduction of snoring prevention of OSAS and reduction of airway collapse.


application_id: 8451595
project_number: 5K23AA018399-04
project_title: Zinc supplementation in alcoholic cirrhosis
administering_ic: NIAAA
award_notice_date: 2013-04-03
opportunity_number: PA-09-043
application_type: 5
activity_code: K23
ic: AA
serial_number: 018399
program_official: WANG, JOE
project_start_date: 2010-04-01
project_end_date: 2015-03-31
study_section: Biomedical Research Study Section[AA-1]
contact_pi_person_id: 9367804
contact_pi: CAVE, MATTHEW C
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This K23 application will enable Matthew Cave M.D. to achieve his goal of becoming an independent investigator focusing on clinical and translational research in alcoholic liver disease (ALD) and nutrition. Dr. Cave will conduct a mechanistic study evaluating the effects of zinc sulfate therapy in patients with alcoholic cirrhosis (AC). Highlights of Dr. Cave's career development plan include: (i) obtaining a Master of Science degree in Interdisciplinary Studies (I-MS) focusing on toxicology clinical trial design and biostatistics and (ii) board certification in nutrition (ABPNS). These activities will occur in the setting of the recently funded University of Louisville Alcohol Research Center (P01) and will be monitored quarterly by an advisory committee. An estimated two million Americans have ALD and there are no FDA approved medications for any stage of ALD. Our preliminary data document (i) zinc deficiency in human subjects with AC and (ii) improvement in liver injury and in postulated mechanisms of liver injury with zinc supplementation in murine models. Our hypothesis is that zinc sulfate therapy will result in improvement in mechanisms postulated to play a role in the development and progression of human AC. To test this hypothesis we will perform a randomized double blind placebo-controlled "drop in" mechanistic study of zinc sulfate 220 mg daily in 30 subjects with Child-Pugh A-B AC for 24 months. The primary endpoints are reduction in (i) serum endotoxemia and (ii) ex vivo basal and endotoxin-stimulated TNF1 production. Secondary endpoints are (i) improved serum zinc status (ii) increased intestinal tight junctions with decreased permeability (iii) improved serum pro-inflammatory cytokine profile (iv) reduced oxidative stress and improved serum antioxidant status (v) reduced hepatocyte death (vi) decreased fibrosis and (vii) improved clinical status. These studies utilize state- of-the art techniques in a translational approach to develop an enhanced understanding of a potential new therapy for AC.

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

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


application_id: 8451396
project_number: 5K01DK080951-05
project_title: Endoplasmic Reticulum-Induced Stress and Apoptosis in the Renal Tubule
administering_ic: NIDDK
award_notice_date: 2013-03-18
opportunity_number: PA-06-001
application_type: 5
activity_code: K01
ic: DK
serial_number: 080951
program_official: RANKIN, TRACY L
project_start_date: 2009-04-01
project_end_date: 2015-03-31
study_section: Kidney, Urologic and Hematologic Diseases D Study Section[DDK-D]
contact_pi_person_id: 9091714
contact_pi: BARATI, MICHELLE T
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 candidate's overall career goal is to establish an independent research program devoted to investigating cellular mechanisms of proteinuric nephropathies with an emphasis on diabetic nephropathy (DN). Currently DN is the leading cause of end stage renal disease in the United States. Proteinuria is an independent risk factor critical to pathogenesis and progression of renal function loss. Regardless of disease origin renal tubule function is critical to the progression of renal damage and development of renal failure. The precise molecular mechanisms and targets of proteinuria and hyperglycemia causing tubule damage in DN remain unclear. This emphasizes the health-related importance for discovery of novel regulatory events as potential therapeutic targets. The endoplasmic reticulum (ER) stress response induced by accumulation of misfolded proteins in the ER is a mechanism elicited by cells to alleviate stress through induction of specific genes. Unresolved ER stress response leads to ER stress-induced apoptosis. Initial studies from our laboratory demonstrate induction of ER stress and ER stress-induced apoptosis in tubules of proteinuric diabetic mice. This suggests the hypothesis that ER stress is pathogenic in renal tubule damage in DN. This project will define the role of proteinuria and hyperglycemia alone and in combination to tubule ER stress and apoptosis in a transgenic mouse model of type I diabetes. Next cell signaling events mediating tubule ER stress and apoptosis induction in DN will be examined. To accomplish this the candidate will be trained in development of speed congenic transgenic mice. In addition the candidate will be trained in protein purification mass spectrometry and informatic techniques to define interactions in protein complexes mediating ER stress. Finally the candidate will receive training in advanced molecular biology techniques to define the specific role of proteins involved in stress response to tubule cell function. The combination of training obtained during this award coupled to the identification of molecular events mediating tubule damage in DN will enable the candidate with resources to continue and expand research pertaining to DN.

project_terms:
Address;Albumins;Apoptosis;Award;Calcium;Cell physiology;Cells;Coupled;Data;Defect;Development;Diabetes Mellitus;Diabetic Nephropathy;Diabetic mouse;Disease;End stage renal failure;Endoplasmic Reticulum;Event;Functional disorder;Generations;Genes;Glucose;Goals;Growth Factor;Health;Homeostasis;Hyperglycemia;Induction of Apoptosis;Informatics;Insulin-Dependent Diabetes Mellitus;Islet Cell;Kidney;Kidney Diseases;Kidney Failure;Laboratories;Lead;Lesion;Mass Spectrum Analysis;Mediating;Molecular;Molecular Biology Techniques;Molecular Chaperones;Mus;Neurodegenerative Disorders;Oxidative Stress;Pathogenesis;Permeability;Play;Process;Protein Export Pathway;Protein Synthesis Induction;Proteins;Proteinuria;Puromycin;Quality Control;Rattus;Reactive Oxygen Species;Renal function;Renal tubule structure;Research;Resources;Risk Factors;Role;Signal Transduction;Speed (motion);Stimulus;Stress;Techniques;Testing;Training;Transgenic Mice;Tubular formation;United States;biological adaptation to stress;career;congenic;cytokine;diabetic;endoplasmic reticulum stress;mouse model;neuron loss;novel;outcome forecast;programs;protein complex;protein misfolding;protein purification;public health relevance;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Currently DN is the leading cause of end stage renal disease in the United States. Proteinuria is an independent risk factor critical to pathogenesis and progression of renal function loss. The precise molecular mechanisms and targets of proteinuria and hyperglycemia causing tubule damage in DN remain unclear. This emphasizes the importance for discovery of novel regulatory events as potential therapeutic targets.


application_id: 8451272
project_number: 5R01CA084374-14
project_title: STUDIES ON CALICHEAMICIN BIOSYNTHESIS AND SELF RESISTANCE
administering_ic: NCI
award_notice_date: 2013-05-01
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 084374
program_official: FU, YALI
project_start_date: 2000-05-01
project_end_date: 2015-04-30
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
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): Natural products (NPs) and NP derivatives are an unrivaled but highly under-represented resource. Arguably among the most notable natural products discovered to date the 10-membered enediynes - exemplified by the saccharide-fused calicheamicins (CLM) and the anthraquinone-fused dynemicins (DYN) - offer unprecedented molecular architecture spectacular biological activity and demonstrated clinical utility. The objective of the first phase of this study (CA84374 years 1-4) was to i) clone and characterize the CLM gene cluster from M. echinospora ii) develop the genetic tools to address CLM biosynthesis in M. echinospora iii) investigate the mechanism(s) of CLM self-resistance and iv) initiate aryltetrasaccharide biosynthetic studies. With these goals largely achieved and new tools/information in place the second phase of this program (CA84374 years 5-9) was focused upon i) cloning and characterization of the DYN gene cluster from M. chersina ii) development of genetic tools to address DYN biosynthesis in M. chersina iii) initiating enediyne core biosynthetic studies iv) structurally characterization of the CLM self-sacrifice resistance protein CalC and v) the elucidation of key aryltetrasaccharide biosynthetic transformations (sugar N-oxidation thiosugar formation and GT-catalyzed aryltetrasaccharide assembly). The successful completion of the majority of phase II aims enables the proposed course of study for this competitive renewal. Specifically we will focus upon i) extending our understanding of enediyne core biosynthesis ii) delineating the potential role of CalC in regulating CLM production in M. echinospora iii) completing the study of key aryltetrasaccharide sugar nucleotide transformations (sulfur installation and sequential C-C alkylation of the N-alkyl dideoxypentose) iv) initiating an enediyne structural biology program and v) synthesizing and evaluating (neo)glycorandomized libraries of CLM and DYN.

project_terms:
Address;Alkylation;Anabolism;Anthraquinones;Architecture;Biochemical;Biological;Biological Factors;Chemicals;Chemistry;Clinical;Cloning;Complex;Coupled;Crystallization;DNA;DNA Binding Domain;Development;Dynemicin;Enzymes;Escherichia coli;Evaluation;Fermentation;Gene Cluster;Gene Proteins;Gene Silencing;Genetic;Goals;In Vitro;Lead;Libraries;Molecular;Participant;Phase;Production;Proteins;Recombinants;Resistance;Resources;Role;Sensory;Series;Solubility;Specificity;Structure;Sulfur;analog;assay development;catalyst;glycosylation;glycosyltransferase;in vitro Assay;in vivo;novel;oxidation;programs;protein expression;public health relevance;research study;structural biology;structural genomics;sugar;sugar nucleotide;thiosugar;tool

public_health_relevance:
This is a second competitive renewal of a productive program ((CA84374) targeting the biosynthesis of 10-membered enediynes (calicheamicin and dynemicin) - a novel class of anticancer natural products. The program is anticipated to provide pioneering discoveries in enzyme-catalyzed chemistries new tools for the chemical diversification of complex natural products and unique anticancer lead compounds.


application_id: 8450228
project_number: 5R01ES017260-05
project_title: Atherogenic Mechanisms of Arsenic
administering_ic: NIEHS
award_notice_date: 2013-06-06
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: ES
serial_number: 017260
program_official: CARLIN, DANIELLE J
project_start_date: 2009-06-15
project_end_date: 2015-03-31
study_section: Special Emphasis Panel[ZRG1-DIG-C(90)S]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this project is to understand the mechanisms by which exposure to arsenic accelerates or aggravates atherosclerosis. Exposure to arsenic-contaminated water is a global problem and results in the manifestation of multiple cardiovascular symptoms including hypertension stroke and myocardial infarction. Increased atherosclerosis is likely to be the major underlying cause of the increased risk of cardiovascular disease in an arsenic-exposed population. Accordingly the intent of this proposal is to understand the mechanism by which arsenic accelerates or exacerbates atherogenesis in a well-controlled animal model. On the basis of supportive preliminary evidence our central hypothesis is that arsenic promotes atherogenic changes in endothelial cells and in macrophages by inducing endoplasmic reticulum (ER) stress which in turn triggers the unfolded protein response (UPR). To test this hypothesis we will: (1) delineate the contribution of ER stress and UPR to arsenic-mediated endothelial cell and macrophage activation; (2) examine the progression of atherogenesis in arsenic-exposed mice; and (3) elucidate the role of UPR in exacerbation of atherogenesis by arsenic. To accomplish these aims we will examine whether exposure to arsenic induces ER stress and triggers UPR in endothelial cells and macrophages. We will identify which aspects of the UPR are triggered by arsenic and whether ER stress contributes to arsenic-induced activation of endothelial cells and foam cell formation. To assess how arsenic affects atherogenesis we will examine early intermediate and advanced lesions for lipid accumulation cellularity inflammation and oxidative stress in apoE-null mice exposed to arsenic. Bone marrow transplants from arsenic-exposed to non-exposed mice will be performed to delineate the specific contribution of macrophages to arsenic toxicity. To identify the in vivo role of UPR in arsenic toxicity we will examine which components of ER stress and UPR are activated in the lesions of arsenic-exposed animals and whether inhibition of the adaptive phase of UPR by deleting the ATF3 gene accelerates or treatment with chemical chaperones of protein folding inhibits lesion formation. Results of this project may lead to a better understanding of the mechanisms by which arsenic affects atherogenesis and how they could be therapeutically prevented.

project_terms:
Ablation;Affect;Animal Model;Animal Testing;Animals;Apolipoprotein E;Apoptosis;Arsenic;Arterial Fatty Streak;Arteriosclerosis;Asia;Asses;Atherosclerosis;Blood;Bone Marrow;Bone Marrow Transplantation;Calcium;Cardiovascular Diseases;Cardiovascular system;Carotid Atherosclerotic Disease;Cause of Death;Cell Adhesion Molecules;Cell Death;Cellularity;Cessation of life;Chemicals;Chronic;Collagen;Control Animal;Cytokine Activation;Disease;Endoplasmic Reticulum;Endothelial Cells;Epidemiologic Studies;Exposure to;Foam Cells;Foot Diseases;Genes;Genetic;Goals;Health;Human;Hypertension;Infant;Inflammation;Inflammatory;Ingestion;Knockout Mice;Laboratories;Lead;Lesion;Lipids;Macrophage Activation;Matrix Metalloproteinases;Measures;Mediating;Mitogen-Activated Protein Kinases;Modeling;Molecular;Molecular Chaperones;Mothers;Mus;Myocardial Infarction;Myocardial Ischemia;Oxidative Stress;Pathway interactions;Peripheral arterial disease;Phase;Population;Process;Production;Proteins;Risk Factors;Role;Signal Transduction;Smooth Muscle Myocytes;Staging;Stress;Symptoms;T-Lymphocyte;Testing;Toxic effect;Vascular Endothelial Cell;Water;activating transcription factor;activating transcription factor 3;arterial lesion;atherogenesis;base;biological adaptation to stress;cardiovascular disorder risk;chemokine;cytokine;design;drinking water;endoplasmic reticulum stress;exposed human population;high risk;in vivo;macrophage;novel;prevent;protein folding;response;stroke;transcription factor

public_health_relevance:
Large sections of human population in the US as well as Asia are exposed to high levels of arsenic in drinking water. Previous epidemiological studies show that people exposed to high levels of arsenic have a higher risk of developing cardiovascular disease. Nevertheless the mechanisms by which arsenic elevates cardiovascular disease risk are not known. This project is designed to mimic human exposures to arsenic in an animal model and test whether exposure to arsenic increases the rate and/or the extent of atherosclerotic lesion formation in atherosclerosis-prone mice. The project seeks to understand the underlying molecular mechanisms by which arsenic increases atherosclerosis; which processes are affected; and which cellular and molecular mechanisms mediate the cardiovascular toxicity of arsenic. Results obtained from this project are likely to provide novel models for testing atherogenic effects of arsenic exposure in developing a better understanding of how arsenic worsens atherosclerosis and how the atherogenic effects of arsenic could be ameliorated and treated.


application_id: 8450127
project_number: 5T35DK072923-08
project_title: Summer Endocrine Research Training Program
administering_ic: NIDDK
award_notice_date: 2013-07-05
opportunity_number: PA-08-227
application_type: 5
activity_code: T35
ic: DK
serial_number: 072923
program_official: PODSKALNY, JUDITH M,
project_start_date: 2006-05-01
project_end_date: 2016-04-30
study_section: Diabetes, Endocrinology and Metabolic Diseases B Study Section[DDK-B]
contact_pi_person_id: 1888054
contact_pi: KLINGE, CAROLYN M.
other_pis: Not Applicable
congressional_district: 03
department: BIOCHEMISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This is a competing renewal of NIH 5 T35 DK072923 which was originally funded for five years with 6 students supported/year. The principal objectives of the Summer Endocrine Research Training Program are to provide research experience for medical students and to stimulate interest among medical students in becoming clinical research scientists. Trainees engage in research activities with faculty members and participate in projects that are germane to the field of endocrinology and the health concerns of this country. Over the past 3 years we have trained 18 second year medical students who participated in our "Summer Endocrine Research Training Program" research programs in Endocrinology Metabolism and Diabetes at University of Louisville School of Medicine and as this application is submitted 6 new second year medical students will begin their summer research in this program. Approximately 25% of our trainees are members of minority populations and 1/3rd of trainees are female. Our program includes didactic instruction ("Summer Endocrine Research Training Seminar Series" and "Bench-to-Bedside: Introduction to Clinical Research") as well as a hands-on-research experience under the direction of a team of experienced basic and clinical research scientists centered on a core of NIDDK-funded investigators and collaborating faculty. Trainees also attend Endocrine-specific seminars and journal clubs in basic and clinical research. The present application addressses 2 Specific Aims: Aim 1: To provide hands-on training in basic and clinical Endocrine-based research to medical students in a structured mentored environment. Aim 2: To provide an interactive educational experience that introduces medical students the fundamental skills necessary for basic translational and clinical Endocrine-based research. The T35 competing renewal funding will provide stipends for a 10-week summer program for 8-10 second year medical students. Our current T35 grant funds 6 students/year. Given the increase in training faculty mentors and NIDDK-funded research at the University of Louisville School of Medicine documented within the text we request funds to increase to 8 students/year in years 6 and 7 (Yr. one and two of the next funding period) 9 in years 8 and 9 (Yr. three and four of the next funding period and 10 in year 10 (Yr. five of the next funding period).

project_terms:
Basic Science;Clinical;Clinical Research;Country;Diabetes Mellitus;Endocrine;Endocrinology;Environment;Faculty;Female;Funding;Grant;Health;Instruction;Journals;Medical Students;Mentors;Minority;National Institute of Diabetes and Digestive and Kidney Diseases;Population;Research;Research Activity;Research Personnel;Research Training;Scientist;Series;Structure;Students;Text;Training;Training Programs;United States National Institutes of Health;Universities;base;bench to bedside;experience;interest;medical schools;member;programs;skills

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This competing renewal T35 application directly addresses the NIH's goal of ensuring that a diverse pool of highly trained scientists are available in the field of Endocrinology to address the Nation's biomedical and clinical research needs.


application_id: 8449847
project_number: 1U01DA033276-01A1
project_title: A Phase 3 Double-Blind Efficacy Safety and Dose-Response Study of Lofexidine (S
administering_ic: NIDA
award_notice_date: 2012-09-19
opportunity_number: PAR-11-109
application_type: 1
activity_code: U01
ic: DA
serial_number: 033276
suffix: A1
program_official: BISWAS, JAMIE
project_start_date: 2012-09-30
project_end_date: 2015-07-31
study_section: Special Emphasis Panel[ZDA1 JXR-D (05)]
contact_pi_person_id: 2408657
contact_pi: GORODETZKY, CHARLES W.
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 087875626
primary_uei: NKGSYBV5UGN1
duns_number: 087875626
uei: NKGSYBV5UGN1
fips: US
organization_id: 10003722
organization_name: US WORLDMEDS, LLC
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic For-Profits
organization_zip: 40241
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The proposed research is aimed at characterizing the safety and efficacy profiles to address FDA-defined gaps in the clinical development program for lofexidine hydrochloride an alpha-2 adrenergic agonist under development for the treatment of acute withdrawal from short-acting opioids. The program includes two linked studies to be conducted consecutively at the same sites: Study 1 will generate pivotal efficacy/safety data for two doses of lofexidine hydrochloride in 600 subjects about to undergo total and abrupt withdrawal from short- acting opioids who will be randomized under double-blind conditions to either placebo (N=150) or lofexidine (2.4 mg or 3.2 mg total daily dose; N=225/group) for 7 days of inpatient treatment. Subsequently all subjects will be permitted to continue under open-label conditions for up to an additional 7 days of inpatient/outpatient variable-dose treatment depending on the wishes of the Site Investigator and subject. Safety will be assessed by evaluation of adverse event (AE) clinical laboratory electrocardiogram (with special attention to
QTc) vital signs and physical exam data. Efficacy will be evaluated daily by subject- and observer-completed scales including the Short Opiate Withdrawal Scale of Gossop (SOWS-G) (the primary outcome measure is SOWS-G score area under the curve for Days 1-7) the Objective Opiate Withdrawal Scale (OOWS-Handelsman) the Visual Analog Scale for Efficacy (VAS-E) and the Modified Clinical Global Impressions scales for efficacy and side effects. Efficacy will also be evaluated by study retention completion rates concomitant medication use incidence of withdrawal-related AEs and subject treatment status 30 days post discharge. Study 2 will follow a similar 14-day dosing format but will be entirely open-label; and 200 to 400 subjects (different from those in Study 1) will receive lofexidine at a variable dose not to exceed
a total of 3.2 mg per day or a single dose of 0.8 mg in an inpatient outpatient or a combination of settings as per the normal standard of care at the enrolling site. Study 2 is a translational research design aimed at gathering "real-world" effectiveness and safety data to supplement the existing lofexidine safety database and enable appropriate product labeling for end-users. Safety will be evaluated for all treated subjects and for two cohorts: those with urines negative and those with urines positive for drugs of abuse so that all possible causes of reported AEs may be considered for analysis. Effectiveness will be evaluated by the Clinical Opiate Withdrawal Scale (COWS) rate of detoxification completion and subject treatment status 30 days post discharge. An open-label variable-dose real-world design as planned in Study 2 is common in Phase 3 drug development and together with Study 1 which will provide pivotal efficacy data needed to support the proposed product indication the program has been designed to address FDA registration requirements for lofexidine. On approval of an NDA lofexidine will be the first approved non-narcotic non-addictive drug indicated for treatment of opioid withdrawal in the US providing an important alternative therapy for this indication.   
   
PUBLIC HEALTH RELEVANCE: With a growing trend of millions of Americans becoming dependent on prescription and other short-acting opioid narcotics there is an unmet medical need for new detoxification treatments. The only drugs approved by the FDA for this indication (methadone and buprenorphine) are opioid replacement or substitution therapies which themselves have abuse potential. The proposed research program on lofexidine hydrochloride will: i) establish the dose range by examining the safety and efficacy of two different doses of lofexidine; ii) confirm that lofexidine may be used until the acute phase of opioid withdrawal is complete (i.e. up to 14 days); and iii) increase the safety database by employing a "real-world" strategy to study additional subjects and increase the likelihood of identifying potential safety issues that may be present in only a small percentage of users. NIDA's support of this development work on lofexidine is necessary to enable FDA approval of the first non-narcotic non-addictive treatment for opioid withdrawal.

project_terms:
Abstinence;Acute;Address;Adrenergic Agonists;Adverse effects;Adverse event;Alternative Therapies;American;Applications Grants;Area Under Curve;Attention;Buprenorphine;Clinical;Data;Databases;Development;Dose;Double-Blind Method;Drug Metabolic Detoxication;Effectiveness;Electrocardiogram;Enrollment;Evaluation;FDA approved;Hydrochloride Salt;Incidence;Inpatients;Laboratories;Life;Link;Literature;Marketing;Medical;Methadone;Narcotics;Opiates;Opioid;Outcome Measure;Outpatients;Pharmaceutical Preparations;Phase;Placebo Control;Placebos;Product Labeling;Program Development;Publishing;Randomized;Reporting;Research;Research Design;Research Personnel;Safety;Severe Adverse Event;Signs and Symptoms;Site;Symptoms;Translational Research;United Kingdom;United States Food and Drug Administration;Urine;Visual;Withdrawal;Work;analog;base;cohort;design;drug development;drug of abuse;experience;impression;lofexidine;meetings;open label;opioid withdrawal;phase 3 study;primary outcome;programs;response;standard of care;therapy development;treatment duration;trend

public_health_relevance:
With a growing trend of millions of Americans becoming dependent on prescription and other short-acting opioid narcotics there is an unmet medical need for new detoxification treatments. The only drugs approved by the FDA for this indication (methadone and buprenorphine) are opioid replacement or substitution therapies which themselves have abuse potential. The proposed research program on lofexidine hydrochloride will: i) establish the dose range by examining the safety and efficacy of two different doses of lofexidine; ii) confirm that lofexidine may be used until the acute phase of opioid withdrawal is complete (i.e. up to 14 days); and iii) increase the safety database by employing a "real-world" strategy to study additional subjects and increase the likelihood of identifying potential safety issues that may be present in only a small percentage of users. NIDA's support of this development work on lofexidine is necessary to enable FDA approval of the first non-narcotic non-addictive treatment for opioid withdrawal.


application_id: 8449694
project_number: 5R01CA149274-04
project_title: Diffuse Optical Monitoring of Head and Neck Tumor Therapy
administering_ic: NCI
award_notice_date: 2013-05-01
opportunity_number: PA-07-279
application_type: 5
activity_code: R01
ic: CA
serial_number: 149274
program_official: BAKER, HOUSTON
project_start_date: 2010-07-01
project_end_date: 2015-04-30
study_section: Biomedical Imaging Technology Study Section[BMIT]
contact_pi_person_id: 8252681
contact_pi: YU, GUOQIANG
other_pis: Not Applicable
congressional_district: 06
department: BIOMEDICAL ENGINEERING
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: GRADUATE SCHOOLS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Project Summary:Treatment with radiation or chemo-radiotherapy is the standard therapy for head and neck cancers but thistreatment is well known to be less efficacious in patients with hypoxic tumors. Furthermore cancer therapymay alter tumor physiological status thus impacting treatment efficacy. Factors that modulate tumoroxygenation include blood flow blood oxygenation oxygen metabolism and nicotine levels (i.e. tobacco use).Tumor hemodynamics and metabolism however are not routinely measured during cancer therapy due to thelack of appropriate technologies. Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) are thebest currently available and reproducible methods to measure target lesions selected for objective responseassessment but these modalities require large and costly instrumentation that severely limits their routine usein clinics. The capabilities of diffuse optics for continuously monitoring tumor hemodynamics and metabolismduring therapy at the clinical bedside have recently been demonstrated in our preliminary studies. Theobjective of this project is to develop and optimize a noninvasive versatile multi-modality clinical opticalinstrument to aid in evaluating and predicting tumor responses at the most early stage possible. Morespecifically this optical instrument will monitor and predict hemodynamic and metabolic responses to chemo-radiotherapy in head and neck tumors. We hypothesize that functional assessment of tumor physiologicalstatus and dynamic changes during therapy will provide information for early prediction of long-term treatmentoutcomes thus enabling clinicians to optimize therapy for each patient in a time sensitive fashion. To achievethis goal we will assemble a hybrid flow and oxygen system that combines a newly developed diffusecorrelation spectroscopy (DCS) flowmeter with a commercial tissue-oximeter for simultaneous measurement oftumor blood flow oxygenation and oxygen metabolism (derived from the flow and oxygenation data). Theinstrument including optical probes and a software platform will be tested and optimized for continuous andlongitudinal monitoring of tumor physiological status and hemodynamic/metabolic changes before during andafter therapy in patients including smokers and nonsmokers (n=125). It is anticipated that significantcorrelations will be observed between therapy outcomes (e.g. tumor volume change tumor toxicity time todisease recurrence survival) and tumor physiological status and changes as well as nicotine levels. Differenttypes of physiological parameters may show different sensitivities to cancer therapy in each patient whichcould reveal the primary factor(s) affecting individual therapy outcomes. Our novel hybrid optical system willprovide hemodynamic and metabolic imaging contrasts complementary to those of CT and MRI and holdsunique potential for early evaluating and predicting cancer therapy responses. Our long-term goal is to developrobust scientific collaborations to optimize and individualize cancer therapy at early stages with noninvasiveoptical technologies.

project_terms:
Accounting;Acute;Affect;Aftercare;Blood;Blood Volume;Blood flow;Cessation of life;Clinic;Clinical;Collaborations;Computer software;Cotinine;Data;Data Analyses;Data Collection;Devices;Diffuse;Disease;Drug Delivery Systems;Evaluation;Exhibits;Fiber Optics;Flowmeters;Forearm;Goals;Head and Neck Cancer;Head and Neck Neoplasms;Hybrids;Hypoxia;Image;Individual;Lesion;Location;Magnetic Resonance Imaging;Malignant Neoplasms;Measurement;Measures;Metabolic;Metabolism;Methods;Modality;Monitor;Muscle;Nicotine;Non-smoker;Optical Instrument;Optical Methods;Optics;Outcome;Oxygen;Patient Care;Patients;Physiological;Progressive Disease;Property;Radiation;Radiation therapy;Recurrence;Reporting;Research;Roentgen Rays;Scanning;Serum;Smoker;Smoking;Spectrum Analysis;Stable Disease;Staging;System;Technology;Testing;Time;Tissues;Tobacco use;Toxic effect;Treatment Efficacy;Treatment outcome;Tumor Oxygenation;Tumor Volume;Ultrasonography;Withdrawal;X-Ray Computed Tomography;base;blood flow measurement;cancer therapy;chemotherapy;cost;design;follow-up;hemodynamics;improved;insight;instrument;instrumentation;novel;prognostic;prototype;response;simulation;therapy outcome;tissue phantom;tool;treatment duration;treatment planning;tumor

public_health_relevance:
Project Narrative:Treatment with radiation alone or in combination with chemotherapy is standard therapy for the head and neckcancers but this treatment is well known to be less efficacious in patients with poorly-vascularized/hypoxictumors. The objective of this project is to develop and test a low-cost clinical-level optical instrument that canquickly assess tumor hemodynamic and metabolic status and responses to cancer therapy in the early stages.This in depth assessment of tumor hemodynamic and metabolic properties will provide essential informationfor the early prediction and evaluation of treatment outcomes thus enabling clinicians to optimize individualtreatment.


application_id: 8448296
project_number: 5R01CA149438-03
project_title: Activation of Cyclin-Dependent Kinases by Fructose-26-Bisphosphate
administering_ic: NCI
award_notice_date: 2013-03-14
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: CA
serial_number: 149438
program_official: SPALHOLZ, BARBARA A
project_start_date: 2011-04-01
project_end_date: 2016-03-31
study_section: Tumor Cell Biology Study Section[TCB]
contact_pi_person_id: 1923745
contact_pi: CHESNEY, JASON A.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The 6-phosphofructo-2-kinase/fructose-26-bisphosphatases (PFKFB) phosphorylate fructose-6-phosphate (F6P) to fructose-26-bisphosphate (F26BP) which is an allosteric activator of 6-phosphofructo-1-kinase a rate-limiting enzyme in the glycolytic pathway. Although there are four PFKFB enzymes PFKFB3 and PFKFB4 are of particular interest since these enzymes have been found to be activated in human cancers to be increased by hypoxic exposure via HIF-1? and in the case of PFKFB3 to be required for the growth of Ras-transformed tumors. In order to better understand the relative contributions of PFKFB2-4 to glycolysis we examined the subcellular localization of these enzymes and were surprised to find that whereas PFKFB2 and PFKFB4 localized to the cytoplasm (the site of glycolysis) PFKFB3 localized to the nucleus. We then over-expressed PFKFB3 in HeLa cells and observed no change in glucose uptake but rather an increase in proliferation. Eukaryotic cell division is controlled by cyclin dependent kinases (CDKs) that bind to regulatory cyclins and phosphorylate hundreds of substrates that control DNA replication transcription and mitosis. We found that over-expression of PFKFB3 stimulated CDK1 activity in HeLa cells and that purified F26BP stimulated recombinant monomeric CDK1 in vitro. We then confirmed the requirement of CDK1 for the pro-proliferative effects of PFKFB3 by demonstrating that CDK1 siRNA but not CDK2 CDK4 or CDK6 siRNA reversed the increased proliferation caused by over-expression of PFKFB3. Importantly transfection of HeLa cells with PFKFB3-specific siRNA decreased endogenous PFKFB3 which in turn reduced CDK1 activity increased p27 expression suppressed G1/S transition induced apoptosis but had no impact on glucose uptake. These data support a distinct role for PFKFB3 in the regulation of cell cycle progression and apoptosis and not glucose metabolism. We propose to test the hypothesis that nuclear F26BP generated by PFKFB3 activates CDKs and promotes cell cycle progression. We anticipate that nuclear F26BP may serve unique roles in regulating CDK1 and other CDKs and that inhibition of PFKFB3 will suppress CDK activities without significantly affecting glucose metabolism in transformed but not in normal cells.

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

public_health_relevance:
The research proposed in this application may enable the identification of a novel molecular target - theCDK1 F26BP-binding domain - that is required for the regulation of the cell cycle and cancer progression.This binding pocket then can be used for receptor-based virtual screening to identify novel anti-neoplasticagents.


application_id: 8448267
project_number: 5R01CA129967-05
project_title: Amplification of tumor hypoxic responses by MIF-dependent HIF stabilization
administering_ic: NCI
award_notice_date: 2013-01-23
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: CA
serial_number: 129967
program_official: SNYDERWINE, ELIZABETH G
project_start_date: 2009-05-01
project_end_date: 2015-02-28
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 7360475
contact_pi: MITCHELL, ROBERT A
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) has the grim distinction of being one of the most prognostically unfavorable human cancers. It has been suggested that low oxygen tensions within PDAC tumors contribute significantly to its metastatic potential and chemotherapeutic resistance. Hypoxia-inducible factors (HIFs) transcribe gene products that contribute to metabolic adaptation neo-angiogenic potential metastatic spread and therapeutic resistance. We recently discovered that macrophage migration inhibitory factor (MIF) one of the oldest cytokines ever described is elevated in PDAC patient's plasma and induced by hypoxia-induced HIF-1a-dependent transcription in pancreatic cancer cells. Intriguingly MIF was found to reciprocally modulate hypoxia- induced HIF-1a stabilization. Several human PDAC cell lines transfected with siRNA against MIF recapitulate MIF-/- fibroblasts in defective hypoxia-induced HIF-1a stabilization and subsequent HIF-dependent transcription. Moreover MIF-deficient PDAC cells display defective xenograft tumor outgrowth less HIF-1a and significantly reduced microvascular density than MIF-containing xenografts. Finally our results indicate that MIF promotes HIF-1a stability by functionally regulating a subunit of the COP9 signalosome CSN5 in repressing a unique HIF-1-specific ubiquitin E3 ligase. Our central hypothesis is that MIF overexpression in pancreatic adenocarcinoma lesions acts to modulate either the levels or activity of free CSN5 that in turn serves to repress or mask a unique oxygen-independent ubiquitin E3 ligase specific for HIF-1a. Studies outlined in this application seek to identify the contribution and requirements for MIF in PDAC growth pathophysiology and hypoxic adaptation. We will additionally delineate the precise mechanisms and molecular determinants involved in MIF-dependent HIF-1 stabilization. In order to fulfill the stated objectives of this application the following experimental aims are proposed: 1) Elucidate the basic mechanism by which MIF contributes to hypoxia-induced HIF-1a stabilization 2) Define the molecular determinants and effectors of HIF-1 degradation in MIF-deficient cells and 3) Determine if MIF contributes to pancreatic ductal adenocarcinoma growth pathophysiology and hypoxic adaptation.

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

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


application_id: 8446990
project_number: 5R01EB012135-04
project_title: Phi29 Motor Nanopore for Single Molecule Sensing
administering_ic: NIBIB
award_notice_date: 2013-03-21
opportunity_number: PA-08-052
application_type: 5
activity_code: R01
ic: EB
serial_number: 012135
program_official: ATANASIJEVIC, TATJANA
project_start_date: 2011-04-01
project_end_date: 2015-03-31
study_section: Nanotechnology Study Section[NANO]
contact_pi_person_id: 1878565
contact_pi: GUO, PEIXUAN
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 PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): All linear double-stranded (ds) DNA viruses package their genome into a preformed procapsid via an ATP-driving motor. The central component of the phi29 DNA-packaging motor is the portal connector composed of twelve copies of the protein gp10 which form a dodecamer channel that acts as a pathway for the translocation of dsDNA. With a diameter of 3.6 nm at its narrowest end it is one of the largest among typical channel proteins that have been incorporated into lipid membranes. Explicit engineering and pore modifications of the phi29 connector are possible due to its available crystal structure thus inspiring the use of such a system as a module in biomedical applications or nanodevices.  The short-term objective of this proposal is to demonstrate the utility of the lipid-embedded channel of the phi29 DNA packaging motor as a highly sensitive device for capture and fingerprinting of chemicals and biopolymers in real time at single molecule resolution using electrophysiological assays. The connector will be reengineered for added functionality and various approaches will be undertaken to modulate the dimensions of the pore. Alteration of the charge distributions will be made by mutagenesis in a controlled fashion to ensure optimal sensing. The channel will be designed to act as a stochastic biosensor and functionalized with recognition groups to bind various analytes of interest. Methods to increase the stability and lifetime of the lipid/connector complex will be developed to facilitate high throughput electrophysiological measurement of a single pore with provisions for rapid and efficient sample and buffer exchange. The long-term objective is to develop the channel into a robust sensing device for detecting biomolecules or chemicals at extremely low concentrations in the presence of many contaminants for a wide range of applications in biotechnology earlier disease diagnosis environmental surveillance custom quarantine drug testing and national security.

project_terms:
Affinity;Ala-Trp-Arg-His-Pro-Gln-Phe-Gly-Gly;Antibodies;Antigens;Area;Automobile Driving;Bacteriophages;Binding (Molecular Function);Biological;Biological Assay;Biological Models;Biopolymers;Biosensor;Biotechnology;Biotin;Buffers;Caliber;Cells;Characteristics;Charge;Chemicals;Complex;Custom;Cysteine;DNA;DNA Packaging;Data;Detection;Devices;Dimensions;Disulfide Linkage;Double Stranded DNA Virus;Engineering;Ensure;Event;Exhibits;Fingerprint;Frequencies (time pattern);Genome;Goals;Housing;Infection;Ions;Kinetics;Length;Life;Ligands;Lipid Bilayers;Lipids;Maleimides;Measurement;Membrane;Membrane Lipids;Methods;Modification;Molecular Conformation;Monitor;Motor;Mutagenesis;Nanotechnology;National Security;Nature;Nickel;Pathway interactions;Pattern;Peptides;Phage Display;Property;Proteins;Quarantine;RNA;RNA-Protein Interaction;Reaction;Regulation;Resolution;Sampling;Shapes;Signal Transduction;Streptavidin;Structure;System;Time;Transportation;Virion;base;chemical fingerprinting;design;disease diagnosis;drug testing;ds-DNA;instrument;interest;macromolecule;nanodevice;nanopore;novel;patch clamp;protein protein interaction;proteoliposomes;public health relevance;research study;sensor;single molecule;thioester;time use

public_health_relevance:
PROJECT NARRATIVE The membrane embedded nanopore of bacteriophage phi29 biomotor will be reengineered characterizedand developed into a single pore sensor for detection of biomolecules and chemicals. The combination ofcapture and fingerprinting with multiple identification parameters for single molecule detection in real time willmake the system highly sensitive to detect molecules at extremely low concentrations in the presence of manycontaminants.


application_id: 8446919
project_number: 5R01AR055974-05
project_title: Respiratory Muscle Weakness in Chronic Inflammation
administering_ic: NIAMS
award_notice_date: 2013-04-19
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AR
serial_number: 055974
program_official: BOYCE, AMANDA T
project_start_date: 2009-04-01
project_end_date: 2015-02-28
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 6197585
contact_pi: ANDRADE, FRANCISCO H
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 long-term goal of this project is to identify therapies that will preserve diaphragm function in chronic inflammatory conditions including heart failure and chronic obstructive pulmonary disease. Our current focus is loss of specific force in diaphragm which promotes exercise intolerance breathlessness and respiratory failure. A promising therapeutic target is tumor necrosis factor (TNF). TNF serum levels are elevated in chronic disease correlate with muscle weakness and are a predictor of morbidity and mortality. TNF depresses contractile function of diaphragm and stimulates oxidant production by diaphragm muscle fibers. The oxidants appear to cause weakness since interventions that limit oxidant activity prevent loss of force. Our central hypothesis is that respiratory muscle function can be preserved in chronic inflammatory disease by inhibiting TNF receptor-mediated effects on diaphragm muscle fibers. This project will define signaling events and redox mechanisms by which TNF depresses force and will evaluate pharmacologic and genetic interventions to preserve diaphragm function. We also will evaluate pathophysiologic relevance defining the role of TNF in a mouse model of disease and testing the capacity of clinical therapeutic agents to preserve diaphragm function. The project addresses three specific aims: Aim 1. To evaluate sphingolipid signaling as an early post-receptor mechanism by which TNF/TNFR1 stimulates oxidant activity and weakness. Cell culture studies will assess sphingomyelinase activation and ceramide-sensitive signaling events downstream of the TNF receptor subtype 1. Aim 2. To assess the source composition and post-translational target of oxidants that mediate TNF-stimulated weakness. Diaphragm fiber bundles and isolated mitochondria will be used to define ROS and NO contributions via redox assays and pharmacologic and genetic tools. Aim 3. To test TNF signaling as a contributor to respiratory muscle weakness in heart failure and a potential target for therapy. An animal model of heart failure will be used to define the diaphragm response to chronic inflammation to test TNF as a systemic mediator and to evaluate potential therapies that are approved for use in humans.

project_terms:
Address;Animal Model;Animals;Antioxidants;Arachidonic Acids;Area;Binding (Molecular Function);Biological Assay;Breathing;Calcium;Cardiovascular Diseases;Cell Culture Techniques;Ceramides;Chronic;Chronic Disease;Chronic Obstructive Airway Disease;Clinical;Complement;Data;Depressed mood;Diaphragm (Anatomy);Disease;Dyspnea;Esthesia;Event;Exercise;Exercise Tolerance;Extracellular Signal Regulated Kinases;Fiber;Functional disorder;Genetic;Goals;Health;Heart failure;Hour;Human;Inflammation;Inflammatory;Intervention;Lead;Life;Ligand Binding;Link;MAPK3 gene;Mediating;Mediator of activation protein;Microfilaments;Mitochondria;Morbidity - disease rate;Mortality Vital Statistics;Muscle;Muscle Fibers;Muscle Weakness;Muscle function;Neurons;Nitric Oxide Synthase;Oxidants;Oxidation-Reduction;Pathway interactions;Patients;Peroxonitrite;Phospholipase;Phospholipase A2;Phosphotransferases;Physiologic intraventricular pressure;Post-Translational Protein Processing;Production;Protein Isoforms;Protein Kinase;Proteins;Publishing;Pulmonary Emphysema;Reactive Oxygen Species;Research;Respiratory Failure;Respiratory Muscles;Role;Serum;Signal Transduction;Source;Sphingolipids;Sphingomyelinase;Symptoms;Testing;Therapeutic Agents;Tumor Necrosis Factor Receptor;Tumor Necrosis Factor-alpha;Work;drug development;gene therapy;mouse model;muscle strength;novel;premature;pressure;prevent;receptor;research study;response;therapeutic target;tool

public_health_relevance:
NARRATIVEChronic inflammatory diseases including heart failure and emphysema weakenthe muscles used for breathing. This promotes the debilitating sensation ofbreathlessness decreases exercise tolerance and can lead to respiratory failure.The goal of this project is to identify new therapies that preserve respiratorymuscle function in order to lessen illness and prolong life.


application_id: 8446498
project_number: 5K23GM095859-03
project_title: Adjunctive Peritoneal Resuscitation in Hemorrhagic Shock
administering_ic: NIGMS
award_notice_date: 2013-03-08
opportunity_number: PA-10-060
application_type: 5
activity_code: K23
ic: GM
serial_number: 095859
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)M]
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
arra_indicator: N
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.

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;public health relevance;research study;socioeconomics;translational approach

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


application_id: 8446339
project_number: 5R21DA033796-02
project_title: Tonic and Phasic Glutamate Release from Psychomotor Stimulants
administering_ic: NIDA
award_notice_date: 2013-03-15
opportunity_number: PAR-09-222
application_type: 5
activity_code: R21
ic: DA
serial_number: 033796
program_official: PILOTTE, NANCY S
project_start_date: 2012-04-01
project_end_date: 2015-03-31
study_section: ZDA1-SXC-E(12)S
contact_pi_person_id: 8383539
contact_pi: GERHARDT, GREG A.
other_pis: Not Applicable
congressional_district: 06
department: ANATOMY/CELL BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This CEBRA R21 application involves the further development characterization and use of an advanced technology to study second-by-second changes in L-glutamate in specific brain regions in rats using enzyme- based microelectrode arrays (MEAs) during self-administration of cocaine. This grant combines the strengths of a recently developed recording technology for glutamate measures (Gerhardt lab) with known expertise in drug self-administration (Bardo lab). This grant will adapt and further develop an innovative technique for addiction research as per the primary goals of the CEBRA program. The new technology can be potentially used by numerous investigators to better understand the role(s) of neuronal and possibly non- neuronal glutamate in addiction. The current proposal will develop and characterize a recently developed recording technology in awake and behaving rats to determine if cocaine self-administration is related to tonic and/or phasic release of glutamate in the nucleus accumbens core and infralimbic prefrontal cortex. The mechanistic framework for the proposed experiments rests on information about the homeostatic regulation of glutamate levels in critical reward-relevant brain regions. While a variety of neurotransmitter systems are involved in drug abuse particularly dopamine recent evidence indicates that glutamatergic tone in nucleus accumbens and related cortico-limbic structures is involved in the long-lasting consequences of stimulant exposure (Kalivas 2009). Our overarching hypothesis is that psychomotor stimulants lead to enhanced neuronal glutamate release in response to subsequent administration of drugs. The proposal is innovative from both health and technological perspectives. While the changes in glutamate homeostasis have been proposed to underlie cocaine self-administration and reinstatement (Kalivas 2009) extracellular glutamate measurements have been studied primarily by microdialysis which does not have the temporal and spatial resolution required to evaluate both tonic and brief phasic pulses of glutamate that characterize neuronal release. Our preliminary results show that the MEA methods in awake animals can measure both tonic and rapid phasic levels of glutamate and that the events may provide different and very important information regarding regulation of glutamate circuitry in the normal brain and in addiction.

project_terms:
Address;Animal Model;Animals;Area;Behavior;Brain;Brain region;Cocaine;Data;Development;Devices;Dopamine;Drug abuse;Enzymes;Event;Glutamates;Goals;Grant;Head;Health;Homeostasis;Impulsivity;Intravenous;Lead;Measurement;Measures;Methods;Microdialysis;Microelectrodes;Modification;Morphologic artifacts;Neurons;Neurotransmitters;Noise;Nucleus Accumbens;Pattern;Pharmaceutical Preparations;Physiologic pulse;Prefrontal Cortex;Rattus;Regulation;Research;Research Personnel;Resolution;Rest;Rewards;Role;Saline;Sampling;Self Administration;Self-Administered;Signal Transduction;Source;Staging;Stress;Structure;System;Tail;Techniques;Technology;Time;Training;Work;addiction;awake;base;drug of abuse;extracellular;improved;innovation;new technology;programs;prototype;research study;response;stimulant abuse

public_health_relevance:
These studies will adapt a new technology for investigating rapid tonic and phasic neurotransmitter signaling (glutamate) in an animal model of drug abuse. Studies will address slow and fast glutamate signals in brain areas critically involved with drug abuse and the effects of psychomotor stimulant drugs such as cocaine. This new technology once developed can possibly be used by many investigators to better understand changes to the brain that occur following repeated use of drugs of abuse.


application_id: 8445756
project_number: 1R03NS077193-01A1
project_title: Glutamate-evoked calcium signaling in spinal cord after nerve injury
administering_ic: NINDS
award_notice_date: 2012-08-27
opportunity_number: PA-11-262
application_type: 1
activity_code: R03
ic: NS
serial_number: 077193
suffix: A1
program_official: OSHINSKY, MICHAEL L
project_start_date: 2012-09-01
project_end_date: 2014-08-31
study_section: Somatosensory and Chemosensory Systems Study Section[SCS]
contact_pi_person_id: 10670168
contact_pi: DOOLEN, SUZANNE
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  A fundamental gap exists in understanding the cellular mechanisms that initiate and maintain neuropathic pain. This gap represents an important problem because current analgesic drugs rarely provide sufficient efficacy without serious side effects. The long-term goal is to understand the mechanisms that lead to injury-induced central sensitization and establish clinically relevant therapeutic targets for chronic pai. The objective in this application is to evaluate the contribution glutamate receptor subtypes to dorsal root stimulation (DRS)-evoked Ca2+ transients in the dorsal horn and correlate enhanced Ca2+ responses with the magnitude of pain-like behavior. Based on preliminary data suggesting that glutamate-evoked Ca2+ responses in mouse spinal cord slices are potentiated after nerve injury the central hypothesis is that nerve injury increases AMPA receptor signaling in the dorsal horn leading to increases in [Ca2+]i that results in central sensitization and neuropathic pain. The rationale for the proposed project is that [Ca2+]i in dorsal horn neurons is essential for central sensitization and pain hypersensitivity. The central hypothesis will be teste by pursuing three specific aims: AIM 1 tests the hypothesis that glutamate-mediated activation of neuronal ionotropic AMPA receptors drives Ca2+ signaling. Electrophysiological recordings and real-time fluorescent labeling of astrocytes will be used to evaluate the cell types that respond to dorsal root stimulation (DRS) with a rise in [Ca2+]i. Next the relative contribution of
glutamate receptor subtypes will be determined by quantifying DRS-evoked [Ca2+]i transients in the presence of selective antagonists. AIM 2 tests the hypothesis that peripheral nerve injury potentiates DRS-evoked Ca2+ responses and this will correlate with the magnitude of hyperalgesia. To allow for a correlation analysis between behavior and [Ca2+]i a variant model of nerve injury has been developed that gradually elicits robust allodynia in 1 week and then resolves in 4 weeks. Behavioral hyperalgesia will be evaluated and compared to DRS-evoked [Ca2+]i in spinal cord slices from sham traditional and variant nerve injured animals sacrificed at 7 14 and 21 d after injury. AIM 3 tests the hypothesis that PKM mediates SNI-induced increases in hyperalgesia Ca2+ signaling and AP frequency in dorsal horn. We will administer multiple PKM inhibitors to sham and SNI mice and measure pain- like behavior Ca2+ transients and/or AP frequency. Based on our preliminary results we predict that PKM blockade will reverse injury-induced hyperalgesia increases in [Ca2+]i and AP frequency.  This project employs innovative wide-field calcium imaging simultaneously from numerous cells in spinal cord slices from adult mice. The proposed research is significant because it reveals the Ca2+ channels that regulate DRS-evoked Ca2+ transients and is a critical first step in understanding nerve injury-induced potentiation of neuronal Ca2+ signaling. Ultimately this knowledge will establish clinically relevant therapeutic targets for alleviating chronic pain.   
   
PUBLIC HEALTH RELEVANCE: Chronic pain management is a major scientific and health care challenge as current analgesic drugs rarely provide sufficient efficacy in the absence of serious side effects. This project is relevant to NINDS's mission because it will 1) determine mechanisms that lead to injury-induced central sensitization and 2) establish clinically relevant therapeutic targets for alleviating chronic pain. This Research Plan employs highly innovative wide-field calcium imaging from numerous cells in a single spinal cord slice from adult mice.

project_terms:
6-Cyano-7-nitroquinoxaline-23-dione;AMPA Receptors;Action Potentials;Adult;Adverse effects;Analgesics;Animals;Astrocytes;Attenuated;Behavior;Behavioral;Calcium;Calcium Signaling;Cells;Chemosensitization;Chronic;Data;Development;Dose;Frequencies (time pattern);Fura-2;Glutamate Receptor;Glutamates;Goals;Healthcare;Hyperalgesia;Hypersensitivity;Image;Injury;Knowledge;Label;Lead;Ligation;Measures;Mediating;Mission;Modeling;Mus;Nerve;Neurons;Operative Surgical Procedures;Pain;Pain Measurement;Pain management;Peripheral Nerves;Peripheral nerve injury;Physiological;Population;Posterior Horn Cells;Receptor Signaling;Relative (related person);Research;Signal Transduction;Skin;Slice;Specificity;Spinal Cord;Stimulus;Substantia Gelatinosa;Tactile;Techniques;Testing;Time;Variant;allodynia;base;cell type;central pain;central sensitization;chronic pain;clinically relevant;dorsal horn;inhibitor/antagonist;injured;innovation;kainate;nerve injury;neurotransmission;painful neuropathy;response;sciatic nerve;spinal nerve posterior root;therapeutic target

public_health_relevance:
Chronic pain management is a major scientific and health care challenge as current analgesic drugs rarely provide sufficient efficacy in the absence of serious side effects. This project is relevant to NINDS's mission because it will 1) determine mechanisms that lead to injury-induced central sensitization and 2) establish clinically relevant therapeutic targets for alleviating chronic pain. This Research Plan employs highly innovative wide-field calcium imaging from numerous cells in a single spinal cord slice from adult mice.


application_id: 8445281
project_number: 5R01AI025098-24
project_title: Plague biofilm formation--regulation and function
administering_ic: NIAID
award_notice_date: 2013-03-22
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: AI
serial_number: 025098
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 1993-09-30
project_end_date: 2015-03-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 1864186
contact_pi: PERRY, ROBERT DONALD
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Yersinia pestis is the causative agent of plague which has caused widespread loss of human life during recurrent pandemics. On average approximately 2500 cases of human plague occur world-wide each year. Recently over 98% of the plague cases are found in Africa. In nature the bacterium cycles between mammals (mainly rodents) and fleas. The interaction of plague with fleas is facilitated by the formation of a biofilm. In the oriental rat flea Xenopsylla cheopis formation of the biofilm leads to blockage of the valve between the esophagus and stomach of the flea known as the proventriculus. Blockage of the proventriculus may extend the transmission time. The hemin-storage genes (hms) of Y. pestis are responsible for the production of a biofilm which is essential for flea blockage. The Hms+ phenotype was initially characterized as the ability of cells grown at 26:C but not 37:C to bind exogenous hemin or the dye Congo red and is due to the production of an exopolysaccharide matrix or biofilm. There are at least 5 genes involved in the synthesis of the Hms- dependent biofilm; hmsHFRS hmsT and hmsP. Two of these gene products HmsP and HmsT are responsible for the synthesis and turnover of the signaling molecule cyclic di-guanylic acid. Over-production of HmsT a diguanylate cyclase or the absence of HmsP a phosphodiesterase leads to increased biofilm formation. Polyamines also play a role in the creation of a Y. pestis biofilm. Mutants that are unable to synthesize polyamines can not form a biofilm unless supplied with exogenous putrescine. This proposal will continue studies on the mechanisms that control biofilm development and the protein-protein interactions needed for biofilm formation. The biochemical functions of the Hms proteins as well as the role of the biofilm in fleas and mice will be addressed. In specific aim 1 the interaction between Y. pestis wild-type cells as well as various hms mutants and different flea species will be investigated. The role of c-di-GMP in virulence of plague will also be examined. Specific factors which regulate biofilm development will be studied in specific aim 2. In specific aim 3 the interactions between the Hms proteins as well as their biochemical and enzymatic characteristics will be addressed. The proposed studies will provide new insights into the regulation of plague biofilm formation and its role in the transmission of the disease from fleas to mammals. Systems similar to that responsible for plague biofilm are present in a number of diverse bacteria. Biofilms are often associated with the ability to survive harsh conditions as well as increased resistance to antibiotics. Understanding the mechanisms involved in producing the plague biofilm as well as the factors that regulate its production will likely be relevant for biofilm formation in other pathogens.

project_terms:
Address;Affect;Africa;Amino Acids;Antibiotic Resistance;Asians;Bacteria;Binding (Molecular Function);Biochemical;Bioterrorism;Blood;Bubonic Plague;Cells;Characteristics;Congo Red;Development;Dinucleoside Phosphates;Disease;Disease Outbreaks;Dyes;Environment;Escherichia coli;Esophagus;Fleas;Genes;Guanosine Monophosphate;Health;Hemin;Human;In Vitro;Individual;Lead;Life;Mammals;Microbial Biofilms;Modeling;Montana;Mus;Mutagenesis;Mutation;Nature;Pathogenesis;Peptide Hydrolases;Phenotype;Plague;Play;Pneumonic Plague;Polyamines;Production;Proteins;Proventriculus;Putrescine;Rattus;Recurrence;Regulation;Rodent;Role;Signaling Molecule;South America;Southeastern Asia;Spermophilus;Squirrel;Stomach;System;Temperature;Testing;Time;Translations;Virulence;Yersinia pestis;bis(3'5')-cyclic diguanylic acid;cell type;diguanylate cyclase;disease transmission;glycosyltransferase;in vivo;insight;macrophage;mutant;pandemic disease;pathogen;periplasm;phosphoric diester hydrolase;prevent;protein protein interaction;transmission process;vector

public_health_relevance:
Project NarrativeYersinia pestis the bacterium that causes bubonic and pneumonic plague produces a sticky substance knownas a biofilm. Biofilms are made by several different kinds of bacteria and are often associated with their abilityto survive harsh environments and in some cases cause disease. Understanding how the plague bacteriummakes biofilm may eventually lead to ways to prevent biofilm formation in other bacterial pathogens.


application_id: 8444478
project_number: 5R01EY020672-04
project_title: Endogenous Specific Inhibitor of Corneal Lymphangiogenesis
administering_ic: NEI
award_notice_date: 2013-04-24
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: EY
serial_number: 020672
program_official: MCKIE, GEORGE ANN
project_start_date: 2010-04-01
project_end_date: 2014-03-31
study_section: Anterior Eye Disease Study Section[AED]
contact_pi_person_id: 2446639
contact_pi: AMBATI, JAYAKRISHNA
other_pis: Not Applicable
congressional_district: 06
department: OPHTHALMOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Absence of blood and lymphatic vessels in the normal cornea is essential for optical clarity andoptimal vision. Numerous pathological disorders result in corneal neovascularization that isresponsible for blindness in hundreds of millions of individuals worldwide. The vascularendothelial growth factor (VEGF) family and their receptors (VEGFR) are critical elements of thetightly regulated balance of endogenous angiogenesis stimulators and inhibitors which whendisrupted results in neovascularization. The principal positive regulators of blood(hemangiogenesis) and lymphatic (lymphangiogenesis) in the cornea are VEGF-A and VEGF-Crespectively. Among the many inhibitors of hemangiogenesis that reside in the cornea we haveshown that soluble VEGFR-1 (sVEGFR-1) by acting as a trap for VEGF-A is essential forcorneal avascularity (Ambati et al. Nature 2006). In contrast the molecular basis of thealymphatic cornea has not been resolved; indeed no endogenous specific inhibitor oflymphangiogenesis in any tissue has yet been reported. In new and exciting studies weidentified the existence of a novel secreted splice variant of VEGFR-2 in mouse and human(sVEGFR-2) (Albuquerque et al. Nature Medicine 2009). Surprisingly loss of sVEGFR-2resulted in spontaneous invasion of lymphatic but not blood vessels into the mouse cornea atbirth. sVEGFR-2 also specifically inhibited injury-induced corneal lymphangiogenesis anddramatically reduced corneal allograft rejection. This proposal will test the hypothesis that thelymphatic specificity of sVEGFR-2 is due to its existence as a monomer that interacts with andantagonizes VEGF-C but not VEGF-A. The Specific Aims of this proposal are to define theexpression and function of sVEGFR-2 during mouse and human corneal development decipherthe molecular mechanisms by which mouse and human sVEGFR-2 inhibit lymphangiogenesisbut not hemangiogenesis and resolve the spatial and temporal expression and function ofsVEGFR-2 in the mouse cornea following injury and allograft rejection. By providing clarifyinginsights into a critical endogenous regulator of lymphangiogenesis and identifying mechanismsthat might serve as potential targets for advancing novel therapies for cornealneovascularization and transplant rejection these studies directly address the 5-year goals ofthe NEI Corneal Diseases program. The impact of these studies also extends to pathologicalstates such as tumor metastasis lymphedema and lymphangioma which can be better studiedand possibly treated by modulating the endogenous uncoupler of lymphatic and blood vesselswe have discovered.

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

public_health_relevance:
Corneal neovascularization and transplant rejection which involve abnormal blood andlymphatic vessels lead to blindness in millions worldwide. We discovered a naturally occurringmolecule (sVEGFR-2) that selectively blocks lymphatic but not blood vessels. By molecularlyuncoupling these intertwined processes we introduce a new research tool that can be used tospecifically study lymphatic vascular biology and a new target that can lead to novel therapiesfor corneal blindness.


application_id: 8443437
project_number: 5R01HL095593-04
project_title: Atherogenic mechanism of lipid peroxidation-derived aldehydes
administering_ic: NHLBI
award_notice_date: 2013-02-22
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: HL
serial_number: 095593
program_official: FLEG, JEROME L
project_start_date: 2010-03-15
project_end_date: 2016-02-29
study_section: Vascular Cell and Molecular Biology Study Section[VCMB]
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this project is to understand the role of lipid peroxidation-derived aldehydes in atherosclerosis. Aldehydes such as 4-hydroxynonenal (HNE) and 1-palmitoyl-2-(5-oxovaleroyl)-3- glycero- phosphatidyl choline (POVPC) are the major bioactive products generated from the oxidation of LDL. Based on supportive preliminary studies we propose to test hypothesis that accumulation of lipid-derived aldehydes in macrophages induces endoplasmic reticulum (ER) stress and triggers the unfolded protein response (UPR) leading to cytokine production and foam cell formation. The specific aims of this project are to: (1) delineate the contribution of ER stress and UPR to aldehyde-mediated macrophage activation; (2) elucidate the role of UPR in regulating atherogenesis; and (3) examine the role of aldehyde metabolism in preventing ER stress and UPR in atherosclerotic lesions. To accomplish these aims we will examine whether exposure of murine bone marrow derived macrophages to model lipid-derived aldehydes - HNE or POVPC induces ER stress and UPR. We will determine the extent and the nature of this response and identify which specific UPR-dependent signaling pathways are activated by aldehydes and how they contribute to macrophage activation foam cell formation and apoptosis. To examine the role of ER-stress and UPR during atherosclerotic lesion formation we will determine stage-specific changes in ER stress and UPR in the arterial lesions of apoE-null mice. To probe causality we will examine whether treatment with chemical chaperones which assist protein folding would decrease lesion formation and improve plaque stability. In addition we will test whether genetic ablation of activating factor 3 (ATF3) a UPR-responsive gene which is dramatically induced by lipid aldehydes increases lesion progression and inflammation. To elucidate the role of aldehydes in inducing ER stress in atherosclerotic lesions we will examine how genetic deletion or overexpression of aldose reductase an enzyme which detoxifies both HNE and POVPC affects aldehyde-induced macrophage activation and foam cell formation in culture and ER stress UPR induction in the arterial lesions of apoE-null mice. Successful completion of this project may lead to a better understanding of the mechanisms by which lipid-derived aldehydes affect atherogenesis and how the effects of these aldehydes could be prevented or therapeutically minimized to decrease atherosclerosis.

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

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


application_id: 8442831
project_number: 5R01AG027297-07
project_title: Calcineurin and inflammatory signaling processes in aging and Alzheimer's Disease
administering_ic: NIA
award_notice_date: 2013-05-02
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AG
serial_number: 027297
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 2006-09-01
project_end_date: 2017-03-31
study_section: Chronic Dysfunction and Integrative Neurodegeneration Study Section[CDIN]
contact_pi_person_id: 1880587
contact_pi: NORRIS, CHRISTOPHER MARK
other_pis: Not Applicable
congressional_district: 06
department: OTHER HEALTH PROFESSIONS
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The experiments in this project use innovative gene delivery techniques and a multipronged approach to assess the fundamental role of astrocyte activation in neurologic function in an intact mouse model of Alzheimer's disease (AD). Studies use adeno-associated virus vectors (AAV) bearing the astrocyte-specific promoter Gfa2 to target the protein phosphatase calcineurin (CN) and NFAT transcription factors in astrocytes of wild-type and APP/PS1 mice. AAV-Gfa2 vectors are bilaterally delivered to the hippocampus at different ages/disease stages and mice are assessed on different AD biomarkers. In Aim 1 cognitive status is assessed using the active avoidance task while synaptic function is evaluated using hippocampal slice electrophysiology and Western blot measures of synaptic proteins. In Aim 2 hippocampal glutamate regulation is investigated using ceramic enzyme-based microelectrode arrays and measures of glutamate transporter levels. In Aim 3 levels of glial activation and neuroinflammation are determined with immunohistochemical (IHC) analyses and assessment of cytokine levels using Multiplex ELISAs. In Aim 4 IHC is used to determine the extent of A? deposition while ELISAs are used to quantify levels of A?40 and A?42 in soluble and insoluble hippocampal tissue fractions and Westerns used to assess BACE protein expression. AAV-Gfa2 vectors encode either potent inhibitors or activators of CN/NFAT signaling and therefore will determine the necessity and sufficiency of this astrocytic pathway in driving and/or maintaining neurologic dysfunction in AD mice. These studies provide a highly novel approach to the study of activated astrocytes and could have a major impact on the development of treatment strategies for AD and other neurodegenerative conditions.

project_terms:
APP-PS1;Age;Aging;Alzheimer's Disease;Alzheimer's disease model;Animals;Astrocytes;Automobile Driving;Avoidance Learning;Behavior;Behavioral;Biochemical Process;Biological Assay;Biological Markers;Brain;Brain Diseases;Calcineurin;Cells;Ceramics;Cognitive;Data;Dependence;Dependovirus;Deposition;Development;Disease;Electrodes;Electrophysiology (science);Enzyme-Linked Immunosorbent Assay;Enzymes;Funding;Gene Delivery;Glial Fibrillary Acidic Protein;Glutamate Receptor;Glutamate Transporter;Glutamates;Hippocampus (Brain);Human;Hypertrophy;Impaired cognition;Implant;In Vitro;Inflammatory;Ipsilateral;Label;Measurement;Measures;Methods;Microelectrodes;Microglia;Mus;NFAT Pathway;Nerve Degeneration;Nervous System Physiology;Neurodegenerative Disorders;Neurologic Dysfunctions;Outcome Measure;Pathologic;Pathology;Pathway interactions;Phenotype;Process;Production;Promotor (Genetics);Protein phosphatase;Proteins;Reaction;Regulation;Resolution;Rodent Model;Role;Signal Transduction;Slice;Staging;Synapses;Synaptic plasticity;Techniques;Testing;Therapeutic;Time;Tissues;Transgenic Mice;Transgenic Organisms;Western Blotting;Wild Type Mouse;adeno-associated viral vector;aging brain;amyloid pathology;astrogliosis;base;beta-site APP cleaving enzyme 1;computerized data processing;cytokine;functional outcomes;improved;in vivo;inhibitor/antagonist;innovation;interest;mouse model;neuroinflammation;neuropathology;neuroprotection;novel strategies;prevent;protein expression;relating to nervous system;research study;response;synaptic function;transcription factor;treatment strategy;vector


application_id: 8442451
project_number: 1K23AR062069-01A1
project_title: Prolonged alterations to muscle following knee surgery and physical therapy
administering_ic: NIAMS
award_notice_date: 2013-02-01
opportunity_number: PA-11-194
application_type: 1
activity_code: K23
ic: AR
serial_number: 062069
suffix: A1
program_official: BOYCE, AMANDA T
project_start_date: 2013-02-01
project_end_date: 2018-01-31
study_section: Special Emphasis Panel[ZAR1 CHW (M1)]
contact_pi_person_id: 10137938
contact_pi: NOEHREN, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Address;Anterior;Architecture;Area;Award;Biology;Biomechanics;Biophysics;Biopsy;Clinical;Clinical Research;Clinical Trials;Coupled;Data;Data Analyses;Degenerative polyarthritis;Development;Diffusion;Disease;Effectiveness;Fascicle;Fiber;Fibrosis;Future;Goals;Growth;Head;Health;Health Sciences;Image;Individual;Intervention;Joints;Kentucky;Knee;Laboratories;Left;Leg;Length;Ligaments;Link;Magnetic Resonance Imaging;Measurement;Measures;Mechanics;Mentored Patient-Oriented Research Career Development Award;Mentors;Mentorship;Methods;Microscopic;Molecular;Morphology;Muscle;Muscle Fibers;Muscle Weakness;Muscle function;Operative Surgical Procedures;Outcome;Patient Outcomes Assessments;Patients;Physical therapy;Physiological;Physiology;Positioning Attribute;Process;Production;Property;Protocols documentation;Quadriceps Muscle of the Thigh;Recovery;Rehabilitation therapy;Research;Research Design;Research Personnel;Scientist;Senior Scientist;Structure;Testing;Time;Tissues;Training;Translating;United States National Institutes of Health;Universities;anterior cruciate ligament reconstruction;base;clinically significant;cohort;college;evidence base;experience;follow-up;functional outcomes;improved;innovation;interest;joint loading;muscular structure;novel;professor;public health relevance;reconstruction;rehabilitation strategy;response to injury;skills;strength training;vastus lateralis

public_health_relevance:
Identification of the underlying cellular and myofiber adaptations that contribute to the loss of quadriceps strength after an ACL reconstruction is essential to develop improved physical therapy interventions and functional outcomes.


application_id: 8442267
project_number: 5R01GM077422-05
project_title: Targeting Nucleic Acids with an Integrated Virtual and Actual Screen
administering_ic: NIGMS
award_notice_date: 2013-03-29
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: GM
serial_number: 077422
program_official: PREUSCH, PETER
project_start_date: 2007-02-01
project_end_date: 2016-03-31
study_section: Macromolecular Structure and Function B Study Section[MSFB]
contact_pi_person_id: 1863983
contact_pi: CHAIRES, JONATHAN B.
other_pis: TRENT, JOHN O
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  DNA remains an underrepresented target for small molecule therapeutic agents. There is mounting evidence to indicate that non-B DNA structures play prominent roles in gene expression and in the function of telomeres. Targeting these structural elements is an attractive and innovative strategy for the development of new therapeutic agents. The use of small molecules in such an antigene strategy is promising for many reasons. Targeting the gene before its amplification to produce multiple mRNA and protein molecules is advantageous because there are fewer targets to hit. In addition is easier to manipulate small molecules (rather than therapeutic DNA or RNA molecules) chemically to optimize binding and pharmacological properties. We seek renewal for our innovative and highly productive program to develop an integrated virtual and actual screening platform for the discovery of new lead compounds that bind selectively to unique DNA structures of biological significance. Progress during the initial funding period was outstanding and we achieved most of the specific aims proposed in our initial proposal. We have discovered several compounds that bind selectively to particular quadruplex structures a target of intense current interest. We propose studies that will continue to develop and optimize the integrated screening platform. During the next funding period we will focus on the discovery of lead compounds that bind selectively to biologically important quadruplex and DNA-RNA hybrid structures. In order to do this we will develop structural models for complex quadruplex structures using a novel approach that integrates molecular dynamics simulations with rigorous experimental validation. We will characterize the biophysical and functional properties of the novel quadruplex binders we have discovered during the initial funding period. Specific aims include: 1. Development and refinement of the virtual screening platform. 2. Development of higher-throughput assays for ligand binding. 3. Discovery of lead compounds that bind to functionally important nucleic acid structures. 4. Biophysical and biological characterization of novel G-quadruplex binding agents discovered during the initial funding period. The proposed studies will deliver an improved integrated platform for the discovery of novel lead compounds and a thorough characterization of several newly-discovered quadruplex binders with unique chemical scaffolds.

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

public_health_relevance:
This project will develop an integrated computational and experimental screening platform for the discovery of new drugs that target specific structures of functional importance within the genome. The initial funding period for this project was successful and productive and we will continue our efforts. Several novel lead compounds were discovered that bind to functionally important quadruplex structures. We will characterize the biophysical and biological properties of these novel agents.


application_id: 8442017
project_number: 1R21AI103980-01A1
project_title: Identification of diagnostic markers for lupus nephritis
administering_ic: NIAID
award_notice_date: 2013-01-18
opportunity_number: PA-11-261
application_type: 1
activity_code: R21
ic: AI
serial_number: 103980
suffix: A1
program_official: JOHNSON, DAVID R
project_start_date: 2013-01-18
project_end_date: 2014-12-31
study_section: Pathobiology of Kidney Disease Study Section[PBKD]
contact_pi_person_id: 8638278
contact_pi: POWELL, DAVID W.
other_pis: MCLEISH, KENNETH R
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Renal involvement in systemic lupus erythematosus (SLE) termed lupus nephritis (LN) occurs in about 60% of patients and is a leading cause of morbidity and mortality. Membranous lupus nephritis (MLN) (class V) is described in 15% to 40% of renal biopsies in these patients. The proposed pathogenesis of all classes LN is the glomerular deposition of immune complexes containing auto-antibodies. Three hypotheses describing how immune complexes containing  nephritigenic antibodies are deposited in glomeruli have been proposed deposition of  circulating immune complexes binding of anti-nuclear antibodies to antigens "planted" in the  glomerulus and cross reactivity of anti-nuclear antibodies with glomerular constituents. A proteomic approach similar to that proposed in this application was used to determine that an auto-antibody to the M-type phospholipase A2 receptor (PLA2R) is responsible for immune complex deposition in idiopathic membranous nephropathy. This antibody is present in 70% to 80% of patients with idiopathic membranous nephropathy but it is not present in patients with MLN. This suggests a new hypothesis that patients with MLN develop unique auto-antibodies against an endogenous component of the glomerular capillary. The current proposal will use proteomic approaches that were successfully employed by our group in idiopathic membranous nephropathy to identify and verify specific glomerular proteins to which autoantibodies that cause MLN are directed.

project_terms:
Actinin;Address;Adrenal Cortex Hormones;African American;Antibodies;Antigen Targeting;Antigen-Antibody Complex;Antineutrophil Cytoplasmic Antibodies;Autoantibodies;Binding (Molecular Function);Biological Markers;Biopsy;Cerebritis;Classification;Collaborations;Collagen Type IV;Deposition;Development;Diagnostic;Disease;Early Diagnosis;Epitopes;Functional disorder;Glomerular Capillary;Heparitin Sulfate;Hepatitis C;Idiopathic Membranous Nephropathy;Immunosuppressive Agents;Kidney;Kidney Diseases;Kidney Failure;Laminin;Lupus;Lupus Nephritis;Membranoproliferative Glomerulonephritis;Membranous Glomerulonephritis;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mus;Neurons;Nuclear;Nucleosomes;Outcome;Pathogenesis;Patients;Phospholipase A2;Plant Antigens;Plants;Prevalence;Proteins;Proteomics;Recombinant Proteins;Reporting;Serum;Systemic Lupus Erythematosus;Tissues;base;cross reactivity;mouse model;novel therapeutics;podocyte;public health relevance;receptor;therapy development

public_health_relevance:
The expected outcomes of the proposed studies will be the identification of specific target proteins for nephritigenic autoantibodies that induce membranous lupus nephritis (MLN). The impact of the proposed studies will be confirmation of a common pathophysiology for idiopathic and lupus membranous nephropathy identification of a biomarker for Class V MLN that allows early diagnosis definition of a biomarker for MLN that can be used to follow efficacy of treatment and development of new therapeutic strategies based on identification of the epitope to which nephritigenic autoantibodies are directed. Additionally definition of the target for nephritigenic autoantibodies and comparison with autoantibodies found in murine models of LN will allow development of a mouse model of MLN.


application_id: 8439944
project_number: 1R01DE022597-01A1
project_title: Bacterial peptidylarginine deiminase a link between gums and joint disease
administering_ic: NIDCR
award_notice_date: 2013-02-01
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: DE
serial_number: 022597
suffix: A1
program_official: LUNSFORD, DWAYNE
project_start_date: 2013-02-01
project_end_date: 2018-01-31
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: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
project_terms:
Affect;Anaphylatoxins;Antibodies;Arginine;Atherosclerosis;Autoantibodies;Autoimmune Responses;Autoimmunity;Bacteria;Bioinformatics;Biological;Bone Resorption;Bradykinin;C-terminal;CAP18 lipopolysaccharide-binding protein;Chronic;Cigarette Smoker;Citrulline;Clinical;Collagen Arthritis;Complement;Complement 3a;Complement 5a;Complex;Connective Tissue;Cysteine Protease;Data;Dental Plaque;Development;Disease;Environment;Enzymes;Epidemiology;Epitopes;Exposure to;Forsythia;Generations;Gingiva;Gingival Crevicular Fluid;Homeostasis;Homologous Gene;Human;Immune;Immune Tolerance;Immune response;Immune system;Individual;Infection;Inflammation;Inflammatory;Intervention;Joints;Kinins;Knowledge;Lesion;Light;Link;Lung;Microbial Genome Sequencing;Molecular;Natural Immunity;Organism;Pathogenesis;Pathogenicity;Pathology;Patients;Peptides;Peptidoglycan;Periodontal Diseases;Periodontitis;Physiological;Population;Porphyromonas gingivalis;Post-Translational Protein Processing;Predisposition;Prevention;Process;Properdin;Protein-arginine deiminase;Proteins;Reaction;Reporting;Research;Research Proposals;Resistance;Rheumatoid Arthritis;Role;Serum;Signal Transduction;Site;Source;Substrate Specificity;Synovial Fluid;System;TNFRSF10A gene;Tissues;Tooth Loss;Tooth structure;Transgenic Mice;Treponema denticola;Validation;Virulence Factors;alveolar bone;arthropathies;bactericide;base;complement pathway;fimbria;gingipain;in vivo;innovation;interest;microbial;novel strategies;pathogen;pathogenic bacteria;polypeptide;preference;protein structure function;public health relevance;three dimensional structure;tool

public_health_relevance:
Rheumatoid arthritis is characterized by the development of autoantibodies against citrullinated proteins within the joints in susceptible individuals. Porphyromonas gingivalis a known periodontal pathogen is the only known bacterium which produces an enzyme (PPAD) that is capable of converting arginine residues in proteins into citrullin. It is hypothesized that PPAD activity in inflamed infected periodontal tissues not only
contributes to the pathology of periodontitis but also may promote breakdown of immunotolerance and initiates the development of rheumatoid arthritis.


application_id: 8439792
project_number: 1R01DK091338-01A1
project_title: Low-dose irradiation as a novel intervention for diabetic nephropathy
administering_ic: NIDDK
award_notice_date: 2013-09-09
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: DK
serial_number: 091338
suffix: A1
program_official: FLESSNER, MICHAEL FRANCIS
project_start_date: 2013-09-15
project_end_date: 2015-08-31
study_section: Radiation Therapeutics and Biology Study Section[RTB]
contact_pi_person_id: 6879103
contact_pi: CAI, LU
other_pis: Not Applicable
congressional_district: 03
department: PEDIATRICS
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 goal of this study is to develop low-dose radiation (LDR) as a new tool to prevent and treat diabetic nephropathy. Currently no effective preventive or therapeutic approaches are available to treat diabetic nephropathy which is the most common cause of renal failure. We have been investigating the biological effects of LDR including its hormesis and adaptive response in vitro
and in vivo. A major advantage of LDR is that it activates many genes in antioxidant and anti-inflammatory pathways rather than just single protective gene potentially making LDR a very potent and novel therapeutic approach. This was borne out by our preliminary studies that show that LDR at 25 mGy decreases diabetic nephropathy by significantly reducing diabetes-induced renal oxidative damage and inflammation. Our latest preliminary data show up-regulation of nuclear factor erythroid 2-related factor 2 (Nrf2) expression and protein kinase B (also called Akt) phosphorylation in the kidney of diabetic mice also exposed to LDR at 25 mGy. NRF2 is a transcription factor involved in expression of a broad range of protective genes. Therefore our central hypothesis is that exposure of diabetic animals to LDR can prevent and treat diabetic nephropathy by activation of many protective genes through stimulation of the Nrf2 pathway.  This hypothesis will be tested through three specific Aims: (1) LDR at the optimal condition not only prevents but also delay diabetic nephropathy; (2) the optimal LDR is safe for diabetic subjects; (3) the renal protection by the optimal LDR is predominantly mediated by up- regulating Nrf2-mediated multiple antioxidant components.  The great advantage of LDR is that it offers a highly controllable non-invasive method for eliciting endogenous synergistic tissue protection and repair mechanisms. This innovative approach will be particularly valuable for the diabetic patient who already has significantly decreased renal function that increases the toxicity
of invasive drugs. Therefore this project will open a new avenue for the prevention and treatment of diabetic complications.

project_terms:
Adverse effects;Animals;Anti-Inflammatory Agents;Anti-inflammatory;Antioxidants;Apoptotic;Biological;Cell Death;Cell Nucleus;Cell Proliferation;Complications of Diabetes Mellitus;Cytogenetics;Cytosol;Data;Diabetes Mellitus;Diabetic Nephropathy;Diabetic mouse;Disease;Dose;Drug Combinations;Drug Targeting;Drug usage;Frequencies (time pattern);Genes;Germ Cells;Glycogen Synthase Kinases;Goals;Harvest;In Vitro;Inflammation;Intervention;Kidney;Kidney Diseases;Kidney Failure;Low Dose Radiation;Mediating;Methods;Modality;Modeling;Mus;Organ;Pathway interactions;Pharmaceutical Preparations;Phosphorylation;Prevention;Preventive;Protein Tyrosine Kinase;Proto-Oncogene Proteins c-akt;Proto-Oncogenes;Radiation;Radiation therapy;Reactive Oxygen Species;Renal function;Renin-Angiotensin System;Risk;Rodent;Role;Safety;Streptozocin;Testing;Therapeutic;Therapeutic Effect;Tissues;Toxic effect;Up-Regulation (Physiology);Work;cytotoxic;diabetic;diabetic patient;in vivo;innovation;irradiation;mouse model;novel;novel strategies;novel therapeutic intervention;nuclear factor-erythroid 2;oxidative damage;prevent;public health relevance;repaired;response;safety testing;tool;transcription factor

public_health_relevance:
The objective of this study is to apply low-dose radiation (LDR) as a new and non-invasive tool to prevent and treat diabetic nephropathy through stimulation of renal multiple protective mechanisms against oxidative damage and inflammation. We will firstly define the optimal condition of LDR to prevent and treat diabetic nephropathy with type 1 and type 2 diabetic mouse models and then determine the safety for diabetic subjects to expose to LDR and underlying mechanisms for the renal protection from diabetes by LDR. This project represents a unique approach to apply LDR to activate multiple protective pathways unlike most currently- used drugs only working on a single pathway.


application_id: 8438609
project_number: 1R01HL113494-01A1
project_title: Treatment of Skeletal Muscle Dysfunction in ICU Patients
administering_ic: NHLBI
award_notice_date: 2013-07-28
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: HL
serial_number: 113494
suffix: A1
program_official: HARABIN, ANDREA L
project_start_date: 2013-08-01
project_end_date: 2018-04-30
study_section: Special Emphasis Panel[ZRG1 MOSS-A (02)]
contact_pi_person_id: 1879110
contact_pi: SUPINSKI, GERALD 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
project_abstract:
DESCRIPTION (provided by applicant): Recent studies indicate that mechanically ventilated MICU patients develop severe respiratory and limb muscle weakness and that weakness is associated with poor clinical outcomes in these patients. As a result administration of drugs that
improve skeletal muscle strength should theoretically reduce the need for mechanical ventilation shorten hospital stay improve mortality and increase exercise tolerance in this patient population. The purpose of the present proposal is to address this issue and evaluate the impact of anabolic agents on strength and outcomes in a large diagnostically broad based MICU patient population. Two experiments are planned:  Aim 1 will test the hypothesis that limb and respiratory skeletal muscle weakness in critically ill patients can be attenuated by administration of hydroxymethylbutyrate (HMB) and/or eicosapentaenoic acid (EPA). We will first measure indices of muscle strength (magnetically stimulated diaphragm and quadriceps strength) muscle size (diaphragm and quadriceps thickness) and quadriceps muscle biopsy characteristics (force-pCa relationships biomarker levels). We will next randomize mechanically ventilated MICU patients to receive either placebo HMB EPA or both HMB+EPA for 10 days. We will then repeat parameter testing (muscle strength size and biopsy characteristics) on days 11 and 21. Data will be analyzed to determine if anabolic treatments improve muscle strength increase muscle size alter muscle biomarker levels and reduce the duration of mechanical ventilation.  Aim 2 will test the hypothesis that muscle training will augment the response to muscle strength enhancers (HMB+EPA) in mechanically ventilated MICU patients. We will measure muscle strength size and biomarker levels. We will then randomize patients to either placebo muscle strength enhancers (HMB+EPA) alone targeted muscle training alone (loaded breathing leg cycling exercise) or the combination of strength enhancers plus muscle training for 10 days. Parameter assessment will be repeated at days 11 and 21. We will determine if these treatments improve muscle strength muscle size alter biomarkers and reduce the duration of mechanical ventilation.  Our pilot study data suggest that both EPA and HMB can induce increases in both limb and respiratory muscle strength shortening the duration of mechanical ventilation in critically ill patients. These data support our hypotheses and suggest that the proposed studies are likely to define a new treatment that will have an important impact on the care of critically ill patients.

project_terms:
Activities of Daily Living;Address;Anabolic Agents;Attenuated;Biological Markers;Biopsy;Breathing;Caring;Characteristics;Clinical;Critical Illness;Data;Diaphragm (Anatomy);Disease;Drug Combinations;Eicosapentaenoic Acid;Enhancers;Exercise;Exercise Tolerance;Financial cost;Functional disorder;Hospitals;Hyperglycemia;Intensive Care Units;Leg;Length of Stay;Limb structure;Measurement;Measures;Mechanical ventilation;Medical;Morbidity - disease rate;Mortality Vital Statistics;Muscle;Muscle Weakness;Muscle function;Outcome;Patient Care;Patients;Performance;Pharmaceutical Preparations;Pharmacotherapy;Physicians;Pilot Projects;Placebos;Pneumonia;Quadriceps Muscle of the Thigh;Randomized;Reporting;Respiratory Failure;Respiratory Muscles;Skeletal muscle structure;Testing;Thick;Training;Ventilator;Work;base;cytokine;design;improved;indexing;muscle strength;patient population;pressure;prevent;public health relevance;research study;respiratory;response;theories;treatment effect

public_health_relevance:
Skeletal muscle weakness is a major contributor to morbidity and mortality in critically ill MICU patients but currently there is no drug therapy available for his problem. The studies in this proposal are designed to identify a practical safe and potent therapy to prevent/reverse skeletal muscle weakness in these patients. We believe this work will define a new treatment that will have a major impact on the care of critically ill patients.


application_id: 8438584
project_number: 1R01HL112085-01A1
project_title: Effects of Sleep Deprivation on Infection Induced Organ Failure
administering_ic: NHLBI
award_notice_date: 2013-02-15
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: HL
serial_number: 112085
suffix: A1
program_official: LAPOSKY, AARON D
project_start_date: 2013-02-15
project_end_date: 2017-01-31
study_section: Surgery, Anesthesiology and Trauma Study Section[SAT]
contact_pi_person_id: 6210708
contact_pi: CALLAHAN, LEIGH 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
project_abstract:
DESCRIPTION (provided by applicant): Recent studies indicate that critically ill patients experience poor sleep frequent disruptions loss of circadian rhythm and a marked reduction of the percentage of sleep time spent in restorative stages. Importantly sleep deprivation in these patients may have adverse consequences. In keeping with this concept two recent animal studies found that sleep deprivation markedly increases death in sepsis but the mechanisms responsible for this phenomenon are completely unknown. We will test the specific hypotheses that sleep deprivation interacts with infection to activate endoplasmic reticulum (ER) stress pathways and that ER stress pathway activation in turn causes failure of multiple organs. Aim 1 will determine if infection and sleep deprivation synergistically induce ER stress in multiple tissues and if ER stress pathway activation produces organ failure. Studies will be performed using animal models of sepsis (cecal ligation and puncture CLP) and sleep deprivation (SD). Experiment 1.1 will test the hypothesis that sepsis and sleep deprivation interact to induce ER stress with ER stress pathways activated in parallel with development of organ failure. Experiment 1.2 will test the hypothesis that chemical activation of ER stress triggers pathological alterations (e.g. activation of downstream proteolytic pathways) that produce organ dysfunction. Aim 2 will elucidate the upstream mechanisms by which sepsis and sleep deprivation activate ER stress pathways. Experiment 2.1 will test the hypothesis that cytokine-induced production of reactive oxygen species (ROS) is the key upstream trigger that activates ER stress in sepsis. Experiment 2.2 will test the hypothesis that upstream alterations in peripheral tissue clock gene function activate ER stress pathways in response to sleep deprivation. Experiment 2.3 will test the hypothesis that disruption of peripheral tissue clock function increases ROS generation and activates ER stress pathways. Aim 3 will determine if administration of pharmacological inhibitors of ER stress pathways improves organ function in sepsis and sleep deprivation. Experiments 3.1 3.2 and 3.3 will test the hypothesis that either z-
ATAD-fmk (a caspase 12 inhibitor) salubrinal (a selective inhibitor of eIF2 dephosphorylation) or melatonin (an endogenous hormone that inhibits the IRE1 pathway) will block ER stress pathway dependent cell damage and improve organ function in CLP+SD. Experiment 3.4 will test the hypothesis that delayed administration of the pharmacologic agent to found to produce the best therapeutic effect will block ER stress pathway dependent cell damage and improve organ function in CLP+SD.

project_terms:
Animal Model;Animals;Area;Cause of Death;Cells;Cessation of life;Chemicals;Circadian Rhythms;Cognitive;Complex;Critical Illness;Data;Development;Diagnostic tests;Disease;Functional disorder;Generations;Genes;Goals;Heart Diseases;Hormones;Hospitalization;Infection;Ligation;Light;Malignant Neoplasms;Melatonin;Modeling;Mortality Vital Statistics;Multiple Organ Failure;Noise;Organ;Organ failure;Pathway interactions;Patients;Peripheral;Pharmaceutical Preparations;Physiological;Population;Production;Protein Dephosphorylation;Puncture procedure;Reactive Oxygen Species;Recovery;Risk;Sepsis;Sleep;Sleep Deprivation;Staging;Survivors;Testing;Therapeutic Effect;Time;Tissues;United States;adverse outcome;caspase 12;cell injury;cytokine;endoplasmic reticulum stress;experience;gene function;improved;inhibitor/antagonist;novel therapeutics;nursing intervention;psychologic;public health relevance;research study;response;septic

public_health_relevance:
During hospitalization patients' sleep is constantly disrupted due to diagnostic tests frequent nursing interventions noise from alarms and changes in light levels. Recent studies show that sleep deprivation increases death when combined with infection but how this occurs is not known. We have discovered that sleep disruption during infection activates pathways that cause several of the body's organs to fail so the purpose of our proposal is to determine the cellular mechanisms responsible for the interaction of sleep deprivation and infection and to define new treatments which may improve survival and recovery in hospitalized patients.


application_id: 8438560
project_number: 2R01DK074816-05A1
project_title: Albumin AFP Gene Family Regulation in Fetal and Adult Liver
administering_ic: NIDDK
award_notice_date: 2012-09-25
opportunity_number: PA-11-260
application_type: 2
activity_code: R01
ic: DK
serial_number: 074816
suffix: A1
program_official: SERRANO, JOSE
project_start_date: 2007-09-01
project_end_date: 2016-06-30
study_section: Hepatobiliary Pathophysiology Study Section[HBPP]
contact_pi_person_id: 1879406
contact_pi: SPEAR, BRETT
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The liver performs numerous metabolic and homeostatic functions in the body including xenobiotic metabolism energy storage/production urea formation glutamine synthesis and cholesterol homeostasis. While some liver functions (such as albumin secretion) can be carried out by all hepatocytes other functions are limited to a subset of hepatocytes and determined by cell position within the lobule. Specifically certain enzymes are expressed only in cells surrounding the central vein whereas others are expressed only in hepatocytes surrounding the portal triads. This phenomenon is called positional (or zonal) heterogeneity or metabolic zonation. This compartmentalization of function enables the liver to perform multiple and sometimes opposing metabolic pathways in distinct hepatocyte subpopulations. Zonal gene regulation is essential for normal liver function. Disruption of zonally
regulated metabolic processes can alter carbohydrate and lipid metabolism ammonia detoxification and biliary function. A number of agents (alcohol drugs and toxins) preferentially damage hepatocytes surrounding the central veins due to restricted expression of P450 enzymes in these cells. Thus zonal control of gene expression has significant clinical implications. The overall objective of this proposal is to develop a better understanding of zonal gene regulation. Based on our studies on mouse alpha-fetoprotein (AFP) gene regulation we have developed a model of zonal regulation. Specifically we have found that AFP enhancer element E3 exhibits highly restricted activity in hepatocytes surrounding the central vein in the adult liver. Building on studies performed by our lab and others we will investigate the role of a
subfamily of orphan nuclear receptors and the Wnt/b-catenin/TCF signaling pathway in the control of E3. These studies utilize a unique set of reagents and transgenic mouse lines developed in our lab. The long-term goal of these studies is to understand the basic mechanisms that govern the zonal regulation of many liver genes which will lead to better treatment of liver disease in humans.   
   
PUBLIC HEALTH RELEVANCE: The liver is a complex organ that must coordinately express numerous proteins to facilitate proper development and maintain normal physiological homeostasis. In the adult liver appropriate gene expression including zonal gene expression must be maintained during normal conditions when hepatocytes are generally quiescent and during disease when some hepatocytes may be damaged and others may be proliferating. Our ongoing studies on the control of alpha-fetoprotein enhancer activity described in this proposal will help elucidate aspects of zonal gene expression in the adult liver.


application_id: 8437692
project_number: 1R01DA033394-01A1
project_title: Targeting GABA and Opioid Systems for a Pharmacotherapy for Methamphetamine Abuse
administering_ic: NIDA
award_notice_date: 2013-09-18
opportunity_number: PA-10-268
application_type: 1
activity_code: R01
ic: DA
serial_number: 033394
suffix: A1
program_official: HAMPSON, AIDAN
project_start_date: 2013-09-30
project_end_date: 2016-08-31
study_section: Special Emphasis Panel[ZRG1 RPIA-N (09)]
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): Methamphetamine (MA) abuse and dependence are significant public-health concerns. Treatment admissions for MA use increased at an alarming rate from 1998 to 2007 in the US. Behavioral treatments reduce MA use. However many patients enrolled in behavioral treatment programs are unable to achieve a significant period of abstinence suggesting other strategies like pharmacotherapy are urgently needed. G-Aminobutyric-acid (GABA) and opioid systems modulate dopamine. GABAA receptor modulators (e.g. oxazepam [OXP]) and opioid antagonists (e.g. naltrexone [NTX]) attenuate the abuse-related effects of amphetamines. The attenuation of the abuse-related effects of amphetamine by GABAA receptor modulators or opioid antagonists while statistically significant is modest in magnitude. Novel strategies are needed to enhance the efficacy of these drugs. Targeting GABA and opioid systems simultaneously is an innovative strategy in that combining NTX and OXP may produce greater attenuation of the abuse-related effects of MA. A rigorous within-subject experiment will be conducted in non-treatment-seeking MA-abusing participants. NTX (0 and 50 mg/day) and OXP (0 and 40 mg/day) alone and in combination will be tested with MA (0 10 20 and 30 mg). The four NTX-OXP maintenance conditions will be tested in random order. Similarly within each NTX-OXP condition the MA doses will be tested in random order. The reinforcing effects of intranasal MA doses will be determined after four days of maintenance on each of the NTX-OXP conditions using a sensitive progressive-ratio procedure. The ability to attenuate the reinforcing effects of drugs is
a reliable predictor of an effective pharmacotherapy. We hypothesize that combining NTX and OXP will produce an additive or supra-additive reduction in the reinforcing effects of MA relative to the constituent drugs alone. This research will provide critical information regarding the initil efficacy a novel drug combination NTX and OXP for MA dependence. Innovations of the proposed research include: 1) testing a combination of marketed drugs that demonstrated some efficacy when tested as mono-therapies; 2) testing a GABAA receptor modulator that has minimal abuse potential and dependence liability which will likely be more acceptable to clinicians; 3) the use of a sensitive drug self-administration procedure; 4) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of NTX-OXP combinations for MA dependence; and 5) demonstrating the initial efficacy of commercially available drugs as opposed to waiting for novel molecules to be available for testing in humans thereby impacting clinical research and practice more quickly. In these ways the proposed project will shift the current clinical research paradigm in pharmacotherapy development and have a significant impact on the treatment of MA dependence.

project_terms:
Abstinence;Admission activity;Adverse effects;Alprazolam;Aminobutyric Acids;Amphetamines;Animals;Attenuated;Behavior Therapy;Behavioral;Cardiovascular system;Chronic;Clinical Research;Clinical Trials;Cocaine Dependences;Cognitive Therapy;Communicable Diseases;Crime;Data;Data Analyses;Dependence;Development;Dopamine;Dose;Drug Combinations;Drug-sensitive;Enrollment;Human;Impaired cognition;Laboratories;Maintenance;Mediating;Medical;Methamphetamine;Methamphetamine dependence;Mono-S;Naltrexone;Narcotic Antagonists;National Institute of Drug Abuse;Opioid;Outcome Measure;Oxazepam;Participant;Patients;Pharmaceutical Preparations;Pharmacotherapy;Phase II Clinical Trials;Physiological;Play;Premature Mortality;Probability;Procedures;Productivity;Questionnaires;Relative (related person);Reporting;Research;Role;Safety;Self Administration;System;Testing;United States;addiction;attenuation;clinical practice;contingency management;cost;dopamine system;double-blind placebo controlled trial;drug efficacy;drug market;drug reinforcement;indexing;innovation;methamphetamine abuse;novel;novel strategies;public health medicine (field);public health relevance;receptor;research study;secondary outcome;stimulant abuse;success;tool;treatment program

public_health_relevance:
The research proposed in this application will provide critical information regarding the initial efficacy safety and tolerability of a novel drug combination naltrexone and oxazepam as a pharmacotherapy for methamphetamine dependence. The proposed research is innovative because it will demonstrate the initial efficacy of commercially available drugs as opposed to waiting for novel molecules to be available for testing in humans thereby impacting clinical research and practice more quickly. The proposed study is important because it will provide the impetus for the conduct of double blind placebo-controlled trials to further demonstrate the efficacy of naltrexone-oxazepam combinations for managing cocaine dependence. If these trials demonstrate efficacy they will provide clinicians with a pharmacological tool for managing methamphetamine dependence.


application_id: 8437263
project_number: 5R01DA027981-04
project_title: Victimization and Women in the Criminal Justice System
administering_ic: NIDA
award_notice_date: 2013-02-19
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: DA
serial_number: 027981
program_official: DEEDS, BETHANY
project_start_date: 2010-04-01
project_end_date: 2015-02-28
study_section: Community Influences on Health Behavior Study Section[CIHB]
contact_pi_person_id: 6472821
contact_pi: GOLDER, SEANA
other_pis: Not Applicable
congressional_district: 03
department: NONE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF SOCIAL WELFARE/WORK
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposed study (R01; PA-07-070) will examine the heterogeneity of victimization its' relationship with substance use and psychological distress as well as the combined affect of these factors on the health seeking process among victimized women in the criminal justice (CJ) system. Study aims are to 1) identify and characterize latent class trajectories based on victimization substance use and psychological distress among 400 victimized women on probation and parole; 2) determine the extent to which women in the identified trajectory classes vary over a two year time period in levels of risk and protection in the health seeking process; and 3) examine the theory based components of the health seeking process among 400 victimized women on probation and parole. Findings from this research will be used to identify those groups of women that are most at risk for engagement in high risk behaviors (current drug use; psychological distress; HIV risk behavior; lawbreaking and continued CJ involvement) and to identify and characterize their associated levels of risk and protection in the health seeking process across a two year time period. Study findings will provide a theoretically guided understanding of the relationship among the component parts of the health seeking process that affect engagement in high risk behavior over time among this population. These data are necessary prerequisites to the development of tailored intervention strategies that target specific groups of women within the CJ system; these data can provide practitioners administrators and policy makers with direct information about which groups of women will be most amenable to which intervention/prevention approaches. Study findings have the potential to have broad relevance within the CJ system and other care systems (e.g. substance abuse and mental health treatment systems) that provide services to this marginalized and growing population.

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

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


application_id: 8435448
project_number: 5R01ES018883-04
project_title: HIF-alphia in Cr(VI) carcinogenesis
administering_ic: NIEHS
award_notice_date: 2013-04-09
opportunity_number: PA-07-070
application_type: 5
activity_code: R01
ic: ES
serial_number: 018883
program_official: QUINN, ASHLINN KO
project_start_date: 2010-08-09
project_end_date: 2015-03-31
study_section: Cancer Etiology Study Section[CE]
contact_pi_person_id: 10011919
contact_pi: ZHANG, ZHUO
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Although the carcinogenicity of Cr(VI) has been well documented by studies both in vitro and in vivo its mechanism of action remains to be investigated. Our recent studies indicate that Cr(VI) induces HIF-11 activation. MAP kinase p38 and reactive oxygen species (ROS) are involved in this process. HIF-11 is a key regulatory protein for angiogenesis which is a physiological process involving the growth of new blood vessels from pre-existing vessels. Solid tumors of smaller than 1 to 2 cubic millimeters are not vascularized. To spread they need to be supplied by blood vessels that bring oxygen and nutrients and remove metabolic wastes. Inhibition of HIF-11 decreases cell transformation capacity in hypoxia and tumor growth in vivo while overexpression of HIF-11 allows anchorage-independent growth in normoxia and development of more aggressive tumors. Since HIF-11 is important in cancer initiation and progression it is likely that HIF-11 activation and angiogenesis could be important in Cr(VI)-mediated carcinogenesis. We hypothesize that ROS and HIF-11 activation play an important role in Cr(VI)-induced carcinogenesis. Human bronchial epithelial BEAS-2B cells and athymic female nude mice (3-4 weeks old) deficient in thymus-dependent (T-cell) immunological functions will be used in the present study. Three specific aims are proposed. Aim 1 will investigate the mechanism of Cr(VI)-induced ROS generation and the role of ROS in activation of HIF-11 and angiogenesis in vitro. The regulation of HIF-1 activity could occur at multiple levels: transcription translation and post-translational modifications. The questions remain open concerning at what level Cr(VI) induces HIF-11 activation. Aim 2 will answer that question in cell system. Aim 3 will investigate the roles of ROS and HIF-1 signaling in Cr(VI)-induced cell transformation in vitro tumorigenesis tumor growth and metastasis in vivo. We anticipate that Cr(VI) induces angiogenesis via HIF-11 activation through ROS and MAP kinase p38 promoting Cr(VI)-induced cell transformation tumorigenesis tumor growth and metastasis. .

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

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


application_id: 8435362
project_number: 5R01HL056652-15
project_title: Molecular Mechanism of Platelet Exocytosis
administering_ic: NHLBI
award_notice_date: 2013-04-04
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: HL
serial_number: 056652
program_official: SARKAR, RITA
project_start_date: 1996-07-01
project_end_date: 2016-03-31
study_section: Hemostasis and Thrombosis Study Section. Committee was terminated on 11/30/2020. [HT]
contact_pi_person_id: 1887348
contact_pi: WHITEHEART, SIDNEY WALDO
other_pis: Not Applicable
congressional_district: 06
department: BIOCHEMISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Platelets are central to hemostasis because they respond to vascular damage and secrete a variety of granule cargo molecules which are critical to thrombosis and its normal as well as pathogenic sequellae. This property makes platelets a target for modulation of hemostasis but it also raises questions about how these anucleated cell fragments function. Are platelets an active participant specifically releasing context-appropriate material or are they random delivery devises? The overall goal of this proposal is to understand the process of platelet secretion at the cellular and molecular level. The first Aim addresses one of the most important questions facing the field. Is platelet secretion thematically responsive? The experiments in Aim 1 will characterize the heterogeneity in cargo release from activated platelets. The goal is to determine if platelet secretion is thematic stochastic or controlled kinetically. Micro-ELISA assays will be used to measure the secretion of several released molecules and detailed mathematical analysis of the release kinetics will be used to identify patterns. The second Aim seeks to dissect a novel signaling cascade that directly controls platelet secretion. The goal is to identify the signaling pathways that activate IkB Kinase to phosphorylate SNAP-23 and to determine how the modification affects platelet secretion. This Aim focuses on the role that IkB Kinase (IKK) plays in regulating platelet secretion by probing both how the kinase is activated and how SNAP-23 phosphorylation affects platelet secretion. Additional studies will determine if IKK inhibitors can be used as anti-thrombotic agents. The final Aim focuses on the mechanism of a limiting element of the platelet secretory machinery Munc13-4. The goal will be to define the mechanism by which Munc13-4 mediates platelet secretion. The experiments in this Aim will characterize the molecular mechanisms of Munc13-4 by probing its interactions and their roles in secretion. Since Munc13-4 is a limiting factor in platelets and is required for normal hemostasis it is an attractive target for therapeutic intervention. The experiments in the final Aim will yield the detailed molecular characterization required for such targeting. In sum the data gained for the proposed experiments will illuminate the process of platelet secretion and thus set the constraints for future models of platelet function in the vasculature. The experiments will also identify aspects of the secretory machinery that can be exploited for therapeutic intervention to modulate thrombosis. Cardiovascular disease is the #1 cause of death in the US and is estimated to cost $500 billion in medical expenses and lost productivity in 2010 (AHA Fact Sheet). These staggering statistics underline the need for new therapeutic agents designed to ameliorate the pathologies associated with platelet dysfunction. The insights gained from the proposed experiments and their potential for identifying novel targets will clearly benefit the search for such agents.

project_terms:
Address;Adhesions;Affect;Agonist;Atherosclerosis;Attenuated;Basic Science;Biochemical;Biochemistry;Biological Assay;Blood Clot;Blood Platelets;Blood Vessels;Blood coagulation;Blood flow;Cardiovascular Diseases;Cause of Death;Cell membrane;Cells;Cellular biology;Cessation of life;Clinical;Coagulation Process;Complex;Cytoplasmic Granules;Data;Defect;Development;Disease;Docking;Elements;Enzyme-Linked Immunosorbent Assay;Event;Exocytosis;Functional disorder;Future;Goals;Hemorrhage;Hemostatic function;Heterogeneity;In Vitro;Inflammation;Integral Membrane Protein;Kinetics;Knockout Mice;Knowledge;Lead;Learning;Measures;Mediating;Medical;Membrane Fusion;Modeling;Modification;Molecular;Monitor;Mus;Myocardial Infarction;Participant;Pathology;Pathway interactions;Pattern;Pharmaceutical Preparations;Phosphorylation;Phosphotransferases;Physicians;Platelet Activation;Play;Process;Productivity;Property;Publishing;Reaction;Risk;Role;S-nitro-N-acetylpenicillamine;SNAP receptor;Signal Pathway;Signal Transduction;Site;Sum;System;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Thrombosis;Time;United States;Work;Wound Healing;angiogenesis;base;cohort;cost;design;disability;enhancing factor;in vivo;insight;kinase inhibitor;neurotransmitter release;novel;novel therapeutics;outcome forecast;protein protein interaction;research study;response;statistics;stroke;target SNARE proteins;therapeutic target;wound

public_health_relevance:
Strokes and heart attacks are major killers in the United States and both are caused by a loss of blood flow usually because a blood clot has formed in the wrong place. This application focuses on how platelets release molecules that cause clot formation. This work is critical because it will direct the development of future drugs needed to decrease the risk of spurious clot formation.


application_id: 8435245
project_number: 1R01CA166499-01A1
project_title: A role for c-Abl/Arg in melanoma progression
administering_ic: NCI
award_notice_date: 2012-09-12
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: CA
serial_number: 166499
suffix: A1
program_official: SATHYAMOORTHY, NEERAJA
project_start_date: 2012-09-12
project_end_date: 2017-08-31
study_section: Tumor Progression and Metastasis Study Section[TPM]
contact_pi_person_id: 1918859
contact_pi: PLATTNER, RINA
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): Despite 35 years of clinical trials there has been little improvement in five-year survival rates with any chemotherapeutic regimen for the treatment of metastatic melanoma. Here we demonstrate a previously unrecognized role for Abl kinases in melanoma cells. We found that c-Abl/Arg non-receptor tyrosine kinases are activated in primary melanomas and in melanoma cell lines and promote proliferation survival cell-cell adhesion migration invasion and lung colonization/metastasis. In addition c-Abl/Arg promote matrigel invasion via STAT3 and MMP-dependent pathways; increase cell-cell adhesion; and dramatically induce degradation of a metastasis suppressor. Moreover drugs targeting c-Abl/Arg and Raf/MEK/ERK pathways cooperate to decrease melanoma viability. Based on these novel findings we hypothesize that c-Abl/Arg activate novel pathways that cooperate with B-Raf to promote melanoma cell-cell adhesion migration invasion and metastasis. We propose a comprehensive hypothesis-driven experimental design that will establish Abl kinases as novel and exploitable drug targets for metastatic melanoma. Aim 1 will define molecular pathways by which Abl kinases promote cell-cell adhesion migration and invasion. To achieve our objective we will combine biochemical molecular and cell biological approaches using RNAi pharmacological inhibitors constitutively active forms of c-Abl/Arg rescue experiments 2D/3D cell culture and melanoma- endothelial co-cultures to identify migration invasion and cell-cell adhesion signaling pathways driven by c- Abl/Arg. Aim 2 will test the prediction that c-Abl/Arg cooperates with Abl-independent pathways (e.g. B-Raf) to promote melanoma cell-cell adhesion migration and invasion. Finally three complementary approaches will be utilized in Aim 3 to identify mechanisms by which c-Abl/Arg promote metastasis. A novel GEM model that develops metastatic UV-induced melanomas and lung colonization and spontaneous metastasis xenograft models will be used to test the prediction that blocking c-Abl/Arg-dependent signaling pathways inhibits metastatic progression. We also will test whether B-Raf and c-Abl/Arg inhibitors cooperate to prevent metastasis of melanomas harboring B-Raf mutations. The data obtained from this proposal not only will allow us to gain insight into the fundamental mechanisms by which c-Abl/Arg drive invasion and metastasis but also will lead to clinical studies testing the efficacy of c-Abl/Arg inhibitors for treating metastatic disease.   
   
PUBLIC HEALTH RELEVANCE: Melanomas are essentially untreatable if they metastasize because they are resistant to all known chemotherapeutic agents. This proposal will solidify Abl kinases as novel druggable targets in melanoma by identifying mechanisms by which Abl kinases promote invasion and metastasis; determining which type of melanomas contain active Abl kinases; and testing whether Abl inhibitors cooperate with B-Raf inhibitors to kill melanoma cells and prevent metastatic progression. Data obtained from this proposal are likely to lead to the initiation of a clinical trial to test these novel drug combinations for treatment of metastati disease. 1

project_terms:
ABL1 gene;Anoikis;Biochemical;Biological;Cathepsin L;Cathepsins;Cell Adhesion;Cell Communication;Cell Culture Techniques;Cell Line;Cell Survival;Cell-Cell Adhesion;Cells;Clinic;Clinical;Clinical Research;Clinical Trials;Coculture Techniques;Data;Dermal;Detection;Development;Disease;Disease remission;Drug Combinations;Drug Delivery Systems;Endothelial Cells;Environment;Experimental Designs;Extravasation;FDA approved;Fibroblasts;Genetic Transcription;Goals;Imatinib;In Vitro;Killings;Lead;Lung;MEKs;Matrix Metalloproteinases;Mean Survival Times;Mediating;Melanoma Cell;Metastatic Melanoma;Modeling;Molecular;Mouse Strains;Mutation;N-Cadherin;NME1 gene;Neoplasm Metastasis;Outcome;Pathway interactions;Patients;Peptide Hydrolases;Phosphotransferases;Play;Positioning Attribute;Prevention;Protein Tyrosine Kinase;RNA Interference;Ras/Raf;Regimen;Research;Residual state;Resistance;Role;STAT3 gene;STI571 (Gleevec);Scientist;Seminal;Signal Pathway;Signal Transduction;Solid Neoplasm;Staging;Survival Rate;Testing;Transcriptional Activation;Treatment Protocols;UV-induced melanoma;Universities;Xenograft Model;base;c-abl Proto-Oncogenes;chemotherapeutic agent;design;efficacy testing;gain of function;inhibitor/antagonist;innovation;insight;leukemia;loss of function;matrigel;melanoma;migration;mutant;novel;novel therapeutics;prevent;research study;tool


application_id: 8435101
project_number: 1R01AA021978-01
project_title: Role of ECM and inflammatory remodeling in alcohol-induced liver and lung damage
administering_ic: NIAAA
award_notice_date: 2014-01-27
opportunity_number: PA-11-260
application_type: 1
activity_code: R01
ic: AA
serial_number: 021978
program_official: RADAEVA, SVETLANA
project_start_date: 2014-02-01
project_end_date: 2019-01-31
study_section: Special Emphasis Panel[ZRG1 DKUS-D (03)]
contact_pi_person_id: 2047731
contact_pi: ARTEEL, GAVIN E
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
project_abstract:
DESCRIPTION (provided by applicant): The overarching theme of this project is to study the role of nutrition and gut flora/intestinal dysfunction on alcohol-induced organ injury. We will focus on two organs that are the most common victims of chronic alcohol abuse: liver and lung. Specifically we will examine how alcohol activates tissue remodeling in liver and lung through the induction of plasminogen activator inhibitor-1 (PAI-1) and the consequences of these events. Novel in vitro and in vivo approaches will be used to address mechanisms of action with the goal of identifying new targets for intervention. We propose that liver and lung share similar mechanisms of organ damage in response to alcohol. We specifically propose that PAI-1 induction and subsequent extracellular matrix (ECM) remodeling are key to the early inflammatory changes in both organs. Considering observations linking the effects of alcohol on tissue remodeling in both organs we further propose that liver and lung not only share mechanisms of injury in response to alcohol but that these mechanisms are linked and represent interdependent events. Based on these observations and other preliminary data this proposal will test the hypothesis that alcohol through the activation of nicotinic acetylcholine receptors (nAChRs) induces the expression of PAI-1 in both liver (e.g. Kupffer cells) and lung (Type II epithelial cells). This in turn triggers a series of downstream events that promote live and lung injury in response to endotoxemia derived from the GI tract. Moreover we propose that liver-derived mediators further exacerbate lung injury through the induction of inflammation and tissue remodeling enhanced by inhibition of fibrinolysis. These hypotheses will be tested in the following Specific Aims: Aim 1: To explore the role of PAI-1 and nAChRs in the susceptibility of liver and lung to acute injury observed in the setting of chronic alcohol exposure. We hypothesize that alcohol stimulates the expression of PAI-1 in both liver and lung cells through effects on specific nAChRs. This in turn sensitizes both organs to acute injury (e.g. LPS). Aim 2: To test the hypothesis that liver-derived mediators are involved in pulmonary changes caused by chronic alcohol exposure and LPS- related organ damage. We propose that alcohol-induced damage to the liver sensitizes the host to acute lung injury in at-risk individuals. To test this e plan to evaluate the effects of alcohol on lung injury in animals with reduced hepatotoxicity using
genetically engineered and chimeric mice. Aim 3: To determine the role of gut- derived products on alcohol-induced lung damage. Gut changes/injury caused by alcohol consumption could directly or indirectly damage liver and lung tissue. However how gut:lung or gut:liver:lung interactions are influenced by alcohol remains unknown. We propose to test these concepts and to explore the effect of novel therapeutic interventions that target the GI tract to protect th lung.

project_terms:
Accounting;Acute;Address;Alcohol abuse;Alcohol consumption;Alcohol-Induced Disorders;Alcoholic Liver Diseases;Alcohols;Animals;Cells;Chronic;Clinical;Data;Deposition;Disease;Endotoxemia;Epithelial Cells;Ethanol;Event;Extracellular Matrix;Fibrin;Fibrinolysis;Functional disorder;Gastrointestinal tract structure;Genetic Engineering;Goals;Health;Hepatic;Hepatotoxicity;Hypoxemia;In Situ;In Vitro;Incidence;Individual;Inflammation;Inflammatory;Inflammatory Response;Injury;Intervention;Intestines;Investigation;Kupffer Cells;Laboratories;Lead;Life;Link;Liver;Lung;Lung Inflammation;Lung Injury Acute;Mediating;Mediator of activation protein;Modeling;Morbidity - disease rate;Mortality Vital Statistics;Mus;Nicotinic Receptors;Organ;Peptide Hydrolases;Plasminogen Activator Inhibitor 1;Predisposition;Preparation;Pulmonary Edema;Relative (related person);Risk;Role;Series;Structure of parenchyma of lung;Testing;Tissues;Translating;Up-Regulation (Physiology);Work;alcohol effect;alcohol exposure;alcohol response;base;in vivo;liver inflammation;liver injury;lung injury;novel;novel therapeutic intervention;nutrition;problem drinker;public health relevance;response

public_health_relevance:
Alcohol-induced organ damage is a major health concern. The liver and lungs are major target organs of alcohol damage but the mechanisms of injury remain unclear and there are no therapies for these diseases. This project test the overall hypothesis that liver and lung inflammation caused by ethanol is mediated by fibrin ECM deposition. Taken together these studies will establish new models of alcoholic injury explore multiple overlapping mechanisms and provide novel targets for therapies.


application_id: 8435052
project_number: 7R01EB012135-02
project_title: Phi29 Motor Nanopore for Single Molecule Sensing
administering_ic: NIBIB
award_notice_date: 2012-03-02
opportunity_number: PA-08-052
application_type: 7
activity_code: R01
ic: EB
serial_number: 012135
program_official: ATANASIJEVIC, TATJANA
project_start_date: 2011-04-01
project_end_date: 2015-03-31
study_section: Nanotechnology Study Section[NANO]
contact_pi_person_id: 1878565
contact_pi: GUO, PEIXUAN
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 PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):   A wide variety of highly-ordered structures of macromolecules and organized nanomachines exist in biological systems for transporting polynucleic acids and polypeptides. The ingenious design of the bacteriophage phi29 DNA packaging motor is an intriguing element in this category. All linear dsDNA viruses package their genome into a preformed procapsid via an ATP-driving motor involving two nonstructural enzymes or ATPases. The central component of the phi29 motor is the portal connector composed of twelve copies of the protein gp10 which form a dodecamer channel that acts as a pathway for the translocation of double-stranded DNA. With a diameter of 3.6 nm at its narrowest end it is one of the largest among typical channel proteins that have been incorporated in lipid membranes. Explicit engineering and pore modifications of the phi29 connector are possible due to its available crystal structure thus inspiring its biomedical applications.  The short-term objective of this application is to demonstrate the utility of the lipid-embedded channel of the phi29 DNA packaging motor as a highly sensitive device for characterizing biopolymers at single molecule resolution using electrophysiological assays. The connector will first be reengineered for added functionality and various approaches to modulate the conductance of the connector will be systematically investigated. The dimensions of the pore and charge distributions will then be altered by mutagenesis for specific pore modifications in a controlled fashion to ensure optimal sensing. Finally the channel will be designed to act as a stochastic biosensor and functionalized with modifying groups to recognize nucleotide bases of double stranded DNA for potential sequencing applications. The long-term objective is to develop the channel into a robust sensing device for detecting pathogens and chemicals at extremely low concentrations for disease diagnosis and environmental monitoring and to utilize it as a high throughput nanopore-based apparatus for the next generation sequencing of double stranded DNA. The channel can further be used as a tool to assay the structure and function of biological molecules and complexes as well as future avenues for therapeutic DNA loading packaging and gene delivery to specific cells for the treatment of cancers viral infections and genetics diseases.    PUBLIC HEALTH RELEVANCE:   The membrane adapted bacteriophage phi29 portal motor nanopore protein will be modified characterized and developed for highly sensitive detection of pathogens and chemicals at extremely low concentrations as well as for characterizing double-stranded DNA at the single molecule level. The channel can further be developed as a tool for therapeutic DNA packaging and gene delivery to specific cells for the treatment of cancers viral infections and genetics diseases.

public_health_relevance:
PROJECT NARRATIVE The membrane adapted bacteriophage phi29 portal motor nanopore protein will be modified characterizedand developed for highly sensitive detection of pathogens and chemicals at extremely low concentrations aswell as for characterizing double-stranded DNA at the single molecule level. The channel can further bedeveloped as a tool for therapeutic DNA packaging and gene delivery to specific cells for the treatment ofcancers viral infections and genetics diseases.


application_id: 8434567
project_number: 1R15CA173693-01
project_title: Highly Specific and Highly Sensitive Aptamer-Gold Nanoparticle Based NIR Contrast
administering_ic: NCI
award_notice_date: 2013-01-09
opportunity_number: PA-12-006
application_type: 1
activity_code: R15
ic: CA
serial_number: 173693
program_official: FARAHANI, KEYVAN
project_start_date: 2013-01-09
project_end_date: 2016-12-31
study_section: Nanotechnology Study Section[NANO]
contact_pi_person_id: 1895231
contact_pi: KANG, KYUNG AIH
other_pis: Not Applicable
congressional_district: 03
department: ENGINEERING (ALL TYPES)
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: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Fluorophores have been indispensable signal mediators for optical imaging. This fluorescent contrast agent can be more effective if it is specific for the target molecule and with higher sensitivity. The surface electro-magnetic (plasmon) field on the gold nanoparticles (GNPs) can be helpful for this contrast agent to have these properties by allowing artificial quenching/enhancing fluorescence. For molecular targeting particular biomolecules aptamers are found to be as good as monoclonal antibodies the traditional targeting agent. Aptamers also have additional beneficial properties such as easier and cheaper production smaller size little immunogenicity etc.  By combining beneficial properties of fluorophores GNPs and aptamers we propose to develop a molecular beacon-like nano-entity for early and accurate detection of aggressive breast cancer with high sensitivity and specificity; and also for concurrently monitoring the efficacy of the therapeutic regimen.  The nano-fluorescent agent to be developed is a breast cancer type expressing MMP-14 which is known as a marker for the breast cancer with aggressive nature. The components of this entity include a breast cancer targeting aptamer AS1411 with two Tymidine nucleotide sequences. One end of a sequence is bound to a GNP and one end of the other sequence is conjugated to Cypate analogue of ICG (FDA approved near infrared fluorophore). The length of the chain is to be approximately a half of the distance producing the maximum fluorescence of Cypate by a GNP. The chains are connected via the substrate of MMP-14 which is small and therefore places the GNP and Cypate very close forcing complete quenching. Initially this entity emits little fluorescence because the strong plasmon field of GNP quenches the fluorescence. When it is applied to human body with breast cancer with aggressive nature it is delivered to the breast cancer specifically via the targeting site of the AS1411 receptor. Then it
will be exposed to the MMP-14 on/in the tumor cell wall. As the substrate gets cleaved by the MMP-14 Cypate moves away from the GNP to the distance specified by the chain length which results in highly enhanced fluorescence emission upon excitation light application.  We have named this entity AptaPET (Aptamer-nanoparticle Plasmon Energy Transfer) and It allows both cancer detection and provides the information on nature of the cancer for our system the aggressiveness of the cancer. By selecting a special aptamer AS1411 with therapeutic properties this entity can also be used both for detection and treatment. In addition with no further modification the AptaPET can be a good contrast agent for X-ray/CT. The same concept can be used for detection diagnosis and prognosis of other diseases as well as of other types of cancer.

project_terms:
Adverse effects;Affinity;Base Sequence;Binding (Molecular Function);Binding Sites;Biological;Breast Cancer Cell;Breast Cancer Detection;Breast Cancer Treatment;Cancer Detection;Cancer cell line;Cell Line;Cell Wall;Characteristics;Cleaved cell;Complex;Contrast Media;Detection;Diagnosis;Disease;Energy Transfer;FDA approved;Fluorescence;Fluorescent Dyes;Goals;Gold;Human body;Length;Light;Magnetism;Malignant Neoplasms;Matrix Metalloproteinases;Mediator of activation protein;Methods;Modeling;Modification;Molecular;Molecular Target;Monitor;Monoclonal Antibodies;Names;Nature;Optics;Outcome;Performance;Process;Production;Property;Regimen;Sensitivity and Specificity;Signal Transduction;Site;Specific qualifier value;Surface;System;Testing;Therapeutic;Thymidine;Treatment Efficacy;Treatment Protocols;Treatment outcome;X-Ray Computed Tomography;analog;aptamer;base;cancer cell;cancer site;cancer therapy;cancer type;design;fluorophore;immunogenicity;interest;malignant breast neoplasm;nano;nanoparticle;nanosized;neoplastic cell;novel;optic imaging;outcome forecast;particle;public health relevance;receptor;tool;tumor

public_health_relevance:
A gold nanoparticle- Aptamer AS1411- and NIR fluorophore Cypate-based optical contrast agent that emits its fluorescence only in the presence of MMP-14 is proposed to develop. This product can be a highly beneficial non-invasively tool for monitoring the efficacy of on-going breast cancer treatment providing clinicians with the guidance for the best treatment direction.


application_id: 8434468
project_number: 2R15GM085722-02
project_title: Mechanisms of Action of UmuD in Regulating DNA Damage-Induced Genes in a umuC Def
administering_ic: NIGMS
award_notice_date: 2013-01-21
opportunity_number: PA-12-006
application_type: 2
activity_code: R15
ic: GM
serial_number: 085722
program_official: WILLIS, KRISTINE AMALEE
project_start_date: 2009-08-01
project_end_date: 2016-12-31
study_section: Special Emphasis Panel[ZRG1 GGG-H (90)]
contact_pi_person_id: 9257147
contact_pi: HARE, JANELLE M
other_pis: Not Applicable
congressional_district: 05
department: BIOLOGY
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:
Enter the text here that is the new abstract information for your application. This section must be no longer than30 lines of text.This AREA R15 renewal will accomplish the objectives of (i) supporting meritorious research (ii) strengtheningthe research environment of non-research intensive universities and (iii) engaging undergraduate students inbiomedical research. The overall goal of this research is to understand how cells respond to DNA damagebecause use of these pathways cause mutations in bacteria that drive increased virulence and drug resistancewhereas defects in this pathway can result in various cancers in humans. This proposal will characterize theunique mechanisms of a translesion synthesis protein (UmuD) homolog that regulates DNA damage responsegenes. The bacterial UmuD2C Y-family polymerase is induced after DNA damage via relief of LexA repressionand conducts mutagenic translesion DNA synthesis. Homologs of bacterial Y-family polymerases exist ineukaryotes where mutations in pol h predispose humans to skin cancer. Unlike other bacteria non-entericAcinetobacter baylyi possesses an operon consisting of a umuD homolog umuDAb and a truncated incompleteumuC. The genotypic and phenotypic characteristics of UmuDAb constitute a chimera of LexA and UmuD: it hasan extended N-terminal domain (NTD) like LexA and a C-terminal domain (CTD) conducting self-cleavagesimilar to both UmuD and LexA. Furthermore umuDAb cannot complement an Escherichia coli umuD mutantbut rather regulates ddrR and itself in response to DNA damage. We hypothesize that UmuDAb is a LexA-likerepressor. The mechanisms of UmuDAb action will be dissected in the translesion-synthesis incompetent A.baylyi as well as in the opportunistic pathogen Acinetobacter baumannii which conducts UV-inducedmutagenesis and has both the ddrR-umuDAb locus and an E. coli-like umuDC operon. The specific Aims of thisproject are to: (1) Delineate the actions of the C- and N-terminal domains of UmuDAb that are required forregulation of genes after DNA damage; (2) Describe the functional roles and regulatory relationship of themultiple umuD alleles of A. baumannii in its response to DNA damage. These Aims will be accomplishedthrough experiments assaying ddrR regulation and UV-induced mutagenesis ability in cells with mutations in theN- or C-terminal domains of UmuDAb. Transcriptome analyses will complement these experiments. This projectwill extend our knowledge of the regulation and function of Y-family polymerases as well as their role in causingmutations in bacterial pathogens. These experiments will be completed by undergraduates mentored and trainedby the PI to perform authentic biomedical research help write scientific manuscripts and communicate theirfindings to the campus community and larger scientific networks. The enhanced research infrastructure as well asthe expectation of and opportunities for student engagement in research will be beneficial to the entire Biologyand Chemistry department at Morehead State University.

project_terms:
Acinetobacter;Acinetobacter baumannii;Alleles;Amino Acids;Antibiotic Resistance;Antibiotic Therapy;Bacteria;Bacterial Model;Bacteriophages;Binding (Molecular Function);Biological Assay;Biology;Biomedical Research;C-terminal;Cancer Etiology;Cell physiology;Cells;Characteristics;Chemistry;Chimera organism;Cleaved cell;Communities;Complement;DNA;DNA Damage;DNA Repair;DNA Replication Damage;DNA biosynthesis;DNA-Directed DNA Polymerase;Defect;Drug resistance;Environment;Escherichia coli;Eukaryota;Exposure to;Family;Funding;Galactosidase;Gene Expression Profile;Gene Expression Regulation;Gene Fusion;Genes;Genetic;Goals;Helix-Turn-Helix Motifs;Homologous Gene;Human;Kinetics;Knowledge;LacZ Genes;Light;Malignant Neoplasms;Manuscripts;Measures;Mentors;Multi-Drug Resistance;Mutagenesis;Mutation;N-terminal;Operon;Pathway interactions;Polymerase;Progress Reports;Promotor (Genetics);Protein Biosynthesis;Proteins;Regulation;Repression;Research;Research Infrastructure;Role;Serine Protease;Site;Skin Cancer;Students;Testing;Text;Training;UV induced;Universities;Virulence;Work;Writing;Yeasts;abstracting;expectation;genetic regulatory protein;member;mutant;novel;pathogen;recombinational repair;repaired;research study;response;undergraduate student

public_health_relevance:
This project investigates common mechanisms that human as well as bacterial cells use to repair their DNA bycharacterizing the action of a novel bacterial regulatory protein that is a homolog of a human error-prone DNApolymerase component. Similar polymerases exist in bacteria yeast and humans where defects in thesepolymerases can cause cancer after exposure to DNA damage. We will extend our previous work in Acinetobacterbaylyi to the multi-drug resistant pathogen Acinetobacter baumannii which will help determine how the DNAdamage response to antibiotic treatment of bacteria leads to the spread of antibiotic resistance and other virulencegenes among bacteria.


application_id: 8433515
project_number: 5R01CA138623-05
project_title: Role of leukotriene B4 receptors in the interplay of inflammation and infection
administering_ic: NCI
award_notice_date: 2013-01-23
opportunity_number: PA-07-256
application_type: 5
activity_code: R01
ic: CA
serial_number: 138623
program_official: HOWCROFT, THOMAS K
project_start_date: 2009-04-01
project_end_date: 2016-01-31
study_section: Gastrointestinal Mucosal Pathobiology Study Section[GMPB]
contact_pi_person_id: 6074575
contact_pi: BODDULURI, HARIBABU
other_pis: Not Applicable
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Colon cancer is a leading cause of cancer related deaths in the United States. Exposure to a number of hazardous environmental agents and consumption of the Western diet are known to contribute to the pathogenesis of malignant colon cancer. While chronic inflammation is known to be a major promoter of tumor development the role of gut microflora in contributing to the colon cancer is unknown. Our laboratory has identified leukotriene B4 receptor BLT1 as a major regulator of inflammation and host response to infections. In a mouse model of spontaneous intestinal cancer (ApcMin/+) we have made the observation that absence of BLT1 greatly enhances intestinal tumor development. This has led to the central hypothesis that Absence of BLT1 enhances colon tumor development by defective immune surveillance and/or altered microbial gut homeostasis. This apparently paradoxical result that loss of a proinflammatory mediator increases inflammation and tumor development suggests that the ever changing micro environment of intestine can have a major influence on the development of colorectal cancer. The current proposal will test this hypothesis in three specific aims. In aim 1 we will examine the mechanisms of leukotriene B4 pathway mediated protection of intestinal cancers in ApcMin/+ mice. Aim 2 will establish the immune functions in tumor bearing mice in the context of BLT1+/+ and BLT1-/- mice. Aim 3 will test the novel concept that defective host response and altered gut microbiota are responsible for rapid development of colon tumors in BLT1-/- mice. These studies will provide a comprehensive model system to examine the interplay of inflammation and infections to the development of colon cancer. Since the mouse ApcMin/+ model is highly related to human colon cancers the result will have direct and immediate impact for the treatment of human colon cancer.

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

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


application_id: 8432804
project_number: 5R01AG037868-03
project_title: Psychosocial stress interactions with electrophysiology and brain aging
administering_ic: NIA
award_notice_date: 2013-04-04
opportunity_number: PA-09-216
application_type: 5
activity_code: R01
ic: AG
serial_number: 037868
program_official: WILLIAMS, BENFEARD LEECHELLE
project_start_date: 2011-03-01
project_end_date: 2016-02-29
study_section: Neuroendocrinology, Neuroimmunology, and Behavior Study Section[NNB]
contact_pi_person_id: 8915754
contact_pi: BLALOCK, ERIC
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This application proposes to address a fundamental unresolved question in the field of psychosocial stress and brain aging the nature of the neurobiological pathways through which psychosocial stress promotes unhealthy brain aging (UBA). The focus of the studies will be on brain aging markers developing near the age of divergence of unhealthy from healthy brain aging as these seem particularly likely to be susceptible to stress. This project will also test the hypothesis that midlife changes in the brain's responses to stress promote the emergence of UBA. This view derives from our recent work with both electrophysiological and microarray techniques showing that stress hormone-sensitive markers of brain aging emerge around midlife in rats the same age range in which unhealthy cognitive aging begins to appear. The proposed studies will comprise a large multidisciplinary project aimed at obtaining a unique integrated perspective on neurobiological pathways affected by psychosocial stress in an established rat model of aging. It will involve state-of-the-art intracellular electrophysiology in brain slices immunohistochemistry with a battery of stains separate microarray analysis of individual rat brains EEG monitoring of sleep patterns and behavioral testing. Multiple techniques will be applied in each animal. These studies will pursue the aims of correlating electrophysiological and genomic markers of unhealthy brain aging in the same animals and will relate exposure to psychosocial stress to the development of UBA as a function of age and under acute vs. chronic conditions. Importantly behavioral and pharmacological interventions to reduce stress and protect sleep patterns will be used to test whether the course of UBA can be altered in long-term studies. Aged animals subjected to psychosocial stress-reducing and sleep-promoting interventions will be evaluated on a battery of behavioral electrophysiological sleep monitoring microarray and immunohistochemical analyses to test the proposition that conversion these interventions may reduce/reverse UBA symptoms and if so to determine through which brain pathways this occurred. Overall these studies should substantially elucidate neurobiological pathways through which psychosocial stress influences brain aging markers and should importantly determine the role of age in modulating stress impact. Further the proposed intervention studies should have direct translational relevance.

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

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


application_id: 8432797
project_number: 5R21AI098371-02
project_title: Contribution of N-glycosylation to the Toxoplasma glycoproteome
administering_ic: NIAID
award_notice_date: 2013-01-23
opportunity_number: PA-10-069
application_type: 5
activity_code: R21
ic: AI
serial_number: 098371
program_official: MCGUGAN, GLEN C
project_start_date: 2012-03-01
project_end_date: 2015-02-28
study_section: Special Emphasis Panel[ZRG1-IDM-S(02)M]
contact_pi_person_id: 6624897
contact_pi: SINAI, ANTHONY P.
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The protozoan parasite Toxoplasma gondii is an important opportunistic infection causing life threatening disease in patients with HIV-AIDS and other immune compromising conditions. The high seroprevalence of the T. gondii worldwide but low incidence of symptomatic disease reflects the fact that the acute phase of infection is effectively handled by the immune response. Unfortunately a sterile cure is not achieved. Rather the parasite establishes a life-long chronic infections mediated by tissue cysts typically formed in the brain and muscle. The tissue cyst is protected by a heavily glycosylated cyst wall. Despite the importance of glycosylation little is known about these pathways in the parasite. With this work we address the contribution of N-linked glycosylation in Toxoplasma. We propose to use lectin affinity coupled with mass spectrometric identification to catalogue the diversity of N-glycosylated glycoproteins in tissue cysts. We further plan to conditionally knock out a key gene in the N-glycosylation TgALG7 in order to assess its role in parasite biology with a focus on protein targeting to its diverse unique secretory organelles. Given the central role for glycosylation in the tissue cyst we propose an experimental strategy to selectively knock out gene expression in the tissue cyst. This technology will be applied to establishing the contribution of TgALG7 and by extension N-glycosylation to tissue cyst formation and stability. This work represents the first in depth study of the cell biologic basis of protein glycosylation i Toxoplasma using state of the art approaches to modulate gene expression.

project_terms:
Acquired Immunodeficiency Syndrome;Acute;Address;Affinity;Affinity Chromatography;Animals;Apicomplexa;Area;Asparagine;Bioinformatics;Biological Process;Biology;Blood;Brain;Cataloging;Catalogs;Cells;Chronic;Chronic Phase;Complex;Computer Simulation;Coupled;Cyst;Development;Disease;Elements;Enzymes;Exhibits;Foundations;Funding Mechanisms;Future;Gene Expression;Genes;Genetic;Glycoproteins;Golgi Apparatus;HIV;Homologous Gene;Immune;Immune response;Immune system;Incidence;Individual;Infection;Investigation;Knock-out;Knowledge;Lectin;Life;Light;Link;Maintenance;Mass Spectrum Analysis;Mediating;Methods;Muscle;Nature;Neospora;Opportunistic Infections;Organelles;Parasites;Pathogenesis;Pathology;Pathway interactions;Patients;Pattern;Phase;Play;Polysaccharides;Protein Glycosylation;Proteins;Proteome;Proteomics;Protozoa;Role;Seroprevalences;Site-Directed Mutagenesis;Sterility;Structure;System;Technology;Testing;Tetanus Helper Peptide;Tissues;Toxoplasma;Toxoplasma gondii;Vision;Work;asexual;base;genetic manipulation;genome analysis;glycosylation;high risk;infancy;knowledge base;member;microbial;rhoptry;sugar

public_health_relevance:
Toxoplasma gondii causes serious illness in immune compromised individuals including patients with HIV- AIDS. Our understanding of the role of glycosylation in parasite biology is very limited. With this work we directly explore N-glycosylation in the with a focus the dormant tissue cyst form. We hope to establish a strong foundation for future studies in this under explored area of investigation.


application_id: 8431861
project_number: 2R01DK074720-06
project_title: Novel hematopoietic effects of C5 cleavage fragment
administering_ic: NIDDK
award_notice_date: 2013-02-28
opportunity_number: PA-11-260
application_type: 2
activity_code: R01
ic: DK
serial_number: 074720
program_official: BISHOP, TERRY ROGERS
project_start_date: 2007-03-01
project_end_date: 2017-02-28
study_section: Special Emphasis Panel[ZRG1 VH-C (02)]
contact_pi_person_id: 2265592
contact_pi: RATAJCZAK, MARIUSZ Z
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Adhesions;Adult;Anaphylatoxins;Blood Vessels;Bone Marrow;Bone Marrow Cells;Bone Marrow Transplantation;CXCR4 Receptors;CXCR4 gene;Cell Adhesion Molecules;Cells;Chemotactic Factors;Circadian Rhythms;Collaborations;Complement;Complement 3a;Complement 5a;Complement Activation;Complement Membrane Attack Complex;Complement component C5;Cytolysis;Data;Defect;Development;Dinoprostone;Distal;Endothelium;Engraftment;Erythrocytes;Exhibits;Fibroblasts;Funding;Generations;Granulocyte Colony-Stimulating Factor;Growth Factor;Hematopoiesis;Hematopoietic;Hematopoietic Stem Cell Mobilization;Hematopoietic Stem Cell Transplantation;Hematopoietic stem cells;Homing;Human;Integrin alpha4beta1;Integrins;Investigation;Lead;Life;Ligands;Light;Link;Lipids;Lytic;Molecular;Mus;Natural Immunity;Nucleotides;Osteoblasts;Patients;Physiological;Plasma;Polysaccharides;Process;Publishing;Role;Stem cells;Syndrome;Testing;Transplantation;Transplantation Conditioning;Umbilical Cord Blood;Vascular Cell Adhesion Molecule-1;Work;base;cathelicidin;ceramide 1-phosphate;chemotherapy;complement C3 precursor;complement C5b;immunodeficient mouse model;leukemia;novel;novel therapeutics;peripheral blood;public health relevance;reconstitution;response;sphingosine 1-phosphate;stem;trafficking

public_health_relevance:
Section In this competing renewal we will focus on the role of a major component of innate immunity namely activation of the complement cascade in trafficking of hematopoietic stem/progenitor cells. This application will allow us to better understand this process as well as lead to the development of novel therapeutic strategies to treat patients with leukemias and inborn defects of hematopoiesis by transplantation of hematopoietic stem cells.


application_id: 8431455
project_number: 5R01AA015407-09
project_title: GSK3beta a mediator of ethanol neurotoxicity
administering_ic: NIAAA
award_notice_date: 2013-02-11
opportunity_number: PA-10-067
application_type: 5
activity_code: R01
ic: AA
serial_number: 015407
program_official: REGUNATHAN, SOUNDAR
project_start_date: 2005-08-01
project_end_date: 2016-02-29
study_section: Special Emphasis Panel[ZRG1-IFCN-C(02)M]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
other_pis: SHI, XIANGLIN
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):  Alcohol is a neuroteratogen; alcohol consumption during pregnancy may cause Fetal Alcohol Spectrum Disorders (FASD) among which fetal alcohol syndrome (FAS) is the most severe form. The depletion of neurons in the developing CNS is the most deteriorating effect of ethanol. The loss of CNS neurons may underlie many of the behavioral deficits observed in FASD. Glycogen synthase kinase 3 (GSK3) a serine/threonine kinase is an important mediator of neuron degeneration. We have demonstrated that ethanol activates GSK3 and the activation of GSK3 leads to neuronal death. Oxidative stress is also considered an important contributor to ethanol-induced neurotoxicity. We have purified a potent antioxidant from blackberries cyanidin-3-glucoside (C3G). Our study indicates that C3G inhibits GSK3 activity and alleviates oxidative stress in cultured neuronal cells. In addition C3G protects neuronal cells against ethanol-induced cell death. C3G-mediated neuroprotection is much more potent than other antioxidants and GSK3 inhibitors. C3G can cross the blood brain barrier (BBB) and distribute in the brain. C3G diminishes ethanol-induced activation of caspase-3 and Bax in the developing brain. Pharmacologically relevant concentrations of C3G are achievable through oral administration or intravenous (iv) injection in animals and no adverse effect is observed. These findings suggest that C3G is a promising neuroprotective agent that may ameliorate/prevent ethanol-induced neuronal damage. We hypothesize that C3G's potent protection against ethanol-induced neuronal loss is mediated by the combined action of its antioxidant property and inhibition of pro-apoptotic signaling GSK3/Bax pathways. To test the hypothesis we will (1) investigate the antioxidant property of C3G and its metabolites and their effects on GSK3 activity; (2) determine whether C3G protection against ethanol- induced neuronal loss is mediated by the combined action of its antioxidant property and the inhibition of GSK3; (3) determine whether C3G ameliorates ethanol-induced behavioral deficits.  C3G is a potent natural antioxidant and has diverse potential benefits for human health. It is a promising neuroprotective agent against ethanol toxicity due to its dual functions as an antioxidant and a GSK3 inhibitor. As a unit the proposed experiments will elucidate the novel role of C3G and provide an important basis for future clinical trials to evaluate the feasibility of C3G to treat ethanol neurotoxicity. Our study will potentially offer a new therapeutic strategy.

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

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


