# projects

application_id: 9131395
project_number: 3R01MH092226-05S1
project_title: A Clinic-Based Safer Sex Program for Young Black Men Who Have Sex with Men
administering_ic: NIMH
award_notice_date: 2015-09-16
opportunity_number: PA-10-067
application_type: 3
activity_code: R01
ic: MH
serial_number: 092226
suffix: S1
program_official: KAMATH, SUSANNAH M A
project_start_date: 2011-08-01
project_end_date: 2017-05-31
study_section: Behavioral and Social Science Approaches to Preventing HIV/AIDS Study Section[BSPH]
contact_pi_person_id: 8234905
contact_pi: CROSBY, RICHARD A
other_pis: Not Applicable
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): The Centers for Disease Control and Prevention (CDC) has termed AIDS a "health crisis" for African Americans and has called for a heightened national response. The crisis is especially dramatic in the South and it is now apparent that young African American men who have sex with men (MSM) are exceedingly likely to be infected. Unfortunately the ever-expanding HIV epidemic experienced by this population has not been matched by equal attention to the development of efficacious prevention programs. The proposed project expands upon an NIMH-funded study (R21 MH066682-01A1) conducted by Dr. Crosby. His study of young African American males found that a brief clinic-based intervention reduced incidence of subsequent STDs by about 50%. This brief one-on-one intervention program known as Focus on the Future (FOF) is a practical alternative to group-based safer sex programs that can be difficult to translate from science into practice. The program is now classified as a "Best Practice" intervention by CDC. This project will begin with an extensive formative phase designed to adapt FOF to MSM. The adapted program will seek to "sexualize" condoms to promote their consistent and correct use to better prevent STD/HIV. The program is uniquely flexible in that it can be applied to MSM regardless of their HIV serostatus. The adapted program will be tested by a two-arm efficacy trail. We will recruit 750 MSM (15-29 years of age) from a publicly-funded STD clinic in Jackson MS. Men in the treatment condition will be compared to men receiving the control condition comprised of standard of care counseling from the clinic plus a free ditty bag of supplies from the "condom and lube buffet" (condom/lube distribution). The trial will test five hypotheses. Men randomized to receive the intervention will: 1) have a lower incidence rate of laboratory-confirmed STDs (by urine assay and rectal swab) at each of three follow-up assessments (3 6 and 12 months) compared to controls; 2) report significantly fewer acts of unprotected penetrative sex (penile-vaginal or penile-anal) between follow-up assessments compared to controls; 3) report having significantly fewer unprotected penetrative (penile-vaginal or penile-anal) sex partners between follow-up assessments compared to controls; 4) report having significantly fewer negative experiences with condom use between follow-up assessments compared to controls; and 5) demonstrate significantly greater improvement in condom application skills throughout the 12-month study compared to those receiving the control condition. Given the dearth of evidence-based options for intervening with this vulnerable population in clinical settings demonstrated efficacy of the adapted program has important implications for public health efforts to prevent STD/HIV. The adapted FOF is also directly responsive to the President's National HIV/AIDS strategy particularly with regards to the target population of this proposal.

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

public_health_relevance:
The proposed efficacy trial will occur in Jackson MS and it tests a brief clinic-based HIV/STD prevention program adapted specifically for young African American MSM. This program is based on a CDC-classified Evidenced-Based Intervention known as Focus on the Future. The randomized trial is designed with 3 follow-up assessments and it uses biomarker outcomes as well as a novel method of collecting self-reported outcomes.


application_id: 9130384
project_number: 1R56HL128597-01
project_title: Epigenetic regulation of EC-SOD in pulmonary hypertension related to lung fibrosis
administering_ic: NHLBI
award_notice_date: 2015-09-10
opportunity_number: PA-13-302
application_type: 1
activity_code: R56
ic: HL
serial_number: 128597
program_official: XIAO, LEI
project_start_date: 2015-09-15
project_end_date: 2017-08-31
study_section: Respiratory Integrative Biology and Translational Research Study Section[RIBT]
contact_pi_person_id: 9705355
contact_pi: ZELKO, IGOR N.
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant):The development of pulmonary hypertension in the setting of fibrosing lung disorders is associated with worse prognosis. Despite the advances in the area of pulmonary hypertension the precise molecular mechanisms underlying pulmonary hypertension in the setting of lung fibrosis remain unclear. Extracellular superoxide dismutase (EC-SOD) is the main extracellular antioxidant enzyme in the pulmonary vascular wall and has been implicated in the pathogenesis of pulmonary hypertension since mice overexpressing EC-SOD develop less severe pulmonary hypertension (PH) while lack of EC-SOD promotes vascular remodeling and PH. However the role of EC-SOD in PH in the setting of lung fibrosing disorders is unknown and the mechanisms controlling its expression in this setting remain to be elucidated. We hypothesize that PH in the setting of lung fibrosis is due to an imbalance between anti-oxidant genes like EC-SOD and pro-oxidant genes like NADPH oxidase 4 (NOX4) and that these derangements are regulated by epigenetic factors such as DNA methylation and histone modifications. If true interventions targeting such changes might ameliorate PH in these disorders. This hypothesis is supported by our own observations. First we found upregulation of Nox4 and downregulation of EC-SOD in pulmonary vascular structures after bleomycin-induced lung fibrosis. Second we found that these genes are regulated by histone deacetylase (HDAC) inhibitors which also attenuate reactive oxygen species levels in pulmonary cells. Third we found evidence of DNA methylation and histone acetylation in the promoter of EC-SOD capable of influencing gene expression. Finally we found that HDAC inhibitors reduce vascular remodeling and right ventricular systolic pressure in the model of bleomycin-induced lung fibrosis. Together these observations suggest that epigenetic factors leading to an imbalance between EC-SOD and NOX4 expression underlie the development of PH in fibrotic lungs. This hypothesis will be tested using the following aims: 1) analyze the epigenetic modifications that control EC-SOD gene expression in pulmonary endothelial cells; 2) identify the epigenetic modifications influencing the expression of EC-SOD and NOX4 in vascular structures in animal models of lung fibrosis; 3) determine the impact of interventions designed to inhibit epigenetic regulation of EC-SOD and NOX4 and the mechanisms responsible for these effects. The proposed work will uncover novel mechanisms responsible for development of PH in fibrotic lungs. Such results will have an important positive impact because the identified molecular mechanisms are expected to provide new targets and approaches for preventative and therapeutic interventions in PH and other cardio-vascular diseases.

project_terms:
Acetylation;Animal Model;Antioxidants;Area;Attenuated;Bleomycin;Blood Vessels;Cardiomyopathies;Cells;Classification;Clinical;DNA Methylation;Data;Development;Disease;Down-Regulation;Endothelial Cells;Endothelium;Epigenetic Process;Excision;Fibrosis;Foundations;Gene Expression;Genes;Goals;Hamman-Rich syndrome;Health;Heart failure;Histone Acetylation;Histone Deacetylase Inhibitor;Histones;Human;Human Genome;Hypoxemia;Interstitial Lung Diseases;Intervention;Knowledge;Lead;Life;Lung;Lung diseases;Maps;Modeling;Modification;Molecular;Mus;NADPH Oxidase;Oxidants;Oxidative Stress;Pathogenesis;Pathway interactions;Patients;Physiology;Predisposition;Prevalence;Prevention;Process;Promoter Regions (Genetics);Promotor (Genetics);Pulmonary Fibrosis;Pulmonary Hypertension;Pulmonary Vascular Resistance;Pulmonary artery structure;Reactive Oxygen Species;Regulation;Research;Right Ventricular Hypertrophy;Role;Structure;Structure of parenchyma of lung;Superoxide Dismutase;Symptoms;Systolic Pressure;Testing;Therapeutic Intervention;Therapeutic Uses;Up-Regulation (Physiology);Vascular Diseases;Vascular remodeling;Ventricular;Wild Type Mouse;Work;World Health Organization;antioxidant enzyme;apicidin;attenuation;base;epigenetic regulation;extracellular;histone modification;improved;innovation;novel;novel therapeutics;outcome forecast;overexpression;pressure;prevent;pulmonary arterial hypertension;therapy design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension is a life-threatening disease characterized by elevated pulmonary artery pressure and pulmonary vascular resistance. This project investigates the role of epigenetic modifications in regulation of vascular antioxidant enzymes with the ultimate goal to slow down or reverse the development of pulmonary hypertension. Upon completion of the proposed research we will have a better foundation upon which to investigate the novel therapeutic strategies to improve treatment of this debilitating disease.


application_id: 9130204
project_number: 4P20GM103492-09
project_title: Project 4 - Cardiac Stem Cell Dysfunction in Diabetes
administering_ic: NIGMS
award_notice_date: 2016-06-17
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5009
contact_pi_person_id: 11675369
contact_pi: HONG, KYUNG UK
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
Type II diabetes (T2D) is a growing pandemic and one ofthe most serious health threats of our time. In addition to the well-characterized central endocrine defects some T2D patients present with distinct manifestation of cardiomyopathy termed diabetic cardiomyopathy. Diabetic cardiomyopathy occurs in the presence of neither clinically identifiable coronary artery disease nor hypertension suggesting that independent of its vascular effects T2D has direct impact on the myocardium. Although its etiology is complex hyperglycemia and dyslipidemla leading to increased oxidative stress may play a central role in the pathogenesis of diabetic cardiomyopathy. Recent studies have proposed that stem cell dysfunction may be responsible for complications related to T2D. The mammalian heart contains a cardiac stem cell (CSC) population with the capacity to maintain and regenerate myocardium. However little is known about CSCs function in the diabetic heart or their involvement in pathogenesis of diabetic cardiomyopathy. Our preliminary data indicate that the growth and differentiation characteristics of CSCs are impaired in diabetes. We hypothesize that T2D alters CSC growth and differentiation and these changes in stem cell function contribute to structural abnormalities and contractile dysfunction in the diabetic heart. To test this hypothesis we will: 1) Identify central defects in CSC biology in the diabetic heart in vivo; 2) Elucidate the cellular defects provoked by diabetes and nutrient excess in CSCs in vitro; and 3) Rescue the CSCs' functional defects in the diabetic heart in vivo. The studies proposed here will 1) Establish correlation between CSC dysfunction and cardiac abnormalities in the diabetic heart; 2) Explore mechanisms by which diabetes and nutrient excess affect function of CSCs; and 3) Decipher whether or not CSC dysfunction significantly contributes to the pathogenesis of diabetic cardiomyopathy using an innovative transgenic mouse model. Results of this study will lead to a better understanding of how diabetes affects CSC competence and function and how these abnormalities contribute to diabetic cardiomyopathy. Successful completion of these studies could illuminate new avenues for preventing or treating T2D.

project_terms:
Adult;Affect;Antigens;Apoptotic;Attenuated;Blood Vessels;Cardiac;Cardiac Myocytes;Cardiomyopathies;Cardiovascular Diseases;Cell Count;Cell physiology;Cells;Characteristics;Competence;Complex;Coronary Arteriosclerosis;Data;Defect;Development;Diabetes Mellitus;Diabetic mouse;Differentiation and Growth;Endocrine;Epidemiologic Studies;Etiology;Fatty Acids;Functional disorder;Gene Expression;Genes;Glucose;Growth;Health;Heart;Heart Abnormalities;Heart failure;Hyperglycemia;Hypertension;In Situ;In Vitro;Individual;Lead;Left;Left Ventricular Dysfunction;Measurement;Measures;Mediating;Mus;Myocardial;Myocardial dysfunction;Myocardium;Natural regeneration;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;Obesity;Oxidative Stress;Pathogenesis;Patients;Play;Proto-Oncogene Protein c-kit;Research;Risk;Risk Factors;Role;Stem cells;Structural defect;Structure;System;Techniques;Testing;Time;Transgenic Mice;Vascular Diseases;Ventricular;atherogenesis;attenuation;cardiac repair;cardiovascular disorder risk;cell growth;db/db mouse;diabetic;diabetic cardiomyopathy;genetic element;heart preservation;hemodynamics;in vivo;innovation;insight;insulin sensitivity;interest;mouse model;non-diabetic;novel;novel therapeutic intervention;pandemic disease;prevent;progenitor;recombinase;repaired;senescence;stem cell biology;stem cell population

public_health_relevance:
Type II diabetes is a growing pandemic. Independent of its vascular effects diabetes directly affects the heart. In this study we will investigate the influence of diabetes on cardiac stem cells. Successful completion of these studies could lead to development of novel therapeutic approaches targeting cardiac stem cells for preventing or treating cardiac dysfunction in patients with diabetes.


application_id: 9130203
project_number: 4P20GM103492-09
project_title: Project 3 - Regulation of Metabolism by Nitric Oxide
administering_ic: NIGMS
award_notice_date: 2016-06-17
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5008
contact_pi_person_id: 9543696
contact_pi: HILL, BRADFORD GUY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
Obesity and type 2 diabetes (T2D) are epidemics in the U.S. and abroad. A better understanding ofthe mechanisms that promote obesity and induce T2D is urgently needed to stem the tide of these epidemics and to control their cardiovascular complications. We suggest that endothelial dysfunction induced by nutrient excess is the primary cause that leads to metabolic changes resulting in an increase in adiposity and whole-body insulin resistance. Our studies show that overexpression of eNOS in mice prevents diet-induced obesity. These changes are accompanied by systemic and adipose tissue-specific changes in metabolism. Our metabolomic analyses indicate that eNOS over expression increases the abundance of circulating bile acids which have been shown to be potent effectors of metabolism and regulators of adipose tissue phenotype. Nevertheless we do not know how NO regulates bile acid production or which metabolic pathways triggered by bile acids are responsible for the lean phenotype of eNOS-TG mice. Therefore we will test the hypothesis that NO exerts an anti-obesogenic effect by regulating bile acid metabolism which promotes the development of adipocytes into a novel "lean" phenotype characterized by high mitochondrial content and fat burning capacity. To test this hypothesis we will: (1) Examine the effects of NO on diet induced obesity; (2) Determine how NO regulates metabolism; and (3) Elucidate the mechanisms regulating adipocyte phenotype. The experimental approaches in these aims will test whether NO directly regulates obesity and whether the anti-obesity effects of NO are mediated through the ability of eNOS to increase bile acid production and to regulate adipose tissue phenotype. The results of these studies will develop a strong platform for constructing a competitive ROI application and will lead to a new understanding of the role of NO in regulating the metabolic changes that contribute to diabetes and obesity. These studies could lay the groundwork for the development of novel therapeutic interventions to prevent manage or reverse obesity and insulin resistance.

project_terms:
Adipocytes;Adipose tissue;Adult;Affect;Bile Acid Biosynthesis Pathway;Bile Acids;Biogenesis;Body fat;Branched-Chain Amino Acids;Burn injury;Cardiovascular system;Cell Differentiation process;Centers for Disease Control and Prevention (U.S.);Cyclic GMP;Development;Diabetes Mellitus;Diet;Endothelium;Epidemic;Europe;Fatty acid glycerol esters;High Fat Diet;Human;In Vitro;Individual;Insulin;Insulin Resistance;Lead;Link;Lipids;Measures;Mediating;Metabolic;Metabolic Pathway;Metabolism;Mitochondria;Mus;NOS3 gene;Nitric Oxide;Nitric Oxide Donors;Nitric Oxide Synthase;Non-Insulin-Dependent Diabetes Mellitus;Nutrient;Obesity;Overweight;Phenotype;Population;Predisposition;Production;Regulation;Reporting;Research;Resistance;Risk;Risk Factors;Role;Secondary to;Signal Transduction;Stem cells;Testing;Tissues;Transplantation;Weight Gain;absorption;adipocyte differentiation;cofactor;diabetic;endothelial dysfunction;enzyme activity;feeding;in vivo;metabolomics;novel;novel therapeutic intervention;obesogenic;overexpression;prevent;stem

public_health_relevance:
Obesity and diabetes are emerging epidemics in the US and Europe. In this project we will examine the mechanisms by which nitric oxide regulates metabolism obesity and susceptibility to diet-induced diabetes. These studies could lay the groundwork for the development of novel therapeutic interventions to prevent manage or reverse obesity and diabetes.


application_id: 9130202
project_number: 4P20GM103492-09
project_title: Project 2 - Effects of Particulate Matter on Insulin Resistance and Endothelial
administering_ic: NIGMS
award_notice_date: 2016-06-17
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5007
contact_pi_person_id: 11375489
contact_pi: HABERZETTL, PETRA
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
Inhalation of fine particulate matter air (PM) pollution (<2.5pm) is associated with an increased risk for cardiovascular disease (CVD) and Type 2 diabetes (T2D). Short-term exposure of mice to concentrated ambient air particulate matter (CAP) decreases vascular insulin sensivity and circulating endothelial progenitor cells (EPCs). EPCs are thought to be involved in endothelial maintenance thus we propose that CAP-induced suppression of circulating and tissue-resident EPCs leads to endothelial injury and insulin resistance which provokes systemic insulin resistance ultimatively increasing the risk for T2D and CVD. CAP exposure affects vascular health by triggering low-grade inflammation via Inflammasome activation. To elucidate both mechanism(s) and causal relationship of endothelial injury EPC depletion and vascular insulin resistance we will examine in the aim 1:1) whether CAP-exposure alone is sufficient to induce systemic insulin resistance or whether it only exacerbates the effects of obesity and 2) the physico-chemical composition and body deposition of CAP to establish a more precise dosimetry and to find potential particle properties responsible for the biological effects. In our second aim we will investigate whether alterations in circulating/tissue resident EPCs and endothelial health are causative for the development of vascular insulin resistance. Finally to find the mechanisms of CAP-induced vascular insulin resistance we will examine in aim 3 a possible role ofthe activation ofthe inflammasome. We will utilize a mouse model of diet-induced obesity (DIO) to investigate effects of HFD-feeding and use mice deficient in NLRP3 and Casp-1 to test the contribution of Inflammasome activation in the development of vascular insulin resistance. Completion of these studies will provide novel insights into the mechanism(s) by which inhaled ambient particles increase the risk for T2D and CVD and as such will provide unique and detailed information of particle dose composition and deposition and their correlation with biological responses which could lead to the development of novel biomarkers and strategies for the regulation of environmental pollutants and the prevention and management of insulin resistance obesity T2D and CVD.

project_terms:
Accounting;Aerosols;Affect;Air;Air Pollution;Arrhythmia;Biological;Blood Vessels;Body Composition;Breathing;Cardiovascular Diseases;Centers of Research Excellence;Cessation of life;Chemicals;Chronic;Data;Deposition;Developing Countries;Development;Diabetes Mellitus;Diet;Dose;Environmental Pollutants;Environmental Risk Factor;Epidemic;Epidemiologic Studies;Epidemiology;Exposure to;Fatty acid glycerol esters;Funding;Future;Health;High Fat Diet;Human;IL18 gene;Incidence;Inflammation;Inflammatory;Injury;Insulin;Insulin Resistance;Interruption;Intervention;Knockout Mice;Lead;Link;Longevity;Maintenance;Measures;Mediating;Metabolic Diseases;Metabolic syndrome;Modeling;Molecular;Mus;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Organ;Particulate Matter;Pathway interactions;Patients;Policies;Prevalence;Prevention;Process;Property;Prospective Studies;Regulation;Research;Risk;Risk Factors;Role;Stem cells;System;Testing;Tissues;Vascular Diseases;Vascular Endothelium;ambient air pollution;ambient particle;base;cardiovascular disorder risk;chemical property;diabetes risk;dosimetry;endothelial dysfunction;feeding;high efficiency particulate air filter;improved;indexing;insight;insulin sensitivity;laboratory experiment;mortality;mouse model;novel;novel marker;novel strategies;particle;physical inactivity;physical property;prevent;repaired;research study;response;stroke

public_health_relevance:
Environmental factors seem to enhance the rapid evolving epidemic of diabetes and obesity. In this project we will investigate a potential link between diabetes and air pollution by determine the role of inhaled PM on the development of vascular and systemic insulin resistance. This project will provide unparalleled findings that PM may cause diabetes and could be the basis for future regulations pre- and intervention strategies.


application_id: 9130201
project_number: 4P20GM103492-09
project_title: Project 1 - Carnosine Metabolism in Diet-Induced Obesity
administering_ic: NIGMS
award_notice_date: 2016-06-17
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5006
contact_pi_person_id: 11110260
contact_pi: BABA, SHAHID P
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
Obesity is a highly prevalent condition and is associated with an increased risk for the development of type 2 diabetes (T2D) and cardiovascular disease. As such an understanding of how obesity develops and the identification of novel therapeutics aimed at controling obesity and its metabolic consequences are of utmost importance. Recent studies demonstrate that the dipeptide carnosine is depleted in the skeletal muscle of patients with T2D and that carnosine feeding decreases diet-induced obesity. Carnosine (ala-his) is a dipeptide present in skeletal muscle brain and heart. It buffers protons during glycolysis and it is a strong antioxidant. Carnosine is synthesized by the enzyme carnosine synthetase and is hydrolysed back to alanine and histidine by carnosinase.The homeostatic balance of carnosine is also maintained by the peptide transporter Pept2 . Although obesity and T2D in humans is associated with a decrease in carnosine levels in the skeletal muscle the mechanisms underiying carnosine depletion and its protective effects against obesity are not entirely known. Our intial studies show that high fat feeding in mice decreases carnosine levels and that restoration of these levels by carnosine supplementation restricts weight gain increases energy expenditure insulin senstivity and glucose tolerance. Based on these observations we propose that chronic carnosine deficiency decreases energy expenditure and antioxidant capacity ofthe muscle resulting in insulin resistance and oxidative stress. To test this hypothesis we will: (1) elucidate the mechanism of carnosine depletion in obesity; 2) test whether carnosine supplementation prevents or reverses obesity and its metabolic consequences; and (3) investigate the mechanism by which carnosine regulates adiposity and insulin sensitivity. To evaluate the clinical relevance of our findings we will also measure carnosine and carnosinase activity in obese and non-obese children. The findings of this project could lead to the development of a novel and validated anti-obesity strategy that could also prevent or reverse diet-induced insulin resistance. Successful completion ofthis project would lay the foundaton and form the rationale for testing the anti-obesogenic and anti-diabetic effects of carnosine in humans.

project_terms:
Alanine;Antioxidants;Back;Brain;Buffers;Cardiovascular Diseases;Carnosine;Child;Chronic;Development;Diabetes Mellitus;Diet;Dipeptides;Energy Metabolism;Enzymes;Equilibrium;Fatty acid glycerol esters;Glycolysis;Heart;Histidine;Human;Insulin;Insulin Resistance;Lead;Ligase;Measures;Metabolic;Metabolism;Mus;Muscle;Non obese;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oxidative Stress;Patients;Peptides;Protons;Research;Risk;Role;Skeletal Muscle;Supplementation;Testing;Weight Gain;base;clinically relevant;diabetic;feeding;glucose tolerance;insulin sensitivity;mouse model;novel;novel therapeutics;obesity in children;obesogenic;prevent;protective effect;restoration

public_health_relevance:
Few options are available to prevent or reverse obesity and its metabolic consequences. In this project we will test the role of the naturally occuring dipeptide carnosine in regulating adiposity and insulin resistance in a mouse model of diet-induced obesity. Results of these studies could lead to the identification of a safe and effective anti-obesity strategy that could be tested in humans.


application_id: 9130200
project_number: 4P20GM103492-09
project_title: Core E - Imaging and Physiology Core
administering_ic: NIGMS
award_notice_date: 2016-06-17
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5005
contact_pi_person_id: 8141999
contact_pi: JONES, STEVEN P
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The Imaging and Physiology Core (Core E) will play a key role in nurturing the growth ofthe Center and developing the Projects by promoting scientific excellence in investigations of cardiometabolic disease. Core E will provide investigators with access to state-of-the-art instrumentation and expert instruction related to confocal imaging assessment of cardiac function and performance of surgery in mice. The Core will promote education on the theory as well as sound technical comprehension related to the various instruments and approaches available. This group will also work closely with the Center members particulariy junior investigators to develop new tailored procedures to answer their experimental questions. The Director will provide guidance not only for the techniques provided by Core E but also mentorship to the junior faculty members in the Center. Dr. Steven Jones (Director Core E) brings approximately ten years of experience in confocal/fluorscent microscopic imaging and mitochondrial function assessment to Core E. The Core will enable Project leaders to use fluorescence microscopy to evaluate either fixed tissue (from Core C) or live cultured cells (from individual Projects). In addition. Dr. Jones' expertise in cardiovascular physiology will allow careful assessment of or surgery on mice generated by Core D. Furthermore the spatial resolution of confocal microscopy complements to high throughput techniques offered by Core B. Given the scope of approaches used in Core E Dr. Jones is perfectly suited to lead this Core. In addition to meeting the needs of the proposed Projects the Core has established a viable plan for a transition to financial independence during Phase II ofthe COBRE. The COBRE University Center and Members have all contributed to extensively to the expansive list of instrumentation in Core E. Such investments reflect the important role of Core E in the progress of the Center. Once the needs of the Projects and Center members are addressed the Director will continue developing new protocols acquiring additional instrumentation and initiating additional collaborations with other investigators in the UofL community. Core E will play a pivotal role in bringing this Center to national prominence in cardiometabolic research.

project_terms:
Address;Biochemical;Cardiac;Cardiovascular Physiology;Cells;Centers of Research Excellence;Collaborations;Communities;Complement;Comprehension;Confocal Microscopy;Cultured Cells;Diabetes Mellitus;Disease;Education;Experimental Designs;Faculty;Fluorescence Microscopy;Growth;Image;Individual;Instruction;Investigation;Investments;Lead;Life;Mentorship;Mitochondria;Modeling;Mus;Obesity;Operative Surgical Procedures;Organ;Organism;Performance;Phase;Physiology;Play;Procedures;Protocols documentation;Research;Research Personnel;Resolution;Role;Techniques;Universities;Work;cardiovascular imaging;data acquisition;experience;insight;instrument;instrumentation;meetings;member;microscopic imaging;sound;theories;tissue fixing

public_health_relevance:
Core E serves the Imaging and Physiology needs of the Projects and others in the Center. This Core enables the integration of biochemical insights at the level of intact cells organs and intact organisms. Core E leverages its expertise in cardiovascular physiology and imaging to provide the Projects and other Center members with insights into model choice experimental design data acquisition and interpretation of results.


application_id: 9130199
project_number: 4P20GM103492-09
project_title: Core D - Animal Models and Phenotyping Core
administering_ic: NIGMS
award_notice_date: 2016-06-17
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5004
contact_pi_person_id: 8767000
contact_pi: CONKLIN, DANIEL JOSEPH
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The Animal Models and Phenotyping Core (Core D) has four major goals. 1) Its primary function is to support the research projects of COBRE-supported Junior Investigators by providing state-of-the-art facilities and intellectual capability for the development and characterization of new and existing animal models used in diabetes and obesity research. Other goals are: 2) to provide training and education to Diabetes and Obesity Center junior investigators and members; 3) to develop new models techniques and protocols to further diabetes and obesity research; and 4) to become a self-sustaining entity that supports the Diabetes and Obesity Center. While the Animal Core will preferentially address the needs of the COBRE-supported junior investigators it will also assist in the development of new protocols maintenance of unique mouse lines and creation of new models for other Diabetes and Obesity Center investigators. It will provide a comprehensive assessment of animal adiposity glucose insulin and pyruvate tolerance physical activity body temperature food and water intake oxygen consumption and carbon dioxide production in order to evaluate the overall metabolic condition ofthe model animal under environmental challenges including high fat diet. Training and educating investigators is an integral function of the Animal Core and it will continue to provide education to Center junior investigators and members. The Animal Core has trained personnel who in turn educate individual junior investigators on how to perform metabolic phenotyping tests correctly. The Animal Core has and will continue to develop new models of interest to investigators for specific mechanistic purposes. It will expand its operations to support future needs by adding infrastructure equipment and by developing state-of-the-art animal models and by establishing new methods refining assays and using statistical modeling approaches useful in metabolic phenotyping. The Animal Core intends to become a selfsustaining entity that will promote the long-term stability of the Center by providing essential services and developing new and unique capabilities for individual and multi-PI projects.

project_terms:
Address;Animal Model;Animals;Biological Assay;Body Temperature;Carbon Dioxide;Centers of Research Excellence;Development;Diabetes Mellitus;Eating;Education;Equipment;Future;Glucose;Goals;High Fat Diet;Human Resources;Individual;Insulin;Maintenance;Metabolic;Methods;Modeling;Mus;Obesity;Oxygen Consumption;Phenotype;Physical activity;Production;Protocols documentation;Pyruvate;Research;Research Infrastructure;Research Personnel;Research Project Grants;Services;Statistical Models;Techniques;Testing;Training;Training and Education;Water consumption;interest;member;metabolic phenotype;operation

public_health_relevance:
The metabolic phenotyping of animal models used in diabetes and obesity research is an integral component of all COBRE-supported Junior Investigator-initated projects and for members ofthe Diabetes and Obesity Center. As such Core D provides the infrastructure animal models techniques and oversight to support the in-depth and state-of-the-art characterization of metabolic phenotypes in models of obesity and diabetes.


application_id: 9130198
project_number: 4P20GM103492-09
project_title: Core C - Pathology and Bio-analytics Core
administering_ic: NIGMS
award_notice_date: 2016-06-17
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5003
contact_pi_person_id: 6871611
contact_pi: SRIVASTAVA, SANJAY
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
Overarching goal of the Center is to understand the mechanisms of pathophysiology of diabetes and obesity and their cardiovascular complications. The Pathology and Bio-analytics Core is an integral part ofthe Center and will play a key role in the evolution of COBRE-funded projects. The Core will render services for rigorous and comprehensive pathological analysis of diabetic specimens. It will provide intellectual input with experimental design and state-of-the-art technical expertise to address the needs of investigators. The Core consists of a group of outstanding scientists with expertise in cardiovascular physiology pathology and analytical biochemistry. Director ofthe Core Dr. Sanjay Srivastava more than twenty years of research experience in analytical biochemistry and pathology and vascular inflammation atherosclerosis and diabetes. He will oversee all the Core operations and will work closely with junior investigators to teach them principles of histology chromatography and mass spectrometry. Dr Srivastava will also help the COBRE investigators with quantification and characterization of atherosclerotic lesions. Dr. Michael Merchant coinvestigator in the Core has extensive experience in analytical biochemistry and will assist the COBRE investigators with proteomics analyses. Drs. Srivastava and Merchant will provide hands on training to junior investigators for various histology and bio-analytical assays. The training acquired at the Core will facilitate them to grow as scientists and expand their repertoire of technical skills. The Core is equipped with state-ofthe- art pathology and analytical biochemistry equipment and is located in the Delia Baxter Building. In addition to address the current requirements of the COBRE projects the Core will continue to expand its knowledgebase and technical expertise to satisfy the future needs of the Center. Long term goal of the Core is to become a fiscally independent entity capable of providing cutting-edge pathology and bio-analytical services to researchers interested in diabetes and cardiovascular pathophysiology. Continued excellence in pathological analyses will foster collaborations which will not only help the Core financially but will also advance the field in combatting diabetic complications.

project_terms:
Address;Analytical Biochemistry;Arterial Fatty Streak;Arts;Atherosclerosis;Biochemical;Biological Assay;Cardiovascular Physiology;Cardiovascular system;Centers of Research Excellence;Chromatography;Collaborations;Complications of Diabetes Mellitus;Diabetes Mellitus;Educational process of instructing;Equipment;Evolution;Experimental Designs;Fostering;Functional disorder;Funding;Future;Goals;Hand;Histology;Mass Spectrum Analysis;Obesity;Pathology;Play;Proteomics;Research;Research Personnel;Scientist;Services;Specimen;Technical Expertise;Tissues;Training;Work;combat;diabetic;experience;interest;knowledge base;operation;vascular inflammation

public_health_relevance:
The Pathology and Bio-analytics Core of the Center will provide technical expertise in the pathological examination and quantification of various analytes in diabetic tissues. The Core will train junior investigators with histological assessment and biochemical analyses of diabetic tissues and tease out the biochemical mechanisms associated with the onset of diabetes and obesity and their cardiovascular complications.


application_id: 9130197
project_number: 4P20GM103492-09
project_title: Core B - Flow Cytometry Core
administering_ic: NIGMS
award_notice_date: 2016-06-17
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103492
study_section: ZGM1-TWD-Y
subproject_number: 5002
contact_pi_person_id: 8911484
contact_pi: O'TOOLE, TIMOTHY E
other_pis: Not Applicable
congressional_district: 03
department: Unavailable
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
The Flow Cytometry Core (Core B) has three major goals. Its primary function is to offer Center Investigators the ability to utilize complex and technically-challenging flow cytometric approaches to characterize cells and their functional and signaling properties. Thus the Core will provide access to state ofthe art equipment for flow cytometric analysis of cellular antigen expression metabolism and signaling and cell sorting capability to support cardiovascular research in diabetes and obesity at the University of Louisville. Core B personnel are highly-experienced investigators who have worked for several years on flow cytometry using various tissues and cells from multiple species and have extensive expertise in rare event sorting and analysis. The complementary nature of their backgrounds and areas of expertise coupled with their collegial nature provides a strong foundation for productive synergy within this Core and its productive interactions with other investigators associated with the Diabetes and Obesity Center. Secondly the Core is committed to an educational goal. Not only will Center members be trained on the operation of instruments it is the intent that all users completely understand cytometric theory application and data analysis. It is hoped that all Project investigators in their transition to independence will be able to competently incorporate flow cytometry as an analytical tool in future studies. The Core is also committed to developing its scope and operation to support multidimensional flow cytometry needs in the future. It will continue to upgrade its equipment and analytical repertoire. Finally this Core has the ultimate goal of developing into a self-supporting and large-scale flow cytometry operation that will cater not only to the specific needs of the Center but to other University investigators interested in diabetes and obesity research. A fully developed Flow Cytometry Core will be a significant asset in developing future multi-investigator projects and for helping researchers conduct multifaceted basic and clinical investigations aimed at the amelioration of health hazards caused by diabetes and obesity.

project_terms:
Antigens;Area;Arts;Cardiovascular system;Cell Separation;Cells;Centers of Research Excellence;Complex;Coupled;Data Analyses;Development;Diabetes Mellitus;Equipment;Evaluation;Event;Flow Cytometry;Foundations;Future;Goals;Health Hazards;Human Resources;Metabolism;Nature;Obesity;Population;Property;Research;Research Infrastructure;Research Personnel;Services;Signal Transduction;Sorting - Cell Movement;Tissues;Training;Universities;Work;analytical tool;clinical investigation;experience;improved;instrument;interest;meetings;member;operation;theories

public_health_relevance:
The isolation characterization and functional evaluation of distinct cell populations or tissues is an essential component of all Projects in the COBRE and studies by several Center members. Core B will provide flow cytometric capability as a facile means to meet these needs. Successful operation of Core B will enhance the scientifc development of junioir investigators provide essential services to Center members and improve the research infrastructure at the University of Louisville.


application_id: 9130193
project_number: 4P20GM103492-09
project_title: Center for Excellence in Diabetes and Obesity Research
administering_ic: NIGMS
award_notice_date: 2016-06-17
opportunity_number: PAR-12-224
application_type: 4
activity_code: P20
ic: GM
serial_number: 103492
program_official: CALDWELL, SHEILA
project_start_date: 2008-09-26
project_end_date: 2018-06-30
study_section: ZGM1-TWD-Y(C2)
contact_pi_person_id: 1885223
contact_pi: BHATNAGAR, ARUNI
other_pis: Not Applicable
congressional_district: 03
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This proposal is for continued support for the multi-disciplinary Diabetes and Obesity Center at the University of Louisville. The central focus of the Center is to enable promote and support research on the cardiovascular causes and consequences of diabetes and obesity. The second major aim of the program is to continue to provide mentoring and guidance to junior investigators in the Center. Specific objectives of the program are to: (1) Enhance and expand a thematic multi-disciplinary research center focused on diabetes and obesity; (2) Foster the research careers of junior investigators leading to their development as independent principal investigators; (3) Develop a nationally-competitive program that will attract the best clinical and post-doctoral fellows graduate students and faculty; (4) Expand and bridge on-going research within the Center and further integrate current expertise into a thematically coherent program; (5) Promote collaborative interactions to build additional complementary research projects both individual and multi-investigator; (6) Build upon existing research capabilities and core facilities to provide state-of-the-art infrastructure support; (7) Develop basic and clinical understanding of the molecular mechanisms of diabetes and obesity and how they contribute to the burden of cardiovascular disease; (8) Discover new and effective means for preventing and treating diabetes and obesity; and (9) Develop and implement a plan for the transition from COBRE support to independent funding. The five related projects of the junior investigators will: (1) Examine the effects of dietary carnosine on diabetes and obesity; (2) Assess the impact of particulate air pollution on insulin resistance; (3)
Elucidate the role of eNOS in obesity; (4) Assess stem cell dysfunction in diabetes; and (5) Develop biomarkers for detecting atherothrombotic events in patients with type 2 diabetes. These investigations will be supported by state-of-the-art core facilities in flow cytometry pathology and bioanalytical chemistry imaging and physiology and animal model development and phenotyping. Continued support to the Center will strengthen the infrastructure of biomedical research at the University of Louisville and will positively impact the field of diabete and obesity research worldwide.

project_terms:
Address;Air Pollution;Biological Markers;Biomedical Research;Cardiology;Cardiovascular Diseases;Cardiovascular system;Carnosine;Centers of Research Excellence;Chemistry;Clinical;Core Facility;Data;Development;Diabetes Mellitus;Diet;Disease;Epidemiology;Event;Faculty;Flow Cytometry;Fostering;Foundations;Functional disorder;Funding;Goals;Health;Image;Individual;Insulin Resistance;Interdisciplinary Study;Investigation;Knowledge;Mentors;Modality;Molecular;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Particulate;Pathology;Patients;Phase;Phenotype;Physiology;Postdoctoral Fellow;Prevention;Principal Investigator;Reagent;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Support;Resource Sharing;Role;Stem cells;Universities;Work;animal model development;career;clinical investigation;design;graduate student;novel;prevent;programs;public health relevance

public_health_relevance:
Research supported by the Diabetes and Obesity Center at the University of Louisville will address two of the most significant health concerns in the nation An established independent Diabetes and Obesity Center at the University of Louisville with a well-supported cadre of new and established investigators would create new knowledge and develop novel treatment and prevention modalities for these diseases.


application_id: 9129818
project_number: 4R37AG004542-27
project_title: Hippocampal Synaptic Structure
administering_ic: NIA
award_notice_date: 2016-03-31
opportunity_number: PA-10-067
application_type: 4
activity_code: R37
ic: AG
serial_number: 004542
program_official: WISE, BRADLEY C
project_start_date: 1998-01-01
project_end_date: 2021-03-31
study_section: NSS
contact_pi_person_id: 2405844
contact_pi: LANDFIELD, PHILIP W.
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Age-Years;Aging;Aging-Related Process;Alzheimer's Disease;Alzheimer's disease risk;Behavioral;Biological Markers;Brain;Calcium;Calpain;Cognitive;Cognitive aging;Corticosterone;Cytoskeletal Proteins;Gene Expression;Glucocorticoids;Goals;Healthcare;Hippocampus (Brain);Hormonal;Hormones;Impaired cognition;Instruction;Intervention;Link;Longitudinal Studies;Mediating;Metabolism;Molecular;Neurons;Outcome;Pathologic;Pathway interactions;Performance;Peripheral;Phase;Play;Population;Predisposition;Quality of life;Rattus;Research;Rodent Model;Role;Structure;Synapses;Syndrome;Tacrolimus Binding Proteins;Techniques;Testing;Vitamin D;Work;age effect;age related;aged;aging brain;aging population;base;care burden;gene therapy;heart cell;knock-down;novel;overexpression;prevent;protein expression;steroid hormone


application_id: 9129777
project_number: 5R01EY024173-03
project_title: Parallel Tectothalamic Pathways
administering_ic: NEI
award_notice_date: 2016-08-11
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: EY
serial_number: 024173
program_official: FLANDERS, MARTHA C
project_start_date: 2014-09-02
project_end_date: 2019-08-31
study_section: Mechanisms of Sensory, Perceptual, and Cognitive Processes Study Section[SPC]
contact_pi_person_id: 1871981
contact_pi: BICKFORD, MARTHA E
other_pis: GUIDO, WILLIAM
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:
Address;Affect;Animals;Back;Butyric Acids;Cell Nucleus;Cells;Code;Detection;Disease;Dorsal;Dyslexia;Electron Microscopy;Electrons;Electrophysiology (science);Health;Homologous Gene;In Vitro;Investigation;Lateral;Lateral Geniculate Body;Lateral posterior nucleus of thalamus;Literature;Microscopic;Motion;Motion Perception;Movement;Mus;Neurons;Output;Pathway interactions;Perception;Population;Process;Property;Pulvinar structure;Reaction;Research;Rodent;Schizophrenia;Signal Transduction;Site;Stimulus;Stream;Structure;Synapses;Techniques;Tectum Mesencephali;Thalamic structure;Vision;Visual;Visual Motion;Visual system structure;Whole-Cell Recordings;area striata;base;brain circuitry;cell type;detector;extrastriate;extrastriate visual cortex;insight;magnocellular;motion sensitivity;novel;optogenetics;parvocellular;receptive field;research study;response;segregation;superior colliculus Corpora quadrigemina;visual neuroscience;visual stimulus


application_id: 9129773
project_number: 5R21NS094891-02
project_title: Characterization of the Fidelity to PD of a Unique Rat Model
administering_ic: NINDS
award_notice_date: 2016-08-17
opportunity_number: PA-13-303
application_type: 5
activity_code: R21
ic: NS
serial_number: 094891
program_official: SIEBER, BETH-ANNE
project_start_date: 2015-09-01
project_end_date: 2019-08-31
study_section: Neural Oxidative Metabolism and Death Study Section[NOMD]
contact_pi_person_id: 8329002
contact_pi: BUTTERFIELD, D. ALLAN
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
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): Parkinson disease (PD) the second most prevalent neurodegenerative disorder of the elderly is associated with movement and cognitive symptoms and current pharmacological treatments result in transient symptomatic relief but are not disease-modifying. PD results from degeneration of dopaminergic neurons in the substantia nigra (SNPC) and loss of striatal dopaminergic function is undoubtedly the cause of the symptoms of PD. Current treatments for PD have been focused on augmenting dopamine levels and include levodopa dopamine agonists and MAO-B inhibitors. Arguably the first biochemical deficits in PD which arise before symptoms appear are loss of parenchymal glutathione (GSH) the brain's major small molecule antioxidant and elevation of its oxidized form (GSSG) (Chinta et al. 2006). This has led researchers to show that PD is associated with oxidative stress though the cause of PD remains unknown. Familial PD cases have been linked to altered genes among which is PTEN-induced putative kinase-1 (Pink-1).  Genetic models of PD mostly mice bearing mutations in PD-relevant genes for unknown reasons do not have pathology or dopaminergic neuronal loss in the SNPC unlike PD patients. An ideal animal model of PD would display progressive loss of dopaminergic neurons and formation of Lewy bodies exhibit motor deficits and also mimic non-dopaminergic characteristics of PD i.e. loss of cognition and sense of smell (anosmia). It is thought that no mouse model of PD fulfills these criteria.  Sage Labs (Horizon) has produced a Pink-1 knockout rat [PINK-1 KO] that exhibits progressive dopaminergic loss in the SNPC moderate to severe motor deficits and non-motor characteristics of PD i.e. anosmia. At 8 months of age abundant pathology in the SNPC and PD-relevant symptomology are present. This may be the only rodent model of PD that has PD-relevant pathology in the SNPC. It would be helpful to utilize this exciting novel biological tool or environmental studies relevant to environmental-gene interaction in the neurodegeneration associated with PD. However this laudable goal is presently premature since this rat has not been fully characterized for goodness of fit to PD. Hence to fill this critical need this R21 proposal will achieve the goal of characterizing this unique rat model of PD to test the overall hypothesis that this unique rat has high fidelity to PD in terms of pathology biochemistry and behavior. If this hypothesis is sustained by these studies future investigations will employ this rat to probe gene-environmental interactions of relevance to PD.

project_terms:
ATP phosphohydrolase;Age;Age-Months;Animal Model;Anosmia;Antioxidants;Autophagocytosis;Behavior;Biochemical;Biochemistry;Biological;Bradykinesia;Brain;Brain region;Caenorhabditis elegans;Characteristics;Cognition;Complex;Corpus striatum structure;Dependence;Disease;Dopamine;Dopamine Agonists;Elderly;Environmental Risk Factor;Etiology;Exhibits;Future;Genes;Genetic;Genetic Models;Glutathione;Glutathione Disulfide;Goals;Health;Heat shock proteins;Heavy Metals;Herbicides;Histopathology;Human;Image;Impaired cognition;Investigation;Knock-out;Knowledge;LRRK2 gene;Lead;Levodopa;Lewy Bodies;Link;Lipid Peroxidation;Metabolic;Mitochondria;Modeling;Molecular;Monoamine Oxidase B;Movement;Mus;Mutation;Nature;Nerve Degeneration;Neurobehavioral Manifestations;Neurodegenerative Disorders;Oxidation-Reduction;Oxidative Stress;PINK1 gene;PTEN-induced putative kinase;Parkinson Disease;Pathogenesis;Pathology;Pathway interactions;Patients;Pharmacological Treatment;Physiology;Process;Proteins;Proteomics;Publishing;Rattus;Research;Research Personnel;Rest Tremor;Rodent Model;Role;Signs and Symptoms;Smell Perception;Solvents;Substantia nigra structure;Susceptibility Gene;Symptoms;Techniques;Testing;age related;alpha synuclein;base;brain size;dopaminergic neuron;drug discovery;environmental stressor;gene interaction;inhibitor/antagonist;innovation;insight;learned behavior;mitochondrial dysfunction;motor deficit;mouse model;neurochemistry;neuron loss;novel;oxidation;parkin gene/protein;pre-clinical research;premature;response;small molecule;stress protein;success;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Parkinson disease (PD) is associated with key susceptibility genes one of which is pink1 and PINK-1 knockout (KO) rats provide arguably the only rodent model of PD that shows pathology in a brain region similar to that of PD patients. This R21 proposal seeks to characterize the fidelity of pathology biochemistry and signs and symptoms to PD in this PINK-1 KO rat. Success will permit future investigations of interactions of environmental stressors and this susceptibility gene thought to be important in PD etiology and pathogenesis.


application_id: 9129523
project_number: 5U18FD004481-05
project_title: ISO/IEC 17025:2005 Accreditation for State Food Testing Laboratories
administering_ic: FDA
award_notice_date: 2016-08-22
opportunity_number: RFA-FD-12-008
application_type: 5
activity_code: U18
ic: FD
serial_number: 004481
project_start_date: 2012-09-01
project_end_date: 2017-08-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 11948441
contact_pi: JENNINGS, CHESTER DARRELL
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-09-01
project_abstract:
Project Summary:The main objective of the Division of Laboratory Services (DLS) at the Kentucky Department forPublic Health is to expand the scope of current accreditation for additional areas within the laboratoryto include Food Microbiology and Food Chemistry analyses. These microbiological and chemicalanalyses shall be performed on behalf of KY State manufactured food regulatory programs (MFRPS)and shall be conducted within the scope of ISO/IEC 17025:2005 Standards. DLS shall seek to obtainaccreditation by an impartial and internationally recognized accrediting body to achieve ISO/IEC17025:2005 standards for food microbiology and chemistry areas. DLS is the primary servicinglaboratory for conducting microbiological and chemical food analyses on behalf of the KY StateMFRPS in the Department for Public Health / Food Safety Branch which has a current food safetyinspection contract with FDA and is enrolled in the MFRPS. We intend to expand our current scope ofaccreditation by adding Food Microbiology and Food Chemistry analyses. This will be conductedthrough certified methods for screening of chemicals such as pesticide residues in processed foodssuch as fruits and vegetables using state- of- the-art analytical equipments including gaschromatographic / mass spectrometric (GC/MS) testing. In addition microbiological testing ofpathogens such as (E. coli S. aureus B. cereus Salmonella Shigella Listeria C. perfringensCronobacter sakazakii) will be performed in a variety of processed foods.Funding of this proposal will assist the KY State manufactured food regulatory program in achievingconformance with Standard 10 "Laboratory Support" of the MFRPS. Laboratory accreditation willcontribute to production of accurate and reliable test data a quicker acceptance of analytical resultsby FDA and other regulatory agencies for enforcement actions surveillance purposes and responseto foodborne outbreaks.

public_health_relevance:
Project Narrative:This proposal will increase the analytical capacity for FDA through the state laboratory (DLS) andenhance efforts to protect the nation's food supply. In the event of nefarious-type activity or otherlarge-scale events affecting foods or food products States and Federal authorities can use DLS testresults for rapid response and surveillance; and these response efforts will enable enforcement ofregulatory compliance to protect the safety of the nation's food supply. By funding this proposal DLSwill assist in achieving conformance with standard 10 "Laboratory Support" of the MFRPS (seeattached letters of support from Food Safety Branch/KY State MFRPS and Food EmergencyResponse Network (FERN)).


application_id: 9129152
project_number: 3P30CA177558-03S2
project_title: University of Kentucky Markey Cancer Center - Cancer Center Support Grant
administering_ic: NCI
award_notice_date: 2015-08-25
opportunity_number: PAR-11-005
application_type: 3
activity_code: P30
ic: CA
serial_number: 177558
suffix: S2
program_official: WHITAKER, DAMIYA EVE
project_start_date: 2013-07-08
project_end_date: 2016-06-30
study_section: Cancer Centers Study Section (A)[NCI-A]
contact_pi_person_id: 1901765
contact_pi: EVERS, BERNARD MARK
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Acute;Appointment;Basic Science;Biology;Biometry;Cancer Biology;Cancer Center;Cancer Center Support Grant;Cancer Control;Cancer Death Rates;Cancer Research Project;Cell Separation;Cellular biology;Clinical Data;Clinical Research;Complement;DNA Repair;Development;Faculty;Flow Cytometry;Free Radicals;Funding;Grant;Health;Health Occupations;Healthcare;Incidence;Informatics;Instruction;Kentucky;Leadership;Malignant Neoplasms;Measurable;Methods;Mortality Vital Statistics;National Cancer Institute;Outcome;Oxidation-Reduction;Oxidative Stress;Patient Care;Patients;Pharmacy facility;Positioning Attribute;Postdoctoral Fellow;Prevention;Recording of previous events;Recruitment Activity;Research;Research Infrastructure;Research Project Grants;Resource Sharing;Science;Seminal;Signal Transduction;Therapeutic;Therapeutic Clinical Trial;Tissue Procurements;United States;Universities;Work;anticancer research;bench to bedside;cancer cell;cancer prevention;cancer research center director;cancer site;college;data management;drug discovery;health disparity;injury and repair;interdisciplinary collaboration;member;programs


application_id: 9128798
project_number: 1H23IP001004-01
administering_ic: NCIRD
award_notice_date: 2015-09-24
opportunity_number: RFA-IP-15-1505
application_type: 1
activity_code: H23
ic: IP
serial_number: 001004
project_start_date: 2015-09-30
project_end_date: 2017-09-29
study_section: ZIP1-SRC(99)
contact_pi_person_id: 9335443
contact_pi: BRAWLEY, ROBERT LEE
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-09-30
budget_end_date: 2017-09-29
project_title:
Utilization of Kentucky's Immunization Information Systems (IIS) for Assessment Feedback Incentives and eXchange (AFIX) Assessments


application_id: 9128736
project_number: 5UH3TR000875-04
project_title: Fruit exosome-like particles for therapeutic delivery of extracellular miRNAs
administering_ic: NCATS
award_notice_date: 2016-08-04
opportunity_number: RFA-RM-12-014
application_type: 5
activity_code: UH3
ic: TR
serial_number: 000875
program_official: TAGLE, DANILO A
project_start_date: 2013-08-01
project_end_date: 2018-07-31
study_section: Special Emphasis Panel[ZRG1-OBT-Z(50)R]
contact_pi_person_id: 1889248
contact_pi: ZHANG, HUANG-GE
other_pis: GUO, PEIXUAN
congressional_district: 03
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop exosome-like nanoparticles as a delivery vehicle for targetable delivery of extracellular RNA (exRNA) primarily focusing on miRNAs which modulate gene expression and induce immune responses upon delivery in mouse tumor models. Development of exRNA-based therapeutics must overcome challenges including issues of delivery potential off-target effects safety toxicity the cost of large scale production elimination of potential biohazards to the environmen and tissue specificity. Unlike the situation with artificially synthesized nanoparticles or liposomes naturally derived nanoparticle-size exosomes are released from many different types of cells. miRNAs and RNAs can be encapsulated in naturally derived exosomes and the RNAs are stable and a number of miRNAs can be naturally encapsulated simultaneously in these exosomes. Recently data published by ours and other groups have demonstrated that mammalian exosomes can deliver poorly soluble agents chemotherapeutic drugs and siRNA in vivo. A limitation of this mode is the need for large-scale production of exosomes and potential biosafety. Our preliminary data show that exosome-like nanoparticles can be isolated in large quantities from the tissue of edible plants including grapes. We have demonstrated that exosome-like nanoparticles from grapes are composed of small RNAs proteins and lipids. An edible plant-derived nano-vector (EPNV) assembled from grape exosome-like derived lipids is capable of encapsulating siRNAs. Co-delivery of folic acid with the chemotherapy drug paclitaxel by EPNVs results in an increased efficiency in tumor tissue targeting. Reducing the size of EPNVs by passing them through an appropriate pore size filter significantly enhances EPNV translocation to the brain and oral administration of the EPNVs results in their migration to the liver. Based on these preliminary data and the current literature we propose to: (1) Determine whether an EPNV can deliver therapeutic miR17 via oral administration to target metastatic colon tumor in the liver subsequently inducing NK cell activation to kill metastatic tumor cells; (2) Determine whether miR155 encapsulated in EPNV promotes differentiation of myeloid derived suppressor cells (MDSCs) into mature dendritic cells in mouse breast/brain tumor models; (3) Determine whether a therapeutic dose of miRNA17 or miRNA155 delivered by EPNV induces no side-effects in mouse tumor models; and (4) Determine whether EPNV can be produced in large scale amounts economically for use in clinical settings. Demonstration of using a EPNV-based delivery system loaded with a desired therapeutic extracellular RNA (exRNA) including microRNA to target to inflammatory cells and tumor cells in vivo would not only be a significant step forward in the treatment of cancer but also provide a powerful tool foridentifying the role and effects of each small RNA encapsulated in resident or circulating microvesicles on the recipient cells. We will accomplish this in our study by knock-out and knock-in strategies.

project_terms:
Adverse effects;Animals;Antibodies;Biohazardous Substance;Biological Assay;Brain;Brain Neoplasms;Breast;Cells;Clinic;Clinical;Colon Carcinoma;Colonic Neoplasms;Curcumin;DNA;Data;Dendritic Cells;Development;Disease;Dose;Down-Regulation;Edible Plants;Encapsulated;Environment;Evaluation;Folic Acid;Fruit;Gene Expression;Goals;Grapefruit;Grapes;Health;Human;Immune response;Immunotherapy;In Vitro;Inflammatory;Intranasal Administration;Killings;Knock-in;Knock-out;Laboratories;Light;Lipids;Liposomes;Literature;Liver;MHC Class I Genes;Malignant Neoplasms;Mammalian Cell;Metastatic Neoplasm to the Liver;MicroRNAs;Modeling;Mus;Myelogenous;Myeloid Cells;NK Cell Activation;Neoplasm Metastasis;Non-Viral Vector;Nucleic Acids;Oral Administration;Paclitaxel;Pharmaceutical Preparations;Phenotype;Play;Prevention;Production;Proteins;Protocols documentation;Publishing;RNA;Research Personnel;Role;Safety;Science;Signal Transduction;Small Interfering RNA;Small RNA;Specificity;Suppressor-Effector T-Lymphocytes;System;Testing;Therapeutic;Therapeutic Agents;Tissues;Tomatoes;Toxic effect;Tumor Tissue;Viral Vector;aqueous;base;cancer cell;cancer therapy;cell type;chemotherapeutic agent;chemotherapy;cost;exosome;expression vector;extracellular;in vivo;intravenous administration;large scale production;microvesicles;migration;mouse model;nanoparticle;nanosized;nanovector;neoplastic cell;overexpression;particle;prevent;receptor;targeted delivery;therapeutic miRNA;tool;trafficking;tumor;vector-induced

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The concept that extracellular RNA (exRNA) may alter target cell phenotypes by way of intercellular signaling is becoming universally accepted in science. Whether exRNA can be used as a therapeutic agent is not known. The overall goal of this study is to develop grape lipid derived nano vectors for the delivery of exRNAs as therapeutic agents to target tumor cells as well as inflammatory cells in animal tumor models. Additionally we will assess the therapeutic potential of exRNA used in a clinical setting.


application_id: 9128727
project_number: 5R44OD018231-03
project_title: A non-surgical embryo transfer device for producing gene modified rats
administering_ic: OD
award_notice_date: 2016-08-10
opportunity_number: PA-14-071
application_type: 5
activity_code: R44
ic: OD
serial_number: 018231
program_official: CONTRERAS, MIGUEL A
project_start_date: 2010-07-15
project_end_date: 2018-08-31
study_section: Special Emphasis Panel[ZRG1-EMNR-S(10)B]
contact_pi_person_id: 10138071
contact_pi: STONE, BARBARA JEAN
other_pis: Not Applicable
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): ParaTechs Corporation develops innovative technologies for biomedical research while seeking to improve animal welfare for laboratory animals. One of ParaTechs' major goals is to further the guiding principles of ethical animal use by 'reducing replacing and refining' the use of animals in research according to the guidelines of Russell and Burch's 3Rs of animal research. ParaTechs already has brought to market a non-surgical embryo transfer device (NSETTM) for mice which replaces surgical embryo transfers with a non-surgical method that has been proven to cause less stress in research animals. The goal of this project is to develop a device and a research protocol for nonsurgical embryo transfer in rats. The device and protocol is to be rapid easy to use cost effective and efficien for embryo transfer. Poof of principle for the project was established during Phase I where multiple prototypes of a rat NSET device were designed manufactured and tested. Rat embryos were transferred and viable rat pups were obtained demonstrating the first successful nonsurgical embryo transfer in rats. The goal of Phase II is to further establish the parameters ofrat NSET technology and to develop the device for commercialization to the biomedical research community. Four objectives are proposed to achieve this goal. First we will determine the efficiency of non-surgical embryo transfer relative to surgical embryo transfer in Sprague-Dawley and Fischer 344 rats for both morula and blastocyst stage embryos. This study will have broad applications for transfer of cryopreserved embryos and for transfer of genetically modified embryos after introduction of embryonic stem cells. Second we will transfer in vitro cultured embryos using the rNSET and compared efficiency to surgical embryo transfer techniques. This aim will address successful transfer of rat embryos that may be modified very early in development; for example after pronuclear injection for the purpose of genetic modification. Third we will test the use of the rat NSET for artificial insemination as an alternative to surgical techniques. This aim will support the use of the device as an alternative t surgical artificial insemination and as a possible alternative to in vitro fertilization. Fourth w will assess the level of stress reduction of the NSET procedure compared to surgical embryo transfer. These aims are consistent with ParaTechs' overall goal to improve animal welfare and support more effective and humane use of animal models in biomedical research.

project_terms:
Address;Adopted;Animal Experimentation;Animal Model;Animal Welfare;Animals;Artificial Insemination;Assisted Reproductive Techniques;Award;Behavior;Biological Markers;Biomedical Research;Birth;Businesses;Cardiovascular Diseases;Categories;Cell Culture Techniques;Collaborations;Communities;Data;Development;Device Designs;Devices;Distress;Embryo;Embryo Transfer;Ethics;Female;Fertilization in Vitro;Funding;Gene-Modified;Genetic;Goals;Guidelines;Health;Implant;In Vitro;Individual;Injection of therapeutic agent;Institution;Knock-out;Laboratories;Laboratory Animals;Laboratory Rat;Laboratory Research;Lead;Letters;Life;Maintenance;Marketing;Measures;Methods;Modeling;Modification;Morals;Morula;Mus;Operative Surgical Procedures;Outcome;Pain;Painless;Pharmaceutical Preparations;Phase;Physiology;Procedures;Protocols documentation;Rat Strains;Rattus;Research;Research Personnel;Resources;Rivers;Services;Societies;Staging;Stress;Techniques;Technology;Testing;Tissue Sample;Toxicology;Transgenic Organisms;blastocyst;commercialization;cost;cost effective;design;embryo culture;embryonic stem cell;genetic manipulation;human disease;human tissue;improved;innovative technologies;meetings;method development;mouse model;prototype;pup;sperm cell;tissue culture

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The ability to genetically modify the laboratory rat is producing increasingly valuable and unique strains to investigate human disease. Currently this technology is dependent on implanting embryos in female rats by surgical means. ParaTechs proposes to develop and commercialize a unique device and technology for fast simple and painless nonsurgical embryo transfer (NSET) in rats which will support the Office of Laboratory Animal Welfare (OLAW) objectives of reducing pain and distress for laboratory animals because it will provide an alternative to surgical methods for assisted reproductive techniques.


application_id: 9128710
project_number: 5R34MH104208-03
project_title: Improving Transition Outcomes in ASD using COMPASS
administering_ic: NIMH
award_notice_date: 2016-06-25
opportunity_number: RFA-MH-14-101
application_type: 5
activity_code: R34
ic: MH
serial_number: 104208
program_official: JULIANO-BULT, DENISE M
project_start_date: 2014-08-22
project_end_date: 2018-06-30
study_section: ZMH1-ERB-K(05)
contact_pi_person_id: 1960113
contact_pi: RUBLE, LISA A
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 EDUCATION
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): This application responds to the identified need for developing and testing a model for transition to adult supports and services for individuals with autism spectrum disorders (ASD) that prevents lapses in services and enhances functional life outcomes. The proposal also addresses concerns raised by the Interagency Autism Coordinating Committee of a "critical lack of tested interventions for adolescents and young adults." Although federal education law mandates that public schools provide transition services as part of the Individualized Education Program (IEP) the promise and potential for a well-coordinated and planned transition is not being met. The proposed study builds on two randomized controlled trials of a parent-teacher consultation intervention called the Collaborative Model for Promoting Competence and Success (COMPASS) for young children with ASD data on efficacy for both traditional face-to-face and videoconferencing technology delivery methods and a book-length treatment manual. COMPASS is an implementation strategy that assists in transferring evidence based approaches into classrooms and assists public school special educators and parents in ecological assessment research-informed goal development and person-centered decision-making for individualizing evidence-based interventions for children with ASD. The COMPASS intervention consists of an initial parent-teacher session (3 hours) occurring near the start of the school year followed by four 1-hour teacher coaching. The first aim is to conduct focus groups with stakeholders including policy makers parents teachers service providers and persons with ASD to get feedback on (i) strengths and weaknesses of state policies and services and resources that exist or are needed to support effective implementation of best practices for transition age youth with ASD; (ii) otherconcerns impacting adult services such as housing social security health insurance transportation; and (iii) specific aspects of COMPASS that would need to be adapted/revised to meet the needs of transition age youth. Based on these results we will identify measures that would need to be adapted/developed and obtain feedback from a subsample of focus group members on the measures. Our second aim is to conduct a two wave pilot randomized controlled trial of the adapted COMPASS for transition planning using the new procedures and measures (n = 32 participant triads-consultant teacher student with ASD) using a mixed methods approach. We will obtain qualitative feedback on the intervention (acceptability feasibility outcomes) and use data to revise/adapt second wave implementation as well as to help inform further applications in adult settings. Lastly we will conduct qualitative case studie based on individuals with ASD who have low and high performing outcomes to understand factors that might explain differential response to the intervention and use to revise/adapt second wave implementation.

project_terms:
Accounting;Address;Adolescent and Young Adult;Adult;Age;Autistic Disorder;Books;Case-Control Studies;Characteristics;Child;Competence;Consultations;Control Groups;Data;Decision Making;Development;Education;Employment;Environmental Risk Factor;Evidence based intervention;Feedback;Focus Groups;Funding;Future;Future Teacher;Goals;Health;Health Insurance;Hour;Housing;Individual;Intervention;Laws;Length;Life;Manuals;Measures;Methods;Modeling;National Institute of Mental Health;Occupations;Outcome;Parents;Participant;Persons;Placebo Control;Policies;Policy Maker;Procedures;Process;Provider;Randomized Controlled Trials;Reporting;Research;Resources;Sampling;School Teachers;Schools;Services;Social Security;Students;Technology;Testing;Transportation;Triad Acrylic Resin;United States National Institutes of Health;Videoconferences;Videoconferencing;Youth;autism spectrum disorder;base;ethnic diversity;evidence base;implementation research;improved;meetings;member;person centered;prevent;programs;research study;response;skills;success;teacher

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This application responds to the need for developing and testing a model for transition to adult supports and services for individuals with autism spectrum disorders (ASD) that prevents lapses in services and enhances functional life outcomes. The parent-teacher consultation intervention called the Collaborative Model for Promoting Competence and Success (COMPASS) for young children with ASD will be adapted based on stakeholder input and tested in a randomized controlled study of 32 participants. Variables to help understand factors that explain optimal and poor outcomes will also be obtained.


application_id: 9128331
project_number: 1R56AI117876-01
project_title: The role of Perforin-2 in Chlamydia pathogenesis
administering_ic: NIAID
award_notice_date: 2015-08-27
opportunity_number: PA-13-302
application_type: 1
activity_code: R56
ic: AI
serial_number: 117876
program_official: HILTKE, THOMAS J
project_start_date: 2015-09-01
project_end_date: 2017-08-31
study_section: Special Emphasis Panel[ZRG1-IDM-U(02)M]
contact_pi_person_id: 7726964
contact_pi: FIELDS, KENNETH A
other_pis: PLANO, GREGORY V
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): Sexually transmitted disease mediated by bacterial pathogens represents a significant burden to human health world-wide. Chlamydia trachomatis remains the most prevalent of reportable cases in the U.S. and infections can lead to sequelae such as ectopic pregnancy sterility and pelvic inflammatory disease. While adaptive immunity is essential for clearance of Chlamydia in a murine model chlamydial infections elicit a robust innate immune response that has been correlated with limiting ascension of infection as well as host tissue pathology. We have recently identified a novel innate immune factor termed Perforin-2 that is capable of killing a wide range of cell-associated bacteria. These observations make it likely that P-2 is a pivotal host factor involved in combating bacterial infection. An obligate intracellular existence like the one exemplified by Chlamydia spp. necessitates evolution of mechanisms to evade or circumvent innate host defenses that would normally neutralize invading microbes. Our preliminary data indicate that Chlamydia block P-2 activity in permissive cells but are susceptible to P-2 mediated killing in non-permissive cells like macrophages. We will take advantage of both in vitro tissue culture and in vivo murine infection models to elucidate the molecular mechanisms governing the sensitivity or resistance of Chlamydiae to P-2-mediated killing. Overall we seek to understand host and bacterial factors that significantly influence the outcome of infection. This study will contribute to that overall gal by studying the infection biology of an important human pathogen and a newly appreciated and essential component of host immunity.

project_terms:
Address;Affect;Amoeba genus;Anti-Bacterial Agents;Area;Bacteria;Bacterial Infections;Biochemical;Biology;Cells;Cellular biology;Characteristics;Chlamydia;Chlamydia Infections;Chlamydia trachomatis;Chlamydiales;Data;Development;Disease;Economic Burden;Ectopic Pregnancy;Epithelial Cells;Equilibrium;Eukaryota;Event;Evolution;Growth;Health;Host Defense;Human;Image;Immune;Immune response;Immune system;Immunity;In Vitro;Infection;Integration Host Factors;Invaded;Killings;Knockout Mice;Lead;Link;Maintenance;Mammals;Mediating;Microbe;Modeling;Molecular;Mus;Natural Immunity;Nature;Outcome;P-2;Parasites;Pathogenesis;Pathology;Pelvic Inflammatory Disease;Phagocytes;Porifera;Predisposition;Probability;Promotor (Genetics);Resistance;Resolution;Role;Sexually Transmitted Diseases;Sterility;Stimulus;Testing;Time;Tissues;Tropism;Vaccines;Virulence;Work;World Health;adaptive immunity;antimicrobial;cell type;co-infection;combat;cytokine;design;genital infection;health economics;in vivo;insight;macrophage;member;microbial;novel;obligate intracellular parasite;pathogen;perforin 2;porin;response;success;tissue culture;transmission process

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Sexually transmitted disease remains a significant health burden world-wide and infections with Chlamydia trachomatis are common. A new murine co-infection model has been developed that enables study of bacterial and host factors involved in pathogenesis. This project seeks to elucidate the role of a novel innate immunity factor termed Perforin-2 in controlling Chlamydia infections.


application_id: 9128245
project_number: 1U01MD010556-01
administering_ic: NIMHD
award_notice_date: 2016-04-25
opportunity_number: RFA-MD-15-010
application_type: 1
activity_code: U01
ic: MD
serial_number: 010556
program_official: ZHANG, XINZHI
project_start_date: 2016-04-26
project_end_date: 2020-12-31
study_section: Special Emphasis Panel[ZMD1 DRI (03)]
contact_pi_person_id: 8931964
contact_pi: SWANSON, MARK
other_pis: SCHOENBERG, NANCY E.
congressional_district: 06
department: PUBLIC HEALTH & PREV MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PUBLIC HEALTH
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-04-26
project_abstract:
DESCRIPTION (provided by applicant):The National Institutes of Health has acknowledged that residents of rural Appalachia experience among the nation's worst health and economic profiles including disability and premature mortality stemming from elevated rates of heart disease and stroke various cancers diabetes all of which are closely associated with suboptimal dietary intake obesity and overweight. Community members are particularly concerned about their children who have among the highest rates of obesity overweight and suboptimal dietary intake in the nation. Eliminating these health disparities requires scientificaly informed community-engaged research to develop and evaluate innovative and sustainable programs and policies. For the proposed application our community-research team will (1) use an innovative information technology CBPR method - Structured Public Involvement - to refine and tailor a package of pilot tested healthy eating interventions; (2) conduct and evaluate this package of interventions that were found to be feasible culturally consonant and promising during R24MD008018 and (3) build community capacity in social marketing an innovative approach to enhance sustainability of the intervention. Our partners include the Community Farm Alliance local school districts the Cooperative Extension Service and other community organizations. For the first aim the innovative CBPR approach Structured Public Involvement will allow us to tailor the intervention while maintaining project fidelity. For the second aim we
will administer and evaluate three interrelated interventions to transform access to and intake of healthy foods for Appalachian children; (1) a school-based water campaign to decrease sugar sweetened beverage consumption (2) healthy cooking classes to encourage healthy cooking on a budget; and (3).a farmer's market-based healthy summer feeding program. Finally in Aim 3 we will administer a CBPR-oriented approach social marketing to enhance sustainability a challenge for all behavioral interventions. Through the schools we will train teachers and administrators to teach social marketing to students who will be encouraged to develop marketing campaigns supporting healthy diets. All of these efforts will be developed implemented and evaluated in conjunction with our Community Advisory Boards. As one of our local stakeholders told us "If you really are what you eat it's no wonder so many of us are unhealthy." By developing sustainable evidence-based programming we aim to transform consumption patterns and the eating environment so the next generation of rural residents can overcome pernicious health disparities.

project_terms:
Administrator;Appalachian Region;Area;Behavior Therapy;Budgets;Child;Clinic;Communities;Community Health;Community Participation;Consumption;County;Diabetes Mellitus;Diet;Diet Habits;Dietary Intervention;Dietary intake;Disease;Eating;Educational process of instructing;Educational workshop;Elements;Environment;Equilibrium;Evidence based program;Farming environment;Food;Food Services;Future;Health;Health Food;Health Priorities;Healthy Eating;Heart Diseases;Home environment;Improve Access;Information Technology;Intake;Intervention;Kentucky;Lead;Life;Malignant Neoplasms;Marketing;Methods;Nutritional;Obesity;Outcome;Overweight;Parents;Pattern;Pilot Projects;Policies;Premature Mortality;Public Housing;Research;Research Personnel;Rural;Rural Health;Schools;Science;Services;Social Marketing;Specific qualifier value;Structure;Students;Teacher Professional Development;Techniques;Technology;Testing;To specify;Trainers Training;U-Series Cooperative Agreements;United States National Institutes of Health;Water;Youth;base;behavior change;community building;community intervention;community living;community organizations;cooking;design;disability;drinking;experience;farmer;feeding;good diet;health disparity;health economics;improved;information gathering;innovation;innovative technologies;insight;meetings;member;multidisciplinary;next generation;novel;outreach;preference;prevent;programs;public health relevance;school district;skills;social;stem;stroke;sugar;sweetened beverage;teacher;theories;user-friendly


application_id: 9128240
project_number: 1R01GM115261-01A1
project_title: Platform technologies for understanding and exploiting methylation
administering_ic: NIGMS
award_notice_date: 2016-07-22
opportunity_number: PA-13-302
application_type: 1
activity_code: R01
ic: GM
serial_number: 115261
suffix: A1
program_official: FABIAN, MILES
project_start_date: 2016-08-01
project_end_date: 2020-07-31
study_section: Special Emphasis Panel[ZRG1 BCMB-W (02)]
contact_pi_person_id: 2212695
contact_pi: THORSON, JON SCOTT
other_pis: PHILLIPS, GEORGE NEAL
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF PHARMACY
organization_zip: 405260001
organization_country: UNITED STATES
project_terms:
Agriculture;Alkylation;Anabolism;Ansamycin Antineoplastic Antibiotic;Anti-Infective Agents;Biological Assay;Biological Process;Catalysis;Cells;Chemicals;Clinical;Complement;Complex;Development;Directed Molecular Evolution;Disease;Engineering;Enzymes;Escherichia coli;Eukaryota;Evolution;Excretory function;Gene Deletion;Goals;Human;Immunosuppressive Agents;In Vitro;Indium;Insecticides;Knowledge;Label;Lead;Life;Ligand Binding;Marketing;Metabolism;Methionine;Methylation;Methyltransferase;Modeling;Mutation;Natural Products;Orthologous Gene;Outcome Study;Pathogenesis;Patients;Pharmaceutical Chemistry;Pharmaceutical Preparations;Polyketide Macrolides;Process;Prokaryotic Cells;Reaction;Reagent;Series;Sirolimus;Small Interfering RNA;Specificity;Staging;Structure;Structure-Activity Relationship;Substrate Specificity;System;Technology;Therapeutic;Toxic effect;Translating;Viral Pathogenesis;Walking;absorption;actionable mutation;analog;assay development;base;catalyst;cellular development;chemical genetics;chemical synthesis;design;flexibility;high throughput screening;human disease;improved;in vivo;inhibitor/antagonist;innovation;loss of function;methionine adenosyltransferase;methylome;microbial;novel;practical application;prototype;public health relevance;tool;treatment response


application_id: 9128022
project_number: 5R01GM112721-02
project_title: Deciphering the Code of N-terminal Post-translational Modification
administering_ic: NIGMS
award_notice_date: 2016-06-22
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: GM
serial_number: 112721
program_official: HAGAN, ANN A
project_start_date: 2015-09-01
project_end_date: 2016-07-31
study_section: Membrane Biology and Protein Processing Study Section[MBPP]
contact_pi_person_id: 8476980
contact_pi: SCHANER-TOOLEY, CHRISTINE E
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): Post-translational modification of the -amino group of proteins has been documented for many decades. However these modifications are little studied and thought to be constitutive with few regulatory roles. Recent data from our laboratory challenges these beliefs. We have identified two novel N-terminal modifying enzymes NRMT1 and NRMT2 and shown that many of their targets are known disease-related proteins (including Retinoblastoma SET Tau -catenin and ataxin- 3). We have constructed the first viable knockout mouse for any N-terminal PTM (NRMT1-/-) which has severe developmental defects. We have also identified the first protein MYL9 which can be either N-terminally methylated or N-terminally acetylated. According to these data we aim to demonstrate that N-terminal post- translational modifications are dynamic serve distinct functional roles and control many pathways regulating human development and disease. Specific Aim #1 will use our newly generated NRMT1-/- mouse embryonic fibroblasts to determine the functional differences between N-terminal mono- and trimethylation. Specific Aim #2 will use a combination of biochemical assays and mass spectrometry to show for the first time that N-terminal methylation and N-terminal acetylation are interchangeable and differentially regulate protein function. Specific Aim #3 will use a combination of isothermal calorimetry protein arrays and SILAC mass spectrometry to determine if N-terminal monomethylation trimethylation and acetylation promote different binding partners. These experiments will begin to place N-terminal post-translational modifications in their relevant signaling pathways and reveal how their misregulation leads to developmental defects and tumor formation. Successful completion of these aims will initiate a new field of protein regulation and identify novel regulatory mechanisms for many cellular pathways known to impact human health.

project_terms:
Acetylation;Acetyltransferase;Address;Belief;Binding;Binding Proteins;Biochemical;Biological Assay;Calorimetry;Cell Culture Techniques;Cell Proliferation;Cell physiology;Cells;Chromatin Structure;Code;Consensus Sequence;Cytotoxic agent;DNA Binding;DNA-Binding Proteins;Data;Defect;Development;Disease;Disease Progression;EMSA;Embryo;Enzymes;Fibroblasts;Frequencies;Genes;Genetic Transcription;Goals;Health;Histone Code;Histones;Human;Human Development;ICAM1 gene;Knock-out;Knockout Mice;Laboratories;Lead;MJD1 protein;Mass Spectrum Analysis;Mediating;Methylation;Modification;Monitor;Mono-S;Myosin Regulatory Light Chains;N-terminal;Nuclear;Nuclear Export;Nuclear Localization Signal;Pathway interactions;Peptides;Perception;Post-Translational Protein Processing;Process;Protein Array;Proteins;Reading;Recruitment Activity;Regulation;Retinoblastoma;Role;Signal Pathway;Signal Transduction;Specificity;Tail;Tertiary Protein Structure;Testing;Time;Translating;amino group;base;beta catenin;cell growth regulation;cell motility;chromatin immunoprecipitation;human disease;innovation;knock-down;mutant;novel;overexpression;protein function;research study;tau Proteins;tumor;tumorigenesis

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Post-translational modification of the N-terminus of proteins is a vastly understudied branch of protein processing. However our data show that its misregulation produces severe developmental defects and leads to oncogenesis. We aim to prove these modifications are dynamic and serving distinct regulatory roles so that their involvement in disease progression can be comprehensively studied and satisfactorily utilized.


application_id: 9127735
project_number: 5F31HL126403-02
project_title: Bringing Advanced Heart MRI to Pediatric Clinics Using an Interactive Videogame
administering_ic: NHLBI
award_notice_date: 2016-03-24
opportunity_number: PA-14-147
application_type: 5
activity_code: F31
ic: HL
serial_number: 126403
program_official: MEADOWS, TAWANNA
project_start_date: 2015-04-20
project_end_date: 2018-04-19
study_section: Special Emphasis Panel[ZRG1-F15-P(20)L]
contact_pi_person_id: 12104869
contact_pi: HAMLET, SEAN MICHAEL
other_pis: Not Applicable
congressional_district: 06
department: ENGINEERING (ALL TYPES)
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: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Congenital heart disease (CHD) affects roughly 2 million people in the US and remains responsible for twice as many years of life lost as all of childhood cancer combined. Cardiac magnetic resonance (CMR) imaging has become the gold standard technique that clinicians use to monitor cardiovascular function in patients over time. Advanced CMR techniques offer incredible potential for improving our ability to diagnose and treat patients with CHD but currently require long acquisition times that limit their feasibility n the clinic. Our overall goal is to make these advanced CMR techniques clinically feasible through dramatically reducing the time required to acquire the image data. We propose a new CMR system which we call videogame interface for diaphragm location (VIDLoc) that can reduce acquisition times by 50%. VIDLoc works by advising children how to alter their breathing patterns in real-time during CMR in order to dramatically reduce the total time required to acquire CMR data. Because the heart moves up and down on the diaphragm as children breathe imaging can only be performed when the diaphragm is within a narrow region called the "acceptance window". Since children breathe very erratically the amount of time they spend in the acceptance window is often as low as 20% (thus imaging can only be performed 1/5th of the time). VIDLoc overcomes this by imaging the child's diaphragm location in real-time and using this to generate a videogame showing a car on a road. The car's location relative to the road represents the diaphragm location relative to the acceptance window. VIDLoc will provide instructions to children to guide their diaphragm (or car) to be within the acceptance window (or road) where the heart can be imaged. We hypothesize that using VIDLoc will increase the amount of time spent in the acceptance window and therefore dramatically reduce CMR acquisition times. This will make advanced CMR techniques clinically feasible in patients with CHD. We will first optimize VIDLoc by adding extra features such as text and voice feedback of breathing instructions which will be tested by children with CHD to determine each feature's effectiveness. Then we will test VIDLoc against conventional free breathing for acquisition time and quality of data derived. Twenty children with CHD will undergo an advanced CMR technique to image three-dimensional cardiac motion. Lastly we will quantify the acquisition time and quality of data derived from VIDLoc with and without pre-CMR training in a simulator. A simulated version of the VIDLoc system outside of the scanner will use a sensor to quantify chest wall excursion as a proxy for diaphragm location. Twenty children with CHD will be randomized to undergo advanced CMR using VIDLoc with or without pre-CMR training in the simulator. Acquisition times and image quality will be used to determine the efficacy of pre-CMR training. The overall goal of this proposal is to use VIDLoc to reduce CMR acquisition time so that we can start using advanced CMR techniques in the clinic to ultimately improve the lives of patients with congenital heart disease.

project_terms:
Adult;Affect;Automobile Driving;Benchmarking;Blood;Breathing;Cardiac;Cardiovascular Physiology;Chest wall structure;Child;Childhood;Clinic;Clinical;Data;Data Quality;Decision Making;Diagnosis;Effectiveness;Feedback;Figs - dietary;Future;Goals;Gold;Health;Heart;Heart Abnormalities;Heart Diseases;Image;Imaging Techniques;Imaging technology;Instruction;Ionizing radiation;Location;Magnetic Resonance;Magnetic Resonance Imaging;Malignant Childhood Neoplasm;Measures;Monitor;Motion;Operative Surgical Procedures;Patients;Pattern;Positioning Attribute;Proxy;Randomized;Reproducibility;Respiratory Diaphragm;Role;Scanning;System;Techniques;Testing;Text;Time;Training;Voice;Work;base;congenital heart disorder;heart function;heart imaging;heart motion;improved;mortality;repaired;sensor;time use;years of life lost

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Advanced imaging techniques for quantifying heart function in children born with heart defects require long imaging times that reduce their clinical feasibility.This project's interactive videogame system has the ability to reduce the imaging times required to perform advanced heart imaging by over 50%. The overall goal of this project is to use this imaging technology to improve our understanding of heart function in order to guide appropriate treatments in children and in the future adults with heart disease.


application_id: 9127436
project_number: 1R21AI120602-01A1
project_title: Bpur a critical regulator of Borrelia burgdorferi infectivity
administering_ic: NIAID
award_notice_date: 2016-02-08
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AI
serial_number: 120602
suffix: A1
program_official: ILIAS, MALIHA R
project_start_date: 2016-02-10
project_end_date: 2018-01-31
study_section: Special Emphasis Panel[ZRG1 IDM-B (80)]
contact_pi_person_id: 7875343
contact_pi: STEVENSON, BRIAN
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): All organisms from bacteria to humans need to "recognize" where they are and respond accordingly. A pathogen must sense its location in the infectious cycle then produce factors necessary for that site while repressing synthesis of inappropriate factors. Thus disruption of key regulatory pathways can inhibit a pathogen's ability to infect indicating useful targets for developing novel antibiotics. In our studies of th Lyme disease bacterium Borrelia burgdorferi we discovered that regulation of a new DNA/RNA-binding protein named BpuR is required for mammalian infection. B. burgdorferi regulates production of BpuR synthesizing it at low levels during mammalian infection processes and at high levels during colonization of vector ticks. We genetically engineered B. burgdorferi to constitutively produce high levels of BpuR during murine infection and found the mutant to be significantly impaired in its ability to colonize mice. Transcriptomic analyses (RNA-Seq) demonstrated that BpuR significantly affects expression of approximately 5% of B. burgdorferi operons disturbing cellular levels of several known virulence factors and metabolic enzymes. We hypothesize that disruption of the processes controlling production of BpuR will significantly inhibit B. burgdorferi infection. The planned studies are designed to elucidate the mechanism by which B. burgdorferi controls expression of this critical regulatory factor and determine how disrupting that mechanism impacts upon infection processes.

project_terms:
Affect;Antibiotics;Arthropods;Bacteria;Bacterial Infections;Binding;Borrelia;Borrelia burgdorferi;DNA;DNA Sequence;Data;Engineering;Enzymes;Genes;Genetic Engineering;Genetic Transcription;Glycine;Human;Infection;Link;Location;Lyme Disease;Mammals;Metabolic;Modeling;Mus;Mutate;Names;North America;Operon;Organism;Patients;Process;Production;Protein Biosynthesis;Proteins;RNA;RNA-Binding Proteins;Regulation;Regulatory Pathway;Research Design;Site;Testing;Ticks;Transcriptional Regulation;Transfer RNA;Virulence Factors;mutant;novel;novel therapeutics;pathogen;public health relevance;transcriptome sequencing;transcriptomics;vector

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The BpuR protein of the Lyme disease bacterium binds specific sequences of DNA and RNA and controls expression of numerous virulence factors and essential metabolic enzymes. Bacteria that do not correctly control BpuR levels are severely impaired in ability to cause mammalian infection. Studies in this proposal will determine the mechanisms by which Lyme bacteria control BpuR production and define how disruption of those mechanisms impacts upon infection processes.


application_id: 9127248
project_number: 5R13GM058252-17
project_title: Interactive Learning Modules for Writing Grant Proposals
administering_ic: NIGMS
award_notice_date: 2016-08-22
opportunity_number: PA-13-347
application_type: 5
activity_code: R13
ic: GM
serial_number: 058252
program_official: SESMA, MICHAEL A
project_start_date: 1998-09-01
project_end_date: 2018-08-31
study_section: Training and Workforce Development Study Section - D[TWD-D]
contact_pi_person_id: 8535385
contact_pi: FRAZIER, DONALD T
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 climate surrounding federal funding for biomedical research has become increasingly competitive lending considerable importance to the development of grantsmanship skills by higher education faculty as a whole and by faculty from underrepresented groups in particular. The proposed conference series Interactive Learning Modules for Writing Grant Proposals offers a highly focused program of grant-writing training that directly addresses issues of diversity in biomedical research through an active participatory training sequence resource modules and post-workshop mentored support. The overall objectives are to empower faculty at institutions with a significant enrollment of underrepresented minorities to develop and submit competitive research proposals and to build capacity at minority-serving institutions to support those efforts. The original goal of our trainig partnership with NIGMS was to translate an innovative proven grant-writing workshop into an interactive hypermedia course on the internet for wide dispersal to eligible faculty and research support staff. That project concept evolved into a highly effective model of direct workshop training on proposal development that was supported by the online course modules. We now propose a new model that engages trainers and participants in direct proposal development activities through guided writing and mentored support. Building on our past experience with faculty research administrators and students the competing renewal has the following specific aims: 1) develop and host active-learning style grant-writing retreats for selected faculty poised to submit proposals ranging from developmental and exploratory research awards to R01s; 2) update the internet course modules as a resource to facilitate active post-workshop learning by incorporating new media content developed using the Echo360 active learning technology platform; 3) provide a pipeline to the writing retreat by conducting off-site regional faculty workshops to motivate mentor and engage prospective faculty in pursuing competitive extramural funding opportunities; and 4) assist faculty workshop participants through invited site visits focused on institution-specific proposal development and submission issues. Through our ongoing scientific and administrative mentoring (via video and/ or teleconferencing and webinars) we will sustain a relationship with our participants well beyond the workshops and internet course. We anticipate that the proposed workshop series will motivate participants and improve the grant-seeking skills and abilities of researchers from institutions that serve significant numbers of underrepresented groups increase the number of scientists from these groups engaged in biomedical research and thereby strengthen the overall research environment at participating campuses.

project_terms:
Active Learning;Address;Administrator;Applications Grants;Attention;Award;Behavior;Behavioral Research;Biomedical Research;Climate;Consult;Consultations;Development;Dimensions;Discipline;Diverse Workforce;Educational workshop;Elements;Enrollment;Environment;Event;Extramural Activities;Faculty;Faculty Workshop;Funding;Funding Opportunities;Goals;Grant;Health;Hypermedia;Institution;Internet;Kentucky;Learning;Learning Module;Mentors;Minority-Serving Institution;Mission;Modeling;National Institute of General Medical Sciences;Participant;Personal Satisfaction;Persons;Principal Investigator;Process;Research;Research Personnel;Research Project Grants;Research Proposals;Research Support;Research Training;Resources;Rest;Scientist;Series;Site;Site Visit;Specialist;Students;Technology;Teleconferences;Training;Translating;Underrepresented Groups;Underrepresented Minority;Underrepresented Populations;United States National Institutes of Health;Universities;Update;Writing;base;career;course module;design;empowered;ethnic disparity;experience;faculty research;faculty support;graduate student;hands-on learning;higher education;improved;innovation;online course;programs;prospective;research and development;skills;symposium;tool;virtual;webinar

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  A diverse workforce in biomedical and behavioral research is essential for exploring socially and culturally sensitive health-related issues concerning underrepresented populations. Our proposed program is designed to motivate and improve the competitiveness of researchers/grant writers at minority institutions and thereby have a substantial impact on the well-being of our citizens.


application_id: 9127218
project_number: 5R01ES022191-06
project_title: Integrated Chemoselective and Informatic Platform for Large-Scale Metabolomics
administering_ic: NIEHS
award_notice_date: 2016-08-23
opportunity_number: RFA-RM-11-019
application_type: 5
activity_code: R01
ic: ES
serial_number: 022191
program_official: BALSHAW, DAVID M
project_start_date: 2014-04-26
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZRG1-BST-P(50)R]
contact_pi_person_id: 7213583
contact_pi: FAN, TERESA WHEI-MEI
other_pis: HIGASHI, RICHARD M;MOSELEY, HUNTER NATHANIEL;NANTZ, MICHAEL H
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Recent advances in metabolomics technologies especially those that combine the complementarily of mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) enables rapid analysis of thousands of peaks representing hundreds of metabolites. Yet key barriers remain for large-scale metabolomics applications most notably: even higher throughput with robust metabolite assignment and quantification; identification of unknown metabolites; analysis of low abundance/labile metabolites; and reconstruction of metabolic networks and regulation. Here we propose an integrated approach that uses chemoselective (CS) tagging of key metabolite functional groups to boost the speed and accuracy of metabolite identification and enhance detection. Such tagged metabolites are inherently amenable for multiplexed analysis and reliable relative quantification via stable isotope encoding. This approach will accelerate analytical throughput while widening the classes of analytes including metabolically enriched isotopologues far beyond current limits. We will achieve our goals via the following specific aims: SA1. To develop CS probes for tagging metabolites by targeting functional groups: Hydrophobic quaternary ammonium (QA)-based CS probes will be developed for tagging carbonyl amino thiol & diol functional groups (FG) in metabolites optimized for direct infusion FT- ICR-MS detection & assignment; SA2. To develop a set of isotope-encoded CS probes for metabolite identification and multiplexed quantification by FT-ICR-MS and NMR: Developing 13C-encoded QA-CS probes will facilitate integrated structural analysis of metabolites by 13C edited 2D NMR and FT-ICR-MS & multiplexed analysis by FT-ICR-MS; SA3. To develop web-based software for large-scale CS-adducted metabolite assignment & pathway reconstruction: Algorithm for robust automated MS assignment of metabolite & labeled isotopologues will be developed based on isotopologue cliques FG profile & molecular formula (MF). NMR- derived substructure & MF will be combined with MS data for semi-automated assignment of metabolite isotopomers & unknowns. Atom-resolved human metabolic database will be refined and tools developed for pathway reconstruction based on labeled metabolite profiles; SA4. To demonstrate the integrated CS profiling and biochemo-informatic approach in three basic and translational projects: Metabolic reprogramming driven by oncogenic gene defects or enzyme deletion in human lung and kidney cancers will be mapped using Stable Isotope-Resolved Metabolomics (SIRM) enhanced by newly developed CS tagging chemistry and automated assignment tools. Our long-term goal is to decipher human disease metabolic networks for drug discovery & early diagnosis.

project_terms:
A549;Aldehydes;Algorithms;Ammonium;Binding;Biochemical Pathway;Cell Extracts;Chemistry;Clinical;Computer software;Crude Extracts;Data;Data Analyses;Databases;Defect;Detection;Development;Diagnosis;Early Diagnosis;Enzymes;Fourier transform ion cyclotron resonance;Fumarate Hydratase;Future;Gene Expression;Genes;Glycols;Goals;Hereditary Leiomyomatosis and Renal Cell Cancer;Human;Human Cell Line;Informatics;Infusion procedures;Isomerism;Isotopes;Ketones;Label;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mass Spectrum Analysis;Metabolic;Molecular;Molecular Profiling;Mus;Mutation;NMR Spectroscopy;Nature;Network-based;Oncogenic;Online Systems;Pathway interactions;Pattern;Plasma;Reaction;Regulation;Renal carcinoma;Role;Sampling;Speed;Sulfhydryl Compounds;System;Technology;Tissues;Tracer;Transgenic Mice;adduct;base;cancer cell;chemical property;design;drug discovery;functional group;human disease;improved;ionization;malic enzyme;metabolomics;nano-electrospray;novel;outcome forecast;programs;protein expression;reconstruction;research study;software development;stable isotope;tandem mass spectrometry;tool;ultra high resolution

public_health_relevance:
The proposed chemoselective tagging of metabolites with integrated informatics tools will enhance both metabolite profiling and elucidation of human disease metabolic networks far beyond current limits. The information gained from these tools will help accelerate at an unprecedented rate our functional understanding of human disease development and progression while improving our ability to diagnose prognose and treat intractable human diseases such as cancer.


application_id: 9126687
project_number: 3R01NR014189-04S1
project_title: Early Detection and Prevention of Mild Cognitive Impairment due to Cerebrovascular Disease
administering_ic: NINR
award_notice_date: 2015-09-10
opportunity_number: RFA-NR-12-010
application_type: 3
activity_code: R01
ic: NR
serial_number: 014189
suffix: S1
program_official: TULLY, LOIS
project_start_date: 2012-09-26
project_end_date: 2016-06-30
study_section: 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
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.

project_terms:
Affect;Age-Years;Alzheimer's Disease;Area;Autopsy;Biological;Biological Markers;Blood;Brain;Brain Diseases;Brain Pathology;Cardiovascular Diseases;Cerebrospinal Fluid;Cerebrovascular Disorders;Clinical;Clinical Trials;Cognition;Cognitive;Data;Dementia;Diagnostic;Diagnostic Imaging;Doctor of Philosophy;Early Diagnosis;Elderly;Ensure;Etiology;Evaluation;Health;Healthcare;Image;Impaired cognition;Individual;Intervention;Kentucky;Medical;Microvascular Dysfunction;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;cohort;design;digital;disorder risk;improved;mild cognitive impairment;multidisciplinary;older patient;programs;standard of care;success;therapy design

public_health_relevance:
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.


application_id: 9126282
project_number: 5U18FD004620-05
project_title: FDA Vet-LRN Veterinary Diagnostic Laboratory Cooperative Agreement Program fundin
administering_ic: FDA
award_notice_date: 2016-08-03
opportunity_number: PA-12-194
application_type: 5
activity_code: U18
ic: FD
serial_number: 004620
project_start_date: 2012-09-01
project_end_date: 2017-08-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 11450267
contact_pi: GASKILL, CYNTHIA LYNN
other_pis: Not Applicable
congressional_district: 06
department: VETERINARY SCIENCES
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-09-01
project_abstract:
Gaskill UKVDL Project Summary/AbstractThe objective of this Food and Drug Administration (FDA) Veterinary Laboratory Response Network (Vet-LRN)Cooperative Agreement Program is to provide increased sample analysis capabilities for the FDA throughpartnership with Vet-LRN laboratories in the event of animal food or drug related illness or other large scaleanimal food/feed emergency events requiring surge capacity testing of implicated diagnostic or animal foodsamples. Testing will include microbiological and chemical analysis of samples such as animalfood/feed/drugs environmental samples related to animal food/feed/drug production and/or animal diagnosticnecropsy or clinical samples. In the event of a large-scale biological or chemical contamination affecting animalfood or drug products the UKVDL will perform selected analyses of diagnostic samples collected and suppliedto the laboratory by FDA or other government agencies. Federal or State surveillance assignments will also bea source of samples for analyses.The overall goal of the cooperative agreement is to complement develop improve and use university stateand federal veterinary diagnostic laboratory testing capabilities. The program will also be used to implementstandardized analysis through the usage of standardized methods equipment analytical worksheets andelectronic reporting. Training and proficiency testing will be provided for each method and Qualitymanagement systems will be enhanced. Small scale method development and method validation projects willbe performed as directed by the Vet-LRN Program Office. Funding will be used for supplies equipmentmaintenance and personnel time.

public_health_relevance:
Project NarrativeThis FDA Vet-LRN Cooperative Agreement Program will strengthen the overall food safety system bydeveloping increased capacity and capabilities to detect adulteration which could affect animals raised forhuman consumption or companion animals consuming ingredients used in both animal and human foodproducts. __SpecificAimsTextDelimiter__ Gaskill UKVDL Research Plan Specific AimsThe overall objective of this FDA Vet-LRN Cooperative Agreement Program is to solve a specific problem ofinadequate animal feed and drug testing capability during large scale events involving these animal products.The goal of the program is to provide increased sample analysis capabilities for the FDA through itspartnership with Vet-LRN laboratories in the event of animal food or drug related illness or other large scaleanimal food/feed emergency events requiring surge capacity testing of implicated diagnostic or animal foodsamples. The FDA Vet-LRN will supply funding for equipment supplies personnel and training for approvedVet-LRN laboratories to enable increased sample analysis capability.The major specific aims of the program are to: 1. Facilitate partnership between the FDA and Vet-LRN laboratories to provide microbiological and toxicological analysis by Vet-LRN laboratories for samples collected by the FDA or other agencies. Analyses will include (a) surveillance assignments as designated by the FDA; (b) animal food and drug emergency outbreak testing; and (c) sample analyses for large-scale animal food and drug emergency event surges.2. Implement standardized analyses by (a) establishing standardized methods equipment platforms analytical worksheet and electronic reporting; (b) participating in multi-laboratory proficiency testing programs; and (c) implementing standardized quality management systems as determined by the FDA Vet-LRN Program Office.3. Participate in small-scale method development and validation as directed by the FDA Vet-LRN Program Office.The expected outcome of participation in this program is that the FDA will dramatically increase its testingcapabilities by partnering with a network of participating Vet-LRN laboratories that have standardizedaccurate precise testing methods well maintained instrumentation and well-trained personnel to perform theanalyses. The program will also result in the enhanced ability to investigate novel or previously unidentifiedcontaminants in animal feeds and drugs by utilizing the wide range of knowledge and experience of theparticipating investigators and scientists in the Vet-LRN system.The impact of this program will be to greatly facilitate early detection of animal food and drug adulteration orcontamination. These efforts will strengthen the overall food safety system by developing increased capacityand capabilities to detect adulteration which could affect animals raised for human consumption or companionanimals consuming ingredients used in both animal and human food products. .


application_id: 9126280
project_number: 5U18FD004619-05
project_title: CVM Vet-LRN Veterinary Diagnostic Laboratory Program
administering_ic: FDA
award_notice_date: 2016-08-01
opportunity_number: PA-12-194
application_type: 5
activity_code: U18
ic: FD
serial_number: 004619
project_start_date: 2012-09-01
project_end_date: 2017-08-31
study_section: ZFD1-SRC(99)
contact_pi_person_id: 12682213
contact_pi: REED, DEBBIE
other_pis: Not Applicable
congressional_district: 01
department: VETERINARY SCIENCES
primary_duns: 041980632
primary_uei: LHC2S92MXG63
duns_number: 041980632
uei: LHC2S92MXG63
fips: US
organization_id: 5591701
organization_name: MURRAY STATE UNIVERSITY
organization_city: MURRAY
organization_state: KY
organization_type: EARTH SCIENCES/RESOURCES
organization_zip: 420712393
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-09-01
project_abstract:
Abstract  The FDA CVM Vet-LRN desires to expand the national laboratory capacity to respond to animal food/drug related illnesses or other large-scale animal food/feed emergency events requiring surge capacity testing of implicated diagnostic or animal food samples.  The Breathitt Veterinary Center is a fully accredited (AAVLD) animal disease diagnostic laboratory strategically located in Western Kentucky.  The objective of this grant application is to provide a cooperative agreement between the FDA CVM Vet-LRN and the BVC whereby the BVC will participate in the Vet-LRN Veterinary Diagnostic Laboratory Program.  Funding provided through the cooperative agreement will be used to provide equipment supplies training and proficiency testing under the aegis of the Vet-LRN Veterinary Diagnostic Program on an annualized basis for a five year period.

public_health_relevance:
Project Narrative Agriculture is Kentucky's number one industry contributing $5 billion to the state's economy annually.  Livestock and livestock product sales generate 65% of the total agricultural revenues.  The Murray State University Breathitt Veterinary Center (BVC) is an animal disease diagnostic laboratory dedicated to protecting the invaluable assets of the region by providing the fastest most accurate and most dependable animal disease diagnostic services possible.  The BVC with a staff of 45 employees is housed in a 44000 sq. ft. facility located on 15 acres of land in Hopkinsville KY.  The facility is centrally located to serve a 200 mile radius including Western Kentucky Southern Indiana and Illinois and Northwestern Tennessee.  The BVC professional staff includes nine members with Doctorates in Veterinary Medicine and/or Masters and PhD degrees in the fields of Pathology Microbiology Virology Immunology and Toxicology.  The professional staff is supported by laboratory bench personnel each of who hold a minimum of a Bachelor's degree and several have Masters degrees.  The laboratory provides full administrative secretarial/clerical and maintenance staff in support of diagnostic and research activities.  The BVC is accredited for all species by the American Association of Veterinary Laboratory Diagnosticians (AAVLD) through December 2014.  The BVC is a member of the USDA National Animal Health Laboratory Network (NAHLN) the Centers for Disease Control Laboratory Response Network (LRN) and the FDA Vet-Laboratory Response Network (Vet-LRN) (See attached FDA Vet-LRN Acceptance Letter).  The center's scope of activity includes the scientific disciplines of Pathology Microbiology Molecular Diagnostics Clinical Pathology Toxicology Serology and Virology.  The BVC processes 24000+ diagnostic cases per year to include over 190000 tests.   The FDA CVM Vet-LRN desires to expand the national laboratory capacity to provide increased sample analyses in the event of animal food or drug related illnesses or other large-scale animal food/feed emergency events requiring surge capacity testing of implicated diagnostic or animal food samples.   Objective:  The objective of this grant application is to provide a cooperative agreement between the FDA CVM Vet-LRN and the BVC whereby the BVC will participate in the Vet-LRN Veterinary Diagnostic Laboratory Program.  The FDA CVM Vet-LRN grant program is a mutually beneficial opportunity in which the FDA CVM Vet-LRN adds to the national laboratory capacity and the BVC receives support to advance its scope of activity.  Funding provided through the cooperative agreement will be used to provide equipment supplies training and proficiency testing under the aegis of the Vet-LRN Veterinary Diagnostic Program on an annualized basis for a five year period.    __SpecificAimsTextDelimiter__ Specific Aims    The specific aim of this proposal is to expand the national laboratory capacity to respond to animal food/drug related illnesses or other large-scale animal food/feed emergency events requiring surge capacity testing of implicated diagnostic or animal food samples.  The Breathitt Veterinary Center is a fully accredited (AAVLD) animal disease diagnostic laboratory strategically located in Western Kentucky.    The objective of this grant application is to provide a cooperative agreement between the FDA CVM Vet-LRN and the BVC whereby the BVC will participate in the Vet-LRN Veterinary Diagnostic Laboratory Program.  Funding provided through the cooperative agreement will be used to provide equipment supplies training and proficiency testing under the aegis of the Vet-LRN Veterinary Diagnostic Program on an annualized basis for a five year period.   Food safety in humans is directly impacted through the food chain by biological and chemical contaminants in animal feeds.


application_id: 9126253
project_number: 4R01CA166499-05
project_title: A role for c-Abl/Arg in melanoma progression
administering_ic: NCI
award_notice_date: 2016-08-01
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: CA
serial_number: 166499
program_official: SATHYAMOORTHY, NEERAJA
project_start_date: 2012-09-12
project_end_date: 2019-08-31
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
arra_indicator: N
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.

project_terms:
ABL1 gene;Anoikis;Biochemical;Biological;Cathepsin L;Cathepsins;Cell Adhesion;Cell Communication;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 Targeting;Endothelial Cells;Environment;Experimental Designs;Extravasation;FDA approved;Fibroblasts;Genetic Transcription;Genetically Engineered Mouse;Goals;Imatinib;In Vitro;Killings;Lead;Lung;MEKs;Matrix Metalloproteinases;Mean Survival Times;Mediating;Melanoma Cell;Metastatic Melanoma;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;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 drug combination;novel therapeutics;prevent;research study;three dimensional cell culture;tool

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.


application_id: 9126187
project_number: 1F31DC015400-01
project_title: TrkB-expression divides taste neurons into subtypes
administering_ic: NIDCD
award_notice_date: 2016-02-24
opportunity_number: PA-14-148
application_type: 1
activity_code: F31
ic: DC
serial_number: 015400
program_official: RIVERA-RENTAS, ALBERTO L
project_start_date: 2016-06-01
project_end_date: 2018-05-31
study_section: Special Emphasis Panel[ZDC1 SRB-Y (53)]
contact_pi_person_id: 12153137
contact_pi: RIOS-PILIER, JENNIFER
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): Peripheral sensory neurons of the visual and somatosensory systems can be divided into different types based on molecular morphological and functional characteristics. These various neuron types contribute to "parallel pathways" that code different aspects of sensation. The taste receptor cells which transduce the chemicals in the food we eat exist as types. It is unclear whether there are types of geniculate ganglion neurons which carry this information from taste buds to the brainstem. Differential expression of the neurotrophin receptor TrkB in half of the taste neurons could be an indicator that these neurons do exist as different types. If this is the case TrkB-expressing taste neurons should be developmentally functionally and morphologically distinctive from neurons that lack TrkB. The goal of this study is to examine this possibility using genetic labeling electrophysiology conditional knockout mice taste nerve labeling and tract tracing. I will use these approaches to determine 1) if adult TrkB expressing neurons arise differently during development than TrkB-negative taste neurons; 2) if adult TrkB-expressing neurons have a specific function; 3) if adult TrkB-neurons have specific projections to the NTS. Together these experiments will test the hypothesis that that TrkB expression divides gustatory neurons in half and that these two groups of taste neurons differ in their development function and CNS projections. If my proposed hypothesis is correct this would provide the first evidence that gustatory neurons can be divided into types based on intrinsic criteria. Understanding how the taste system develops and is organized in adulthood is imperative for taste system repair following disruption. For example both middle ear surgeries and basal cell carcinoma treatment disrupt gustatory structure and function. This study could contribute to the design of improved treatment that will offer better quality of life to patients with taste disturbances.

project_terms:
Adult;Afferent Neurons;Axon;Basal cell carcinoma;Biological Preservation;Brain;Brain Stem;Brain-Derived Neurotrophic Factor;Characteristics;Chemicals;Code;Development;Eating;Electrophysiology (science);Esthesia;Excision;Exhibits;Fiber;Food;Genetic;Goals;Hair;Imagery;Individual;Injection of therapeutic agent;Knockout Mice;Label;Ligands;Molecular;Mus;Nerve;Nerve Growth Factor Receptors;Neuraxis;Neuronal Differentiation;Neurons;Neurotrophic Tyrosine Kinase Receptor Type 2;Nucleus solitarius;Otologic Surgical Procedures;Palate;Pathway interactions;Patients;Pattern;Peripheral;Prevention;Quality of life;Receptor Cell;Signal Transduction;Sodium Chloride;Spinal Ganglia;Stimulus;Structure;Structure of geniculate ganglion;Synapses;System;Tamoxifen;Taste Buds;Taste Perception;Testing;Tongue;Visual;base;chorda tympani;design;differential expression;experience;improved;middle ear;public health relevance;repaired;research study;response;segregation;somatosensory;taste stimuli;taste system;therapy design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Preservation of the chorda tympani nerve function is important for prevention of taste disturbances in patients that experience middle ear surgeries and basal cell carcinoma treatment. Understanding how TrkB-expression defines the development and function of geniculate ganglion neurons is important for the design of treatment that will offer better quality of life to patients with taste disturbances.


application_id: 9126164
project_number: 1F31HL132527-01
project_title: Exosomal Delivery of TFAM:Novel Therapeutic Approach to Cardiomyocyte Recovery in Heart Failure
administering_ic: NHLBI
award_notice_date: 2016-04-19
opportunity_number: PA-14-148
application_type: 1
activity_code: F31
ic: HL
serial_number: 132527
program_official: MEADOWS, TAWANNA
project_start_date: 2016-07-01
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1 F10A-S (20)]
contact_pi_person_id: 11850117
contact_pi: KUNKEL, GEORGE H.
other_pis: Not Applicable
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Regulation of mitochondrial dynamics is essential for cardiovascular disease (CVD) related issues like chronic heart failure (CHF). Up regulation of proteolytic activities such as calpains and matrix metallo-proteinases (MMP's) are found within the CHF model. Although calpains have been known to underline the degradative roles leading to cell death the molecular mechanisms are unclear. Additionally the mitochondrial aspects of myocyte death need much to be determined. Mitochondrial Transcription factor A (TFAM) is a protective coil wrapped around mitochondrial DNA (mtDNA) and acts to stabilize cardiomyocyte mtDNA via regulation of serca2a and lon protease. As observed in the literature loss of TFAM is negatively correlated with proteolytic activation of calpain and MMP's. Our preliminary data of healthy versus impaired cardiomyocytes suggests involvement of calpain-1 MMP9 TFAM and lon protease. Through western blotting and PCR analysis we found that up regulated protein and RNA expressions of calpain 1 and MMP 9 was negatively correlated with decreased expression of TFAM. TFAM's regulatory role over ROS production and calcium mishandling leads to our main hypothesis that TFAM treatment to impaired cardiomyocytes will resuscitate physiological and potentially contractile activity of cardiomyocytes in CHF models. Exosomes are nanovessicles acting as biomolecular conservatories transporting mRNA miRNA proteins and nucleic acids. Exosomal delivery of TFAM to an AVF mouse model of CHF will ameliorate impaired cardiomyocytes and delay heart failure. Current literature focused on the molecular functions of TFAM support this claim. Hypothesis: Exosomal delivery of TFAM will improve cardiomyocyte survival by mitigating mitochondrial dysfunction found in CHF. Aims Proposed in F31 Kirschstein Pre-doctoral Fellowship (PA-14-148): Aim #1: To determine whether the mitochondrial transcription factor A contributes to cardiomyocyte function. Aim#2: To rehabilitate impaired cardiomyocytes via exosomal delivery of mitochondrial transcription factor A in chronic heart failure. This is a novel study utilizing an exosomal vehicle for TFAM treatment of chronic heart failure. Ameliorating effects of this treatment are promising based on the literature and preliminary studies. This proposal is clinically relevant and if successful will significantly impct the treatment of heart failure patients.

project_terms:
Affect;Calcium;Calpain;Cardiac;Cardiac Myocytes;Cardiomyopathies;Cardiovascular Diseases;Cell Death;Cell Line;Cells;Cellular Membrane;Cessation of life;Chronic;Congestive Heart Failure;Data;Down-Regulation;Fellowship;Fistula;Genes;Genetic Transcription;Heart;Heart failure;Impairment;Laboratories;Lead;Literature;MMP9 gene;Matrix Metalloproteinases;Mediating;Messenger RNA;MicroRNAs;Mitochondria;Mitochondrial DNA;Modeling;Molecular;Mus;Muscle Cells;Nucleic Acids;Organ;Patients;Peptide Hydrolases;Physiological;Play;Production;Proteins;Reactive Oxygen Species;Recovery;Regulation;Reverse Transcriptase Polymerase Chain Reaction;Role;Testing;Therapeutic;Time;Transgenic Model;Ultracentrifugation;Up-Regulation;Vesicle;Western Blotting;Work;base;clinically relevant;endopeptidase La;exosome;improved;insight;instrument;mitochondrial dysfunction;mouse model;mtTF1 transcription factor;nanovesicle;novel;novel therapeutic intervention;novel therapeutics;pre-doctoral;protein expression;public health relevance;transcription factor;translational study;treatment effect

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Understanding the role of mitochondrial transcription factor A (TFAM) in cardiomyocyte function could provide important insight into chronic heart failure. Loss of TFAM is observed in cardiomyopathies and the literature states that TFAM transgenic models are cardioprotective. This project seeks to explore the cardioprotective therapeutic potential of TFAM packed exosomes on chronic heart failure.


application_id: 9125596
project_number: 1R21AI124649-01
project_title: Mutagenesis in Chlamydia trachomatis via allelic exchange
administering_ic: NIAID
award_notice_date: 2016-02-04
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AI
serial_number: 124649
program_official: HILTKE, THOMAS J
project_start_date: 2016-02-08
project_end_date: 2018-01-31
study_section: Special Emphasis Panel[ZRG1 IDM-V (02)]
contact_pi_person_id: 7726964
contact_pi: FIELDS, KENNETH A
other_pis: Not Applicable
congressional_district: 06
department: MICROBIOLOGY/IMMUN/VIROLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Chlamydia trachomatis represents a significant health concern in the United States. A substantial burden exists due to the prevalence and the combined health and socioeconomic impact of acute and chronic disease. Chlamydiae are obligate intracellular parasites that undergo a complex developmental cycle. All Chlamydia species express a type III secretion system (T3SS) and based on analogy with other T3SS-expressing pathogens this mechanism likely contributes significantly to overall pathogenesis. Although definitive association of T3S with chlamydial virulence has proven difficult the newly-acquired ability to genetically manipulate chlamydiae has opened new doors for progress. We present preliminary data describing the first ever Chlamydia-specific suicide vector and propose to leverage this new approach to target T3SS genes for inactivation. Specifically we will further develop the suicide vector system and directly create null mutations in specific T3S effector genes. We also propose approaches to conditionally inactivate T3S capability. At the end of these studies we will have established molecular tools that will benefit the entire Chlamydia research community. In addition we will gain a better understanding of how the T3SS contributes to chlamydial virulence.

project_terms:
Acute Disease;Biology;Cells;Chlamydia;Chlamydia Infections;Chlamydia trachomatis;Chronic Disease;Communities;Complement;Complex;Data;Development;Dissection;Dominant-Negative Mutation;Ectopic Expression;Epithelial Cells;Essential Genes;Gene Deletion;Gene Silencing;Gene Targeting;Generations;Genes;Genetic;Genome;Goals;Growth;Health;Human;Infection;Investigation;Learning;Left;Methods;Microbiology;Molecular;Mutagenesis;Pathogenesis;Prevalence;Protein Secretion;Proteins;RNA Interference;Research;Role;Sexually Transmitted Diseases;Staging;Suicide;System;Techniques;Type III Secretion System Pathway;United States;Virulence;Work;base;chemical genetics;gene product;genetic approach;genetic manipulation;inducible gene expression;inhibitor/antagonist;link protein;loss of function;member;mutant;new technology;novel;novel strategies;null mutation;obligate intracellular parasite;pathogen;protein function;protein protein interaction;public health relevance;socioeconomics;success;suicide vector;tool;vector

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Sexually transmitted disease remains a significant health burden world-wide and infections with Chlamydia trachomatis are common. We have developed a novel method to generate null mutations in chlamydial genes and will leverage this approach to gauge the importance of selected type III secretion proteins in chlamydial pathogenesis.


application_id: 9124940
project_number: 5R01NS089515-03
project_title: The Role of Perlecan Domain V in Vascular Dementia
administering_ic: NINDS
award_notice_date: 2016-08-11
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NS
serial_number: 089515
program_official: CORRIVEAU, RODERICK A
project_start_date: 2014-09-01
project_end_date: 2019-07-31
study_section: Brain Injury and Neurovascular Pathologies Study Section[BINP]
contact_pi_person_id: 7568819
contact_pi: BIX, GREGORY JAYE
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): Despite its prevalence VaD remains woefully understudied and poorly understood in part due to its diverse etiology. The outcome of these multiple causes of VaD however remains the same- disruption of the complex coupling between endothelial cells astrocytes pericytes neurons and the extracellular matrix the components of the neurovascular unit. We hypothesize that the extracellular matrix plays a critical role in the neurovascular disruption of VaD. In particular we have identified a biologicaly active fragment of one prominent matrix component the heparan sulfate proteoglycan perlecan to play a major role in regulating endothelial cell function after experimental ischemic stroke. This fragment termed domain V (DV) is actively generated in the stroked brain and appears to be important to the brain's response to injury inasmuch as its absence results in more significant stroke injury and worse outcome. Furthermore DV stroke treatment after stroke enhances peri-infarct new blood growth (angiogenesis) and important component of neurorepair. As extracellular matrix remodeling is likely to occur in the vascular pathology leading to VaD we hypothesize that DV is actively generated plays a key role in regulating brain endothelial cell function and may improve endothelial cell function and neurovascular coupling when administered in two experimental mouse models of VaD the BCAS and the DB/AD models which differentially impact white matter and gray matter respectively. This will allow us to determine both the impact of white and gray matter endothelial cell dysfunction on VaD and DV's potential impact on it. To investigate these hypotheses we propose three aims: Aim 1. Determine the extent and significance of DV generation in the BCAS and DB/AD mouse models. Aim 2. Determine the therapeutic potential of DV in the BCAS and DB/AD mouse models. Aim 3. Determine the extent and significance of DV generation in human autopsy brain from subjects with VaD. Successful completion of these studies will increase our understanding of the role of the extracellular matrix and angiogenesis in VaD and support the therapeutic potential for DV.

project_terms:
APP-PS1;Acute;Age;Alzheimer's Disease;Alzheimer's disease model;Animal Model;Animals;Arteriovenous malformation;Astrocytes;Autopsy;Bilateral;Biochemical;Blood;Blood Vessels;Brain;Brain region;Carotid Stenosis;Cell Communication;Cell physiology;Cerebral Amyloid Angiopathy;Cerebrovascular system;Cognitive;Complex;Coupling;Dementia;Development;Endothelial Cells;Etiology;Experimental Animal Model;Extracellular Matrix;Failure;Functional disorder;Gene Expression;Generations;Growth;Health;Heparan Sulfate Proteoglycan;Homo;Human;Immunohistochemistry;Impaired cognition;Infarction;Injury;Integrin alpha5beta1;Ischemic Stroke;Knock-in Mouse;Methods;Mus;Neurons;Outcome;Pathologic;Pathology;Patients;Pericytes;Phenotype;Play;Prevalence;Process;Protein Fragment;Proteins;Replacement Therapy;Role;Therapeutic;Time;Vascular Dementia;angiogenesis;blood vessel development;brain endothelial cell;cerebrovascular;cognitive function;combat;diabetic;gray matter;hypoperfusion;improved;mouse model;neurovascular;neurovascular coupling;neurovascular unit;novel;perlecan;post stroke;prevent;receptor;response;response to brain injury;stroke;stroke treatment;white matter

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Although vascular dementia is the second leading cause of dementia behind Alzheimer's disease it remains woefully understudied and poorly understood in part due to its diverse etiology. The gradual failure of compensatory new brain blood vessel formation (angiogenesis) in the face of ongoing cerebrovascular insult appears to contribute to vascular dementia regardless of the etiology. We propose to determine the role and therapeutic potential of an angiogenic extracellular matrix fragment in human and novel animal models of vascular dementia.


application_id: 9124758
project_number: 5K07CA181351-03
project_title: The Dynamics of Smoking Cessation After Cancer Diagnosis: A Naturalisitic Study
administering_ic: NCI
award_notice_date: 2016-08-12
opportunity_number: PAR-12-067
application_type: 5
activity_code: K07
ic: CA
serial_number: 181351
program_official: PERKINS, SUSAN N
project_start_date: 2014-09-01
project_end_date: 2019-08-31
study_section: Career Development Study Section (J)[NCI-J]
contact_pi_person_id: 9524802
contact_pi: BURRIS, JESSICA L
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 activities proposed in this NCI K07 application are designed to advance the career development of Dr. Jessica Burris whose long-term career goal is to sustain an independent innovative and meaningful clinical research program that focuses on tobacco use and cessation in cancer patients. Most clinicians view cancer diagnosis as a teachable moment and thus urge immediate smoking cessation after delivery of cancer diagnosis. However most quit attempts end in relapse and extant interventions for smoking cessation in cancer patients have limited success. A cancer diagnosis brings about many intra- and inter-personal changes (e.g. increase in emotional distress greater need for social support increase in saliency of personal risk) but there is very little understanding as to how such changes influence smoking cessation. With an eye toward intervention development the independent research proposed in this application will examine the naturalistic course of smoking cessation after cancer diagnosis as well as the dynamics that underlie changes in smoking behavior. Specific aims are 1) to describe key events in the process of smoking cessation and 2) to uncover cognitive and affective variables that promote or undermine the occurrence of a quit attempt lapse and relapse among newly diagnosed cancer patients. After a baseline assessment (N=120 head and neck cancer patients) participants will initiate a 30-day period of daily assessment via interactive voice response technology with a final assessment to occur three months after the baseline assessment. Biochemical verification of abstinence at the end of the 30-day daily IVR assessment and final assessment will be achieved through use of saliva cotinine samples. Statistical analysis will allow novel tests of how and to what extent day-to-day changes in cognitive and affective variables influence smoking cessation outcomes in newly diagnosed cancer patients. Innovation is achieved by: 1) a focus on the process of smoking cessation as opposed to the treatment of abstinence as a discrete outcome 2) equal attention given to cognitive and affective predictors of smoking cessation outcomes 3) use of mobile technology as the primary means of data collection among cancer patients and 4) proper application of longitudinal data analysis techniques to rich within-subjects data. A training plan that complements the independent research includes coursework seminars workshops mentored research journal clubs and conferences the combination of which will cover these topics: nicotine dependence; individual-level and public health approaches to tobacco control; longitudinal research design coordination and execution; advanced statistical techniques; research dissemination; grantsmanship; and ethical conduct of research. The strong support of an excellent team of mentors and the vast resources and outstanding scientific environment of the Medical University of South Carolina create an optimal training environment. Collectively the integrated research and training plan proposed in this NCI K07 application are an ideal mechanism to promote the career development of Dr. Burris.

project_terms:
Abstinence;Affective;Alcohol consumption;Attention;Behavior;Belief;Biochemical;Cancer Control;Cancer Patient;Cancer Survivor;Cereals;Clinical;Clinical Investigator;Clinical Research;Cognitive;Complement;Complex;Cotinine;Data;Data Analyses;Data Collection;Distress;Educational workshop;Electronic cigarette;Ensure;Environment;Ethics;Event;Eye;Future;Goals;Head and Neck Cancer;Health;Health Status;High-Risk Cancer;Home environment;Hour;Individual;Intention;Intervention;Journals;Knowledge;Lead;Life;Measures;Medical;Mentors;Modeling;Motivation;Nature;Newly Diagnosed;Nicotine Dependence;Outcome;Outcome Study;Participant;Perception;Play;Prevention;Process;Public Health;Recurrence;Relapse;Research;Research Design;Research Training;Resources;Risk;Risk Behaviors;Risk Factors;Role;Saliva;Sampling;Second Primary Cancers;Self Concept;Smoke;Smoker;Smoking;Smoking Behavior;Smoking Cessation Intervention;Social Environment;Social support;South Carolina;Statistical Data Interpretation;Survival Rate;Techniques;Technology;Testing;Time;Tobacco;Tobacco Use Cessation;Training;Universities;Voice;Withdrawal;Withholding Treatment;Work;behavioral outcome;cancer complication;cancer diagnosis;cancer prevention;cancer recurrence;cancer therapy;career;career development;cigarette smoking;craving;design;emotional distress;factor A;head and neck cancer patient;innovation;longitudinal design;mobile computing;novel;programs;psychologic;research data dissemination;response;skills;smoking cessation;smoking restriction;success;symposium;therapy development;tobacco control;treatment response

public_health_relevance:
PUBLIC HEALTH RELEVANCE:Cigarette smoking after head and neck cancer diagnosis can lead to a number of significant health problems including a high risk of cancer recurrence and second primary cancer. The goal of this research is to uncover the process of smoking cessation in newly diagnosed head and neck cancer patients and to identify the dynamics of cognitive and affective variables that underlie quit attempts lapses and relapses. The results will inform the design of more effective smoking cessation treatments which has clear implications for the prevention of future threats to the health of cancer patients.


application_id: 9124416
project_number: 1F31GM117868-01A1
project_title: Analysis of chronic muscle weakness in post-septic mice using a novel resuscitation protocol
administering_ic: NIGMS
award_notice_date: 2016-04-11
opportunity_number: PA-14-147
application_type: 1
activity_code: F31
ic: GM
serial_number: 117868
suffix: A1
program_official: BARSKI, OLEG
project_start_date: 2016-04-11
project_end_date: 2018-04-10
study_section: Special Emphasis Panel[ZRG1 F15-P (20)]
contact_pi_person_id: 12654514
contact_pi: OWEN, ALLISON M.
other_pis: Not Applicable
congressional_district: 06
department: SURGERY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant):  Sepsis is a severe life-threatening condition that damages multiple physiological systems which manifest in a devastating acute critical illness. After discharge from the hospital 70-100% of severe sepsis survivors report sustained weakness which prevents them from resuming a normal lifestyle. As the mortality rate of sepsis declines due to advancements in critical care medicine and the incidence rate increases due to an aging US population there are more than 1 million new sepsis survivors every year. It is predicted that the rate of sepsis survivors will continue to rise as the population ages and advancements continue to be made in treatment of sepsis. However despite recognition of this clinical issue the molecular mechanisms contributing to chronic muscle dysfunction after sepsis are not well understood due to the lack of an appropriate animal model. Current models are either too mild to induce muscle weakness or are too severe and cause death within a few days. To circumvent this problem I developed a clinically relevant ICU-like sepsis resuscitation protocol with which 70% of middle-aged mice are rescued from otherwise completely lethal sepsis. The Aims of this project are (1) to test whether the mice that are rescued from lethal sepsis by the ICU-like resuscitation protocol exhibit muscle weakness and (2) to identify the primary mechanism(s) responsible for muscle weakness after sepsis. Muscle functional analyses will be performed using in vivo and ex vivo strength tests at different time points after sepsis which will be carefully designed so that the presence of atrophy and/or myopathy can be detected. I have already found that animals with lethal sepsis but rescued using my resuscitation protocol have significant muscle weakness 2 weeks after sepsis induction. Although the mechanisms by which sepsis-induced muscle weakness becomes a chronic condition are unknown my preliminary data suggest that mitochondria are involved. Therefore a series of molecular analyses will be performed to assess the time course and severity of muscle dysfunction and how it may cause reduction in force generating capacity by oxidizing sarcomeric proteins. These studies will promote the development of numerous scientific skill sets including proper animal research design implementation and interpretation as well as an assortment of molecular analysis techniques. Successful completion of this project will yield an understanding of the mechanism(s) responsible for muscle weakness after sepsis which could help elucidate a novel therapeutic target to prevent sepsis-mediated from developing in patients.

project_terms:
Abdomen;Acute;Age;Aging;Animal Experimentation;Animal Model;Animals;Antioxidants;Atrophic;Biological Assay;Cause of Death;Cessation of life;Chronic;Clinical;Communities;Complex;Critical Care;Critical Illness;DNA Damage;Data;Development;Evaluation;Exhibits;Female;Focal Infection;Functional disorder;Future;Generations;Goals;Hand Strength;Health;Hospitals;Immune response;Immune system;Incidence;Infection;Isometric Exercise;Life;Life Style;Longitudinal Studies;Mediating;Medicine;Mitochondria;Mitochondrial DNA;Modeling;Molecular;Molecular Analysis;Mus;Muscle;Muscle Fibers;Muscle Weakness;Myopathy;Pathogenesis;Patients;Peripheral Nerves;Physicians;Physiological;Polyneuropathy;Population;Process;Production;Proteins;Protocols documentation;Reactive Oxygen Species;Recovery;Reporting;Research Design;Respiration;Resuscitation;Risk;Sepsis;Series;Severities;Skeletal Muscle;Survival Rate;Survivors;System;Techniques;Testing;Time;aging population;base;clinically relevant;cytokine;design;effective therapy;enzyme activity;falls;improved;in vivo;middle age;mortality;new therapeutic target;novel;novel therapeutics;oxidation;prevent;public health relevance;research study;septic;sex;skills;trend

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  For decades sepsis survivors and physicians alike have reported muscle weakness that persists for years but the lack of an appropriate animal model has been a critical barrier for identifying the underlying cause of this phenomenon. In this proposal a newly optimized protocol that rescues animals from severe abdominal sepsis will be used to investigate muscle dysfunction in sepsis survivors. This will help to elucidate therapies for inhibiting the development of sepsis-mediated physical dysfunction such as a mitochondria-targeted anti-oxidant.


application_id: 9123885
project_number: 1F31NS093904-01A1
project_title: Mitochondria Transplantation for Functional Recovery after Spinal Cord Injury
administering_ic: NINDS
award_notice_date: 2016-03-24
opportunity_number: PA-14-147
application_type: 1
activity_code: F31
ic: NS
serial_number: 093904
suffix: A1
program_official: JAKEMAN, LYN B
project_start_date: 2016-04-01
project_end_date: 2018-03-31
study_section: Special Emphasis Panel[ZRG1 F01A-F (20)]
contact_pi_person_id: 12110259
contact_pi: GOLLIHUE, JENNA LEIGH
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): Contusion spinal cord injury (SCI) is a mechanical insult to the spinal cord which results in immediate tissue damage followed by excitotoxicity increased production of reactive oxygen species and compromised mitochondrial function. Each of these contributes to secondary pathophysiological cascades which are responsible for increasing the spread and severity of the injured tissue. Importantly the loss of mitochondrial function is implicated in most of the pathways in these cascades. As such this proposal will determine whether supplementation with exogenous healthy mitochondria after SCI can attenuate secondary injury damage possibly salvaging at-risk tissue that would have otherwise been compromised. Mitochondrial transplantation has been tested successfully in other tissue injuries but never following SCI. In doing so it may be possible to restore some functional recovery of the hind limbs over time after injury. A rat model of contusion SCI will be used to tes the overall hypothesis that supplementation of healthy mitochondria into an injured spinal cord will result in improved functional recovery via preservation of compromised tissues. In the first set of experiments mitochondria labeled with turbo green fluorescent protein (tGFP) will be isolated from cultured cells and transplanted directly into the injured rat spinal cord at three different concentrations and two time points after injury. To test the hypothesis that mitochondrial supplementation restores cellular bioenergetics and reduces oxidative stress molecular/biochemical outcome measures will be used including mitochondrial respiration calcium buffering capacity and markers of oxidative damage or inflammation. A second experiment is designed to determine which cell types are incorporating the exogenous tGFP mitochondria employing the injection concentration found to most closely maintain normal mitochondrial bioenergetics. Confocal microscopy of double and triple immunolabeling will allow visualization of cell-type colocalization with exogenous tGFP mitochondria as well as establish their rostral-caudal distribution. Most critically injections of isolated tGFP mitochondria after CI will be used to test the hypothesis that mitochondrial transplantation improves long-term hindlimb functional recovery after injury. The extent of hindlimb functional recovery will then be correlated with tissue sparing afforded by mitochondrial supplementation. Taken together results from these experiments will show that healthy mitochondria can be injected into an injured spinal cord and integrate into host cells thus increasing both mitochondrial function and cellular bioenergetics. Such maintenance of cellular homeostasis is expected to be correlated with increased tissue preservation and improved long-term hindlimb functional recovery. Once found to be a viable therapeutic mitochondrial supplementation therapy may be implemented as a novel bioenergetics medicine in the clinic to treat individuals after SCI.

project_terms:
Acute;Address;Adult;Americas;Animals;Attenuated;Autologous;Biochemical;Bioenergetics;Biological Preservation;Buffers;Calcium;Cardiac;Cell Survival;Cell Transplantation;Cell Transplants;Cell physiology;Cells;Clinic;Confocal Microscopy;Contusions;Cultured Cells;Development;Evaluation;Female;Free Radical Scavengers;Gait;Green Fluorescent Proteins;Hindlimb;Homeostasis;Hour;Imagery;Immune system;Immunohistochemistry;In Vitro;Individual;Infarction;Inflammation;Injection of therapeutic agent;Injury;Intervention;Label;Laminectomy;Lateral;Life;Limb structure;Locomotor Recovery;Macrophage Activation;Maintenance;Measures;Mechanics;Medial;Medicine;Mental Depression;Methods;Microglia;Mitochondria;Modeling;Molecular;Numbness;Organelles;Outcome Measure;Oxidative Stress;Oxygen Consumption;Paralysed;Pathway interactions;Play;Process;Production;Quality of life;Rattus;Reactive Oxygen Species;Recovery;Recovery of Function;Reperfusion Therapy;Reporting;Respiration;Respiratory System;Risk;Rodent Model;Secondary to;Severities;Site;Spectrophotometry;Spinal Cord;Spinal cord injury;Sprague-Dawley Rats;Supplementation;Testing;Therapeutic;Time;Tissue Preservation;Tissues;Toxic effect;Translations;Transplantation;United States;Work;cell type;clinically relevant;design;dosage;excitotoxicity;gray matter;improved;in vivo;injured;mitochondrial dysfunction;neuroprotection;novel;oxidative damage;prevent;public health relevance;research study;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: There are a reported 12000 new cases of traumatic spinal cord injury (SCI) in the United States of America each year resulting in lifelong debilitating consequences including paralysis loss of sensation compromised immune and respiratory systems and depression. This project proposes that supplementing the acutely injured spinal cord with healthy mitochondria the major energy producing organelle in cells will rescue damaged tissue and prevent the injury from spreading in a rodent model of SCI. Translation of this therapy into the clinic may improve the potential for locomotor recovery and have a high impact on the long-term quality of life for individuals living with SCI.


application_id: 9123588
project_number: 5R44DK089892-07
project_title: NOVEL ASSAY TO DETECT CHRONIC KIDNEY DISEASE
administering_ic: NIDDK
award_notice_date: 2016-07-21
opportunity_number: PA-14-071
application_type: 5
activity_code: R44
ic: DK
serial_number: 089892
program_official: GOSSETT, DANIEL ROBERT
project_start_date: 2010-09-20
project_end_date: 2018-06-30
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 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. Currently two complimentary tests - estimated GFR (eGFR) and urine albumin-to-creatinine ratio (UACR) - are used to identify CKD and are effective once the onset of disease has occurred. 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 critical events in the pathophysiology of kidney disease. Preliminary results suggestthat our CKD-ASSAY could replace or compliment both predicate assays. Further the specificity and reproducibility of the results may reduce or eliminate the need for repeat testing.Aside from increased convenience and reduced time to treatment this may mean that the cost of screening for CKD may be greatly reduced.  Our CKD-ASSAY would give physicians the ability to evaluate patients that have been recently diagnosed with hypertension diabetes or a family history of CKD. In Phase I we evaluated the feasibility and proof-of principal of this testand found that the prototype assay in both at-risk populations was highly sensitive and specific. In Phase II we confirmed the specificity of our CKD-ASSAY established concordance with other assays and looked for other factors that might have impacted on assay performance. We request Phase IIB support so that we can prepare cGMP kits perform the pivotal clinical evaluations submit our 510(k) application to the FDA and prepare for commercial launch.

project_terms:
Acute Renal Failure with Renal Papillary Necrosis;Adult;Affect;Agreement;Albumins;American;Biological Assay;Biological Markers;Blinded;Calibration;Cardiovascular Diseases;Child;Chronic Kidney Failure;Clinical;Clinical Research;Clinical Trials;Code;Communities;Creatinine;Cyclic GMP;Detection;Development;Devices;Diabetes Mellitus;Diagnosis;Diagnostic;Diagnostic tests;Disease;Doctor of Philosophy;Early Diagnosis;Early treatment;End stage renal failure;Enzyme-Linked Immunosorbent Assay;Equation;Event;Family history of;Functional disorder;Funding;Goals;Health;Health Insurance Portability and Accountability Act;Hemodialysis;Howard Temin Award;Hypertension;ICD-9;In Vitro;Injury;Intellectual Property;Kidney;Kidney Diseases;Legal patent;Measures;Methods;Minority Groups;Morbidity - disease rate;Onset of illness;Patients;Performance;Phase;Physicians;Polycystic Kidney Diseases;Population;Populations at Risk;Premature Infant;Prevalence;Process;Publishing;Quality Control;Records;Regulatory Pathway;Reproducibility of Results;Series;Sickle Cell;Site;Specificity;System;Testing;Time;United States;United States National Institutes of Health;Urine;Work;base;cardiovascular risk factor;cohort;commercialization;cost;cost effective;cost efficient;economic impact;high risk;loss of function;manufacturing process;mortality;novel;novel marker;polyclonal antibody;post gamma-globulins;pre-clinical;prevent;programs;prototype;research clinical testing;screening;success;validation studies

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Chronic Kidney Disease affects nearly 26 million people in the United States which places them at higher risk of cardiovascular disease hemodialysis and end stage renal disease. We will develop an assay for 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: 9123174
project_number: 1F32AR069985-01
project_title: Enhancing myoblast fusion in muscular dystrophy
administering_ic: NIAMS
award_notice_date: 2016-03-07
opportunity_number: PA-14-149
application_type: 1
activity_code: F32
ic: AR
serial_number: 069985
program_official: BOYCE, AMANDA T
project_start_date: 2016-04-01
project_end_date: 2019-03-31
study_section: Special Emphasis Panel[ZRG1 F10B-B (20)]
contact_pi_person_id: 11651573
contact_pi: HINDI, SAJEDAH M
other_pis: Not Applicable
congressional_district: 03
department: ANATOMY/CELL BIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) is a devastating genetic muscle disorder. Augmenting the regeneration potential of endogenous muscle progenitor cells is one of the potential approaches to attenuate disease progression in DMD. Moreover introduction of exogenous muscle stem cells can be used as an approach to restore dystrophin levels in DMD patients. However transplantation of muscle stem cells into dystrophic muscles typically results in minimal engraftment which is attributed at least in part o the poor fusion of the introduced myogenic cells with injured myofibers. While the mechanisms of myoblast fusion remain less understood enhancing fusion of endogenous or introduced myogenic cells has enormous potential for the development of novel cellular therapies for DMD patients. Ongoing studies in my laboratory have identified myeloid differentiation primary response gene 88 (Myd88) as a major positive regulator of myoblast fusion. Our preliminary studies have shown that levels of Myd88 are increased during muscle regeneration and upon induction of differentiation in cultured myoblasts. Genetic deletion of Myd88 specifically inhibits
myoblast fusion without affecting their proliferation and differentiation. While our preliminary studies clearly demonstrate that Myd88-mediated signaling promotes myoblast fusion it remains unknown whether augmenting the levels of Myd88 in myoblasts can stimulate myofiber regeneration and improve engraftment of introduced myoblasts in DMD. In this project we have proposed to investigate the effects of myoblast-specific ablation and overexpression of Myd88 on disease progression in a preclinical mouse model of DMD. Our hypothesis and specific aims are: AIM I: Investigate the effects of myoblast-specific deletion of Myd88 in myopathy of mdx mice. Hypothesis I: Myoblast-specific deletion of Myd88 will inhibit repair of injured myofibers and exaggerate myopathy in mdx mice. AIM II: Investigate the effects of myoblast-specific overexpression of Myd88 in the pathogenesis of mdx mice. Hypothesis IIa: Overexpression of Myd88 in exogenous myoblasts (before transplantation) will improve their engraftment in dystrophic muscle of mdx mice; and Hypothesis IIb: Myoblast-specific transgenic overexpression of Myd88 will enhance myofiber regeneration and mitigate myopathy in mdx mice. Successful completion of this work will provide basis for considering Myd88 as therapeutic target in preclinical trials for patients with DMD. Furthermore the project will provide me outstanding new training to achieve my goal of becoming a tenure-track faculty in an academic institution.

project_terms:
Ablation;Adult;Affect;Attenuated;Caliber;Cell Therapy;Cells;Cessation of life;Complementary DNA;Defect;Development;Disease Progression;Duchenne muscular dystrophy;Dystrophin;Engraftment;Faculty;Fibrosis;Fluorescence;Future;Gene Expression;Genes;Genetic;Genomics;Goals;Hereditary Disease;In Vitro;Inbred mdx Mice;Individual;Injury;Institution;Interleukin-1;Knock-out;Knockout Mice;Laboratories;Lentivirus Vector;Life;Mediating;Messenger RNA;Mus;Muscle;Muscle Fibers;Muscle function;Muscle satellite cell;Muscular Atrophy;Muscular Dystrophies;Myelogenous;Myoblasts;Myopathy;Natural regeneration;Pain;Pathogenesis;Pathway interactions;Patients;Phenotype;Physiological;Pre-Clinical Model;Process;Proteins;Proteomics;Reporting;Role;Signal Pathway;Signal Transduction;Signaling Protein;Skeletal Muscle;Small Interfering RNA;Staging;Stem cells;Toll-like receptors;Training;Transgenic Mice;Transgenic Organisms;Transplantation;Wild Type Mouse;Work;barium chloride;base;disability;gain of function;improved;injured;interleukin-18 receptor;knock-down;loss of function;molecular targeted therapies;mouse model;muscle regeneration;novel;overexpression;pre-clinical;preclinical trial;premature;promoter;public health relevance;reduced muscle strength;repaired;response;tenure track;therapeutic target;tibialis anterior muscle

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Duchenne muscular dystrophy (DMD) is the most prevalent form of muscular dystrophy which involves severe muscle-wasting fibrosis and premature death of afflicted individuals. We have identified Myd88 as a major regulator of myoblast fusion. We will investigate whether enhancing the levels of Myd88 in myoblasts can improve their fusion and improve regeneration of myofibers in preclinical models of DMD. Our proposed studies will provide strong basis whether Myd88 can be used as novel molecular target for treatment of DMD patients in future therapies.


application_id: 9122469
project_number: 4R01HL120746-04
project_title: Tobacco Products and Atherosclerotic Disease
administering_ic: NHLBI
award_notice_date: 2016-08-16
opportunity_number: PAR-12-267
application_type: 4
activity_code: R01
ic: HL
serial_number: 120746
program_official: PUNTURIERI, ANTONELLO
project_start_date: 2013-09-19
project_end_date: 2018-08-31
study_section: Special Emphasis Panel[ZRG1-HDM-Q(54)R]
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: Smoking is the leading cause of preventable deaths. Although cigarette smoking increases the risk of several chronic diseases nearly half of smoking related mortality could be linked to cardiovascular deaths. Therefore regulation of cigarettes and other tobacco products could significant lower the global burden of cardiovascular disease (CVD). The Family Smoking Prevention and Tobacco Control Act gives the FDA the authority to regulate the manufacturing marketing and distribution of tobacco products to protect public health. However to set standards for tobacco products it is important to know how cardiovascular effects of new and emerging tobacco products could be measured and which components of tobacco products induce cardiovascular injury. Because CVD is a chronic disease that develops over several years biomarkers of tobacco-induced cardiovascular injury are urgently needed to assess CVD risk in a time-frame sufficient for product evaluation. Moreover to relate biomarkers of injury with exposure to specific harmful and potentially harmful (HPHC) tobacco constituents it is essential to identify biomarkers that reflect exposure to specific constituents of tobacco products. Elucidation of the relationship between biomarker of exposure and biomarkers of injury will enable comparisons between the toxicities of different tobacco products and inform the design of future human studies for evaluating the cardiovascular effects of tobacco product use. Accordingly the overall goal of our project is to identify biomarkers of exposure to tobacco products and to relate them to atherosclerosis the underlying cause of several cardiovascular diseases. To accomplish this goal we will examine tobacco-induced injury in apoE-null mice and apoE-null rats. We will expose animals to varying intensities of tobacco smoke and smokeless tobacco we will identify urinary metabolites of exposure-derived aldehydes and determine how they relate to the extent and duration of exposure as well as to atherosclerotic lesion formation and lesion stability and how the relationship between the biomarkers of injury and biomarkers of exposure is affected by gender and the species and duration of exposure. In these experiments we will identify specific indices of atherosclerosis and thrombosis and how these biomarkers of injury are related to the biomarkers of exposure. To delineate the contribution of HPHCs we will identify which constituents of tobacco and tobacco smoke contribute to atherogenesis we will examine atherogenesis in mice exposed to individual constituents of exposure - nicotine acrolein and crotonaldehyde and determine how removal of these constituents affects atherosclerosis due to tobacco smoke and whether increases in the extent of exposure to these aldehydes and related reactive chemicals exacerbate atherosclerosis. Successful completion of this project will lead to the development of validated animal models to establish standard toxicitychanges and the discovery of novel biomarkers of cardiovascular injury that can be associated with measures of tobacco exposure. The findings of this project will provide new information regarding the contribution of reactive aldehydes such as acrolein and crotonaldehyde to the cardiovascular toxicity of cigarette smoke and smokeless tobacco. These findings will be useful in evaluating the contribution of HPHCs to tobacco product toxicity in humans; assessing the extent of harm reduction in PREPs and in developing policies for regulating HPHCs in smokeless tobacco cigarettes and emerging tobacco products. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

project_terms:
2-butenal;Acrolein;Affect;Aldehydes;Animal Model;Animals;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Biological Markers;Blood Platelets;Cardiovascular Diseases;Cardiovascular system;Cessation of life;Chemicals;Cholesterol Homeostasis;Chronic Disease;Cigarette;Development;Doctor of Philosophy;Evaluation;Excision;Exposure to;Family Smoking Prevention and Tobacco Control Act;Future;Gender;Goals;Harm Reduction;Health;Heart Diseases;Heart failure;Human;Individual;Injury;Ischemia;Knockout Mice;Lead;Lesion;Link;Marketing;Measures;Mediating;Mus;Nature;Nicotine;Policies;Principal Investigator;Public Health;Rattus;Regulation;Reperfusion Therapy;Risk;Risk Factors;Smoke;Smokeless Tobacco;Smoking;Surrogate Markers;Thrombosis;Time;Tobacco;Tobacco smoke;Tobacco use;Toxic effect;atherogenesis;authority;cardiovascular disorder risk;cardiovascular injury;cigarette smoke;cigarette smoking;design;indexing;mortality;novel marker;programs;research study;stroke;tobacco exposure;urinary

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Smoking is the leading cause of preventable deaths. Although cigarette smoking increases the risk of several chronic diseases nearly half of smoking related mortality could be linked to cardiovascular deaths. In the proposed studies we will identify biomarkers of exposure to tobacco products and relate them to atherosclerosis in experimental animals the underlying cause of several cardiovascular diseases. These studies will lead to the development of validated animal models to establish standard toxicity changes and the discovery of novel biomarkers of cardiovascular injury that can be associated with measures of tobacco exposure. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page


application_id: 9121373
project_number: 5R01AA017226-09
project_title: Alcohol and Breast Cancer
administering_ic: NIAAA
award_notice_date: 2016-08-04
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AA
serial_number: 017226
program_official: MURRAY, GARY
project_start_date: 2008-03-05
project_end_date: 2019-08-31
study_section: Special Emphasis Panel[ZRG1-DKUS-C(90)]
contact_pi_person_id: 1896035
contact_pi: LUO, JIA
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): Alcohol consumption promotes the development of human cancers and environmental factors play an important role in the etiology. Epidemiological studies indicate that alcohol consumption not only increases breast cancer risk but also enhances the progression and the aggressiveness of existing breast tumors. Nonetheless the mechanism by which alcohol contributes to breast tumor initiation or progression has yet to be established. ErbB2 is a member of epidermal growth factor receptor family. Amplification of ErbB2 is found in 20-30% of breast cancer patients and is associated with poor prognosis. We have previously demonstrated that over-expression of ErbB2 sensitized breast cancer cells to alcohol-induced tumor promotion. Recently we identified a novel component in ErbB2 signaling pathways that may regulate cancer cell aggressiveness the p38?. We hypothesized that alcohol enhances NOX-dependent production of ROS which activates ErbB2 or MKK6. The activation of ErbB2 and MKK6 causes selective phosphorylation of p38? which recruits SAP97/DLG. The activated SAP97/DLG promotes epithelial to mesenchymal transition (EMT) increase cancer stem cells (CSC) population and invasiveness of breast cancer cells. This leads to an enhanced aggressiveness. There will be three specific aims. Specific Aim 1 will determine the role of p38? in alcohol- induced aggressiveness in vitro. Specific Aim 2 will investigate the mechanisms underlying alcohol-induced p38? activation as well as the mechanisms how p38? mediates aggressiveness of breast cancer cells. Specific Aim 3 will investigate the role of p38? in alcohol-induced tumor aggressiveness in animal models. The study will not only explore the basic cell biology of breast cancer aggressiveness but also elucidate the mechanisms of alcohol's tumor promotion action. The outcomes will help developing new therapeutic strategy for breast cancer treatment and alcohol-mediated tumor promotion.

project_terms:
Alcohol consumption;Alcohols;Amino Acid Sequence;Animal Model;Animals;Attention;Breast Cancer Cell;Breast Cancer Patient;Breast Cancer Treatment;Cancer Etiology;Cancer stem cell;Cell Culture System;Cell Polarity;Cells;Cellular biology;Characteristics;DLG1 gene;Data;Development;Diet;Environmental Risk Factor;Epidemiologic Studies;Epidermal Growth Factor Receptor;Etiology;Family;Funding;Genes;Health;Heavy Drinking;Human;In Vitro;Knockout Mice;Liquid substance;MAP2K6 gene;MAPK14 gene;MAPK8 gene;Malignant Neoplasms;Mammary Neoplasms;Mammary Tumorigenesis;Mediating;Mediator of activation protein;Mitogen-Activated Protein Kinase Kinases;Mitogen-Activated Protein Kinases;Molecular;Mus;Neoplasm Metastasis;Outcome;Patients;Phosphorylation;Phosphotransferases;Physiological;Play;Production;Protein Tyrosine Kinase;Reactive Oxygen Species;Recruitment Activity;Risk;Role;Signal Pathway;Signal Transduction;Stream;Testing;Time;Transgenic Organisms;Tumor Promoters;Tumor Promotion;Xenograft Model;alcohol effect;alcohol exposure;alcohol sensitivity;anticancer research;cancer cell;cancer risk;cancer therapy;epithelial to mesenchymal transition;feeding;in vivo;indexing;malignant breast neoplasm;member;mitogen-activated protein kinase p38;novel;novel therapeutic intervention;outcome forecast;overexpression;research study;stem;stem cell population;therapeutic target;tumor;tumor initiation;tumor progression;tumor xenograft

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Excessive alcohol consumption is associated with advanced and aggressive breast cancers suggesting that alcohol may enhance mammary tumor progression and metastasis. We found that p38? signaling is down stream of ErbB2 and hypothesize that alcohol activates p38? which promotes tumor aggressiveness and accelerates mammary tumor development. This proposal will elucidate the mechanisms by which alcohol promotes the progression of mammary tumors and identify therapeutic targets for alcohol-associated tumor promotion.


application_id: 9121282
project_number: 3R01AA021978-02S1
administering_ic: NIAAA
award_notice_date: 2015-08-27
opportunity_number: PA-12-149
application_type: 3
activity_code: R01
ic: AA
serial_number: 021978
suffix: S1
program_official: RADAEVA, SVETLANA
project_start_date: 2015-02-01
project_end_date: 2018-01-31
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
budget_start_date: 2015-09-01
project_title:
Role of ECM and inflammatory remodeling in alcohol-induced liver and lung damage-diversity supplement

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 usinggenetically 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;response;targeted treatment

public_health_relevance:
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: 9120913
project_number: 5P30GM110788-03
project_title: CTDL Laboratory Core
administering_ic: NIGMS
award_notice_date: 2016-08-02
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110788
study_section: ZGM1-TWD-C
subproject_number: 8149
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-08-01
budget_end_date: 2017-07-31
project_abstract:
The CTDL was designed to provide a centralized service to support investigators in the College of Dentistry who required biologic measures fortheir clinical translational and basic science projects. The core support services in the Phase III center operations include: (1) an array of measures of host responses in a range of biologic fluids (eg. serum saliva cervico-vaginal fluids cell culture supernatants tissue homogenates etc.); (2) microbiological/virological assays for oral bacteria and bacteria from other mucosal sites and viruses related to oral diseases. This includes cultivation molecular analysis and preparation of batches of organisms for in vitro studies; (3) genetics/genomics analysis which include preparation of DNA and RNA from various samples analytic approaches for GWAS SNP miRNA and epigenetic variations related to specific project needs; and (4) mineralized tissue analysis including both histomorphometric microCT and cellular studies of bone biology.

project_terms:
Bacteria;Basic Science;Biological Assay;Biology;Cell Culture Techniques;Clinical Sciences;Communities;DNA;Dentistry;Genetic;Genomics;Immune response;In Vitro;Knowledge;Laboratories;Liquid substance;Measures;MicroRNAs;Molecular Analysis;Mouth Diseases;Oral;Oral health;Organism;Outcome;Phase;Population;Preparation;RNA;Research Personnel;Saliva;Sampling;Serum;Services;Specimen;Systemic disease;Tissues;Translational Research;Virus;base;bone;college;design;epigenetic variation;genome wide association study;improved;microCT;mucosal site;operation;oral bacteria;oral biology;vaginal fluid

public_health_relevance:
While the CTDL is primarily designed to support UK investigators for a range of analytic services specimens evaluated in this core could also be derived from populations derived from community-based partners. In either case these outcomes will help create new knowledge of the biology of oral-systemic disease relationships to improve oral health in the population.


application_id: 9120912
project_number: 5P30GM110788-03
project_title: DDKCRC Clinical Core
administering_ic: NIGMS
award_notice_date: 2016-08-02
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110788
study_section: ZGM1-TWD-C
subproject_number: 8148
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-08-01
budget_end_date: 2017-07-31
project_abstract:
The DDKCRC is the principal clinical research facility in the College of Dentistry at UK. It is partnered with the Clinical Research Development and Operations Center (CRDOC) medical clinical operations under the UK Centerfor Clinical and Translational Research. The facility is staffed by managers and multiple clinical coordinators that contribute to supporting investigators in the development of projects IRB application process marketing and recruiting for studies clinical evaluation biologic specimen collection and management and reporting requirements for UK and the federal government. Thjs 6-operatory facility will continue to provide these services as well as extending its interface with other clinical activities in the College of Dentistry.

project_terms:
Address;Clinical;Clinical Research;Dental Care;Dentistry;Development;Federal Government;Health Services Accessibility;Institutional Review Boards;Marketing;Medical center;Oral;Oral health;Patients;Phase;Process;Recruitment Activity;Reporting;Research Personnel;Research Project Grants;Services;Systemic disease;Time;Translational Research;base;college;improved;operation;research and development;research clinical testing;research facility;sample collection

public_health_relevance:
The DDKCRC is critical to the development and implementation of clinical and translational research in the College of Dentistry. The patients coming to the College of Dentistry for dental care are offered opportunities to participate in research projects that address their specific needs. This interaction takes place at the time of registration at the college. Thus this core helps provide greater opportunities for patients to access care and improve their oral health.


application_id: 9120910
project_number: 5P30GM110788-03
project_title: Administrative Core
administering_ic: NIGMS
award_notice_date: 2016-08-02
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110788
study_section: ZGM1-TWD-C
subproject_number: 8147
contact_pi_person_id: 1897360
contact_pi: EBERSOLE, JEFFREY L
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-08-01
budget_end_date: 2017-07-31
project_abstract:
The Administrative/Educational Core (AEC) ofthe Phase III COBRE is designed to provide oversight to the center organizational structure to support management of the cores and support for the solicitation and awarding of pilot grants. This core includes a center director and administrator to provide the interface to the other activities in the center. Additionally the AEC houses biostatistical/bioinformatics liaison support for linking investigators to thpse resources existing at UK and a training education and outreach activity that will cultivate participation of dental faculty and students in clinical and translational sciences research as well as working through the Dental Public Health outreach program and the UK Health Services Research Center to move the COBRE research accomplishments towards technology transfer and community adoption of new evidence in practice.

project_terms:
Administrator;Adoption;Award;Bioinformatics;Centers of Research Excellence;Clinical Sciences;Communities;Dental;Dental Faculty;Dental Students;Education and Outreach;Grant;Health;Health Services Research;Housing;Kentucky;Knowledge;Link;Oral;Oral health;Phase;Play;Population;Public Health;Research;Research Personnel;Resources;Role;Systemic disease;Technology Transfer;Training and Education;Translational Research;Work;base;design;improved;organizational structure;outreach program

public_health_relevance:
The AEC plays multiple roles in overseeing the progress ofthe COBRE; however these can be stratified into internal and external effects. Internally it will oversee the use of key resources and investigators to develop new knowledge to improve oral health. Externally it will work with community partners in Kentucky to identify opportunities with this new knowledge will be put into action to change oral and systemic health metrics for the population.


application_id: 9120909
project_number: 5P30GM110788-03
project_title: Center for the Biologic Basis of Oral/Systemic Diseases (Phase III)
administering_ic: NIGMS
award_notice_date: 2016-08-02
opportunity_number: PAR-13-238
application_type: 5
activity_code: P30
ic: GM
serial_number: 110788
program_official: GAO, HONGWEI
project_start_date: 2014-08-15
project_end_date: 2019-07-31
study_section: ZGM1-TWD-C(C3)
contact_pi_person_id: 6200819
contact_pi: KYRKANIDES, STEPHANOS
other_pis: Not Applicable
congressional_district: 06
department: DENTISTRY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Systemic Diseases (CBBO/SD)" is to continue sustainability of a nationally competitive transdisciplinary research center focusing on oral healt sciences and systemic diseases within the University of Kentucky. This proposal builds upon the Phase l/ll funding for developing the research infrastructure in the College of Dentistry and supporting junior investigators to develop competitive research programs using this infrastructure. The CBBO/SD represents the concrete realization of the Specific Aims of the Phase l/ll funding that was designed to: (i) expand the critical mass of funded investigators at UK in the areas of oral and systemic health research; (ii) create and enhance cutting-edge scientific core resources that can continue to serve as platforms to increase the competitiveness of existing research faculty as well as for recruiting new faculty; and (iii) implement the range f infrastructure improvements in the research enterprise to successfully transition the COBRE funding into long-term competitive renewable support from a diverse array of federal and non-federal sources. The UKCD created a position for an Associate Dean for Research and a Center for Oral Health Research (COHR) housed in the college to develop and oversee a broad range of basic and applied research beginning in 2000. This was followed by events that created a vibrant environment for implementation of the CBBO/SD in 2003 with an explicit goal of developing a center conducting research on oral and systemic health and housed in the College of Dentistry. The CBBO/SD provides a strong thematic research focus and unique resources along with research training of graduate students post-doctoral fellows and junior faculty mentoring. From the outset this was accomplished in a collaborative framework that emphasized mentoring scientific advancement academic career development competitive grantsmanship and productivity. The Phase III proposal incorporates 4 interactive cores: Adminstrative/Educational Core Delta Dental of Kentucky Clinical Research Center (DDKCRC) Core; Core Translational Diagnostics Laboratory (CTDL); and Oral Health Pilot Program (OI-IPP) core. The CBBO/SD Phase Ill objectives are to: (1) focus efforts and resources towards creating a sustainable university-wide research center with unique clinical and translational scientific cores providing interdisciplinary research interactions in oral and general health investigations (2) continue to identify Stimulate and nurture investigators at the University of Kentucky to ascertain and pursue important questions related to diseases of the oral and craniofacial complex and (3) enhance the expansion of collaborative research programs by supplying structure and expertise in specialized core facilities supporting these research initiatives. The major research theme of the CBBO/SD generally remains similar to those throughout the Phase l/ll tenure of the center. This focused on chronic inflammatory diseases with infections and dysregulated host responses linking oral and systemic health. The CBBO/SD has a parallel goal in providing the fundamental basis for the research enterprise in the UK College of Dentistry (UKCD) to actively participate in the national clinical and translation research environment with a focus of moving clinical findings into improving health of the population with enhanced implementation of new clinical findings. As the flagship land-grant University of the Commonwealth of Kentucky the UKCD has a major role in helping to solve the massive health care needs of the Appalachian population inhabiting 54 counties in Kentucky by addressing multigenerational oral and general health disparities in Appalachian Kentucky. This will require effective interprofessional education collaborative research initiatives and emphasizing external funding from a wide array of NIH institutes other federal agencies and independent private and public funding sources. The Strategic Objectives of the Phase III aspect of the center include: understand the molecular mechanisms underlying periodontal disease; foster collaborations enabling definition of the biologic mechanisms linking periodontal disease with systemic disease(s); support collaborative efforts across the UK campus to engage additional research teams into the offering of the Genetics/Genomics services and the Mineralized Tissue services; and continue the research relationship with the Center for Clinical and Translational Sciences at UK to implement community-based initiatives to reduce oral disease burden.

project_terms:
Address;Applied Research;Area;Basic Science;Centers of Research Excellence;Chronic;Clinical;Clinical Research;Clinical Sciences;Collaborations;Communities;Core Facility;County;Dental;Dentistry;Diagnostic;Disease;Education;Environment;Event;Faculty;Fostering;Funding;Funding Agency;Future Generations;Genetic;Genomics;Goals;Grant;Health;Health Sciences;Healthcare;Housing;Immune response;Individual;Infection;Inflammatory;Institutes;Interdisciplinary Study;Investigation;Kentucky;Laboratories;Link;Mentors;Modeling;Molecular;Mouth Diseases;Oral;Oral cavity;Oral health;Periodontal Diseases;Phase;Population;Positioning Attribute;Postdoctoral Fellow;Productivity;Recruitment Activity;Research;Research Infrastructure;Research Personnel;Research Support;Research Training;Resources;Role;Rural Population;Science;Services;Source;Structure;Systemic disease;Tissues;Translational Research;United States National Institutes of Health;Universities;base;burden of illness;career development;college;craniofacial complex;design;faculty mentor;faculty research;graduate student;health disparity;improved;population health;programs

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The COBRE core infrastructure will focus on supporting clinical and translational research that impacts health of the oral cavity and the individual. The substantially poor oral health metrics of the population of Kentucky particularly rural populations needs to be addressed with new science and new models to deliver improved health for future generations.


application_id: 9120353
project_number: 5R01DA037621-02
project_title: Long-term activation of spinal opioid analgesia after inflammation
administering_ic: NIDA
award_notice_date: 2016-05-09
opportunity_number: PA-13-118
application_type: 5
activity_code: R01
ic: DA
serial_number: 037621
program_official: LIN, YU
project_start_date: 2015-08-15
project_end_date: 2020-05-31
study_section: Special Emphasis Panel[ZRG1-IFCN-B(03)M]
contact_pi_person_id: 1879170
contact_pi: TAYLOR, BRADLEY K.
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Severe tissue injury generates central sensitization (increased responsiveness of CNS nociceptive neurons to normal or sub-threshold afferent input) that contributes to hyperalgesia. Latent sensitization (LS) is a silent form of central sensitization that persists after tissue has healed and overt signs of hyperalgesia have resolved. LS can be revealed with opioid receptor antagonists or inverse agonists that "rekindle" or reinstate hyperalgesia. Thus pain remission during LS is likely maintained by tonic opioid receptor activity that masks the pronociceptive components of LS. LS is important because it primes nociceptive systems such that when inhibitory systems fail a pain episode ensues. A key first step in understanding LS is to demonstrate the translational significance and we now show that the opioid receptor inverse agonist naloxone can reinstate experimental pain when delivered 1 wk after the resolution of secondary hyperalgesia following first degree thermal injury. Specific Aim 1 tests the hypothesis that burn or surgery triggers LS and long-term opioid analgesia in humans. To further study the neurobiological mechanisms of LS we will also use a mouse model that is long-lasting powerful broad range repeatable and translates to human studies. We found that mu opioid receptor (MOR) inverse agonists reinstated behavioral and molecular signs of hyperalgesia even when administered months after tissue injury and this required NMDA receptor activation of adenylyl cyclase type 1 (AC1). Our results are important because they suggest that any event such as stress that interferes with MOR analgesia during LS will lead to relapse of hyperalgesia in chronic pain syndromes in humans. Specific Aim 2 tests the hypothesis that MOR constitutive activity (MORCA) and/or activation of MOR delta (DOR) or kappa (KOR) receptors by opioid peptides in the DH or rostroventromedial medulla maintains endogenous analgesia and thereby restricts LS to a state of pain remission. Specific Aim 3 determines the extent to which MORs inhibit spatially coordinated neural activity in the DH (using an innovative 64-channel field recording system) and synaptic strength in presynaptic terminals of primary afferent nociceptors or on DH neurons (using patch clamp electrophysiology) during LS. Specific Aim 4 then tests whether MORs specifically inhibit spinal NMDA receptor subunits (GluN2A or GluN2B) and/or Epac1 (exchange protein directly activated by cAMP recently found to contribute to peripheral pain senstization) to block pain during LS. Completion of this project will bring us closer to our long-term goal of alleviating chronic pain b either: a) facilitating endogenous opioid analgesia thus restricting LS within a state of remission; or b) extinguishing LS altogether for example with a selective AC1 or Epac1 inhibitor. Our general model and hypothesis shares similarities with the concept of allostasis: a pathologically-elevated balance between opposing processes (MOR and LS) that facilitate each other by mutual feedback. Our long-term vision is a new conceptual strategy for chronic pain therapy to restore homeostasis where there is neither central sensitization nor MOR compensatory responses.

project_terms:
Absence of pain sensation;Acute;Acute Pain;Address;Adenylate Cyclase;Affect;Affective;Agonist;American;Analgesics;Behavior;Behavioral;Binding;Brain;Burn injury;Chronic;Cutaneous;Cyclic AMP;Cyclic AMP Receptors;Cyclic AMP-Dependent Protein Kinases;Data;Development;Disease remission;Dynorphins;Electrophysiology (science);Endogenous Opiates;Enkephalins;Equilibrium;Event;Excitatory Postsynaptic Potentials;Failure;Feedback;Figs - dietary;Goals;Guanosine Triphosphate;Healed;Health;Hernia;Homeostasis;Human;Hyperalgesia;Inflammation;Inguinal region;Injury;Knockout Mice;Knowledge;Lead;Masks;Mediating;Messenger RNA;Modeling;Molecular;Mus;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;NR1 gene;Naloxone;Naltrexone;Neurons;Nociception;Nociceptors;Operative Surgical Procedures;Opioid;Opioid Analgesics;Opioid Peptide;Opioid Receptor;Pain;Pain Nature;Pain management;Phase;Phosphorylation;Physical Function;Physiologic pulse;Posterior Horn Cells;Postoperative Pain;Presynaptic Terminals;Process;Productivity;Protein Isoforms;Proteins;Public Health;Publishing;Quality of life;Receptor Activation;Receptors Opioid delta;Receptors Opioid mu;Relapse;Resolution;Science;Secondary Hyperalgesias;Signal Transduction;Site;Slice;Spinal;Spinal Cord;Stress;Synapses;Synaptosomes;Syndrome;System;Testing;Tissues;Translating;Traumatic injury;Vision;Work;adenylyl cyclase 1;allostasis;central sensitization;chronic pain;cost;dorsal horn;healing;heat injury;inhibitor/antagonist;innovation;mental function;mouse model;naltrexol;neurobiological mechanism;pain behavior;patch clamp;peripheral pain;prevent;receptor;relating to nervous system;repaired;response;spinal nerve posterior root;spontaneous pain;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Chronic pain is a public health problem which affects the physical and mental functioning quality of life and productivity of over 100 million Americans costing $600 billion dollars annually. Our recent work suggests that our body's own natural opioid pain killers exert an extremely powerful and very long-lasting ability to prevent chronic pain. This project seeks to elucidate the molecular mechanisms that create this pain relief system such as opioid systems being stuck in a constant "ON" state and to demonstrate its importance in humans after suffering from a traumatic injury.


application_id: 9120107
project_number: 3R01AG034605-05S1
project_title: Hippocampal Electrophysiology and Myelinogenesis in Healthy Cognitive Aging
administering_ic: NIA
award_notice_date: 2015-08-28
opportunity_number: RFA-AG-09-010
application_type: 3
activity_code: R01
ic: AG
serial_number: 034605
suffix: S1
program_official: WAGSTER, MOLLY V
project_start_date: 2009-09-01
project_end_date: 2016-08-31
study_section: ZAG1-ZIJ-5(M2)
contact_pi_person_id: 2405844
contact_pi: LANDFIELD, PHILIP W.
other_pis: Not Applicable
congressional_district: 06
department: PHARMACOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): This application proposes to address a fundamental unresolved question in the field of cognitive aging the nature of the neurobiological factors that distinguish individuals with healthy cognitive aging (HCA) from those with unhealthy cognitive aging (UCA). The focus of the studies will be on biomarkers developing near the age of divergence of unhealthy from healthy cognitive aging as these appear particularly likely to provide important insights into causal mechanisms. A major emphasis of the project will also be testing the hypothesis that midlife activation of myelinogenic programs in the hippocampus is an important factor in converting HCA to UCA. This view derives from our recent work with both microarray and immunohistochemical techniques showing that myelinogenesis is increased 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 correlates of cognitive aging in an established rat model of aging. It will involve state-of-the-art intracellular electrophysiology in hippocampal slices concomitant Ca2+ imaging in recorded neurons extensive immunohistochemistry with a battery of stains diffusion tensor imaging (MRI/DTI) separate microarray analysis of each individual rat and substantial behavioral testing of each animal. Multiple techniques will be applied in each animal. These studies will pursue the aims of correlating electrophysiological and genomic markers of cognitive aging in the same animals and will relate cognitive function to myelin structure and density in cross-sectional and longitudinal analyses. Further the course of myelinogenesis will be altered in long-term studies that manipulate dietary iron and/or treat with cuprizone. Animals subjected to altered myelinogenesis will be tested on a battery of behavioral electrophysiological microarray and immunohistochemical analyses to test the proposition that conversion to UCA has been slowed and if it has to determine through which hippocampal pathways this occurred. Overall these studies should substantially elucidate neurobiological markers distinguishing UCA from HCA and should importantly determine the role of myelinogenic programs in cognitive aging. Further the proposed longitudinal studies should have direct translational relevance.

project_terms:
Address;Age;Age-Months;Aging;Anemia;Animal Feed;Animal Model;Animals;Astrocytes;Behavioral;Binding (Molecular Function);Bioenergetics;Bioinformatics;Biological Markers;Brain;Cholesterol;Cognition;Cognitive aging;Corpus Callosum;Cuprizone;Data;Diet;Dietary Iron;Diffusion Magnetic Resonance Imaging;Elderly;Electrophysiology (science);Event;Exhibits;Fostering;Gene Expression;Genes;Genomics;Guanosine Triphosphate Phosphohydrolases;Hemochromatosis;Hippocampus (Brain);Human;Image;Immune;Immunohistochemistry;Impaired cognition;Individual;Inflammation;Inflammatory;Intake;Intervention;Investigation;Iron;Left;Link;Lipids;Liver;Longitudinal Studies;Magnetic Resonance Imaging;Measures;Mediating;Methods;Microarray Analysis;Modeling;Monkeys;Myelin;Nature;Neurites;Neurobiology;Neurons;Oligodendroglia;Oxidative Stress;Pathway interactions;Performance;Phase;Play;Process;Protocols documentation;Rattus;Regulation;Research;Resources;Role;Sampling;Serum;Signal Transduction;Slice;Staining method;Stains;Stimulus;Structure;Techniques;Testing;Therapeutic;Translating;Up-Regulation (Physiology);Validation;Work;age related;aged;aging brain;base;behavior test;biological adaptation to stress;cognitive function;cognitive performance;density;indexing;insight;interest;iron deficiency;middle age;morris water maze;multidisciplinary;myelination;programs;protein degradation;response;spatial memory;trafficking;young adult

public_health_relevance:
This proposed research will be conducted in an established rat model of aging which shows demonstrated relevance to human aging. These studies will elucidate neurobiological markers of and processes influencing the divergence of healthy and unhealthy cognitive aging. Therefore the proposed studies should have both predictive and therapeutic value in determining the course of human cognitive aging.


application_id: 9119601
project_number: 4R01AR061939-05
project_title: BetaCatenin Regulation of Skeletal Muscle Hypertrophy
administering_ic: NIAMS
award_notice_date: 2016-06-25
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: AR
serial_number: 061939
program_official: BOYCE, AMANDA T
project_start_date: 2012-07-01
project_end_date: 2017-06-30
study_section: Special Emphasis Panel[ZRG1-MOSS-C(90)S]
contact_pi_person_id: 1873134
contact_pi: MCCARTHY, JOHN JOSEPH
other_pis: ESSER, KARYN A
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):  As the "house-building" macromolecule of the cell ribosome biogenesis is essential for cell growth. Despite this central role in cell growth there remains a fundamental gap in our understanding of the role of ribosome biogenesis in adult skeletal muscle hypertrophy. Studies from our laboratory have provided evidence which supports a role for increased ribosome biogenesis in skeletal muscle hypertrophy. The current proposal will begin to directly examine the importance of ribosome biogenesis to muscle hypertrophy by testing the hypothesis that -catenin is necessary for muscle hypertrophy by increasing protein synthesis through c-myc activation of ribosome biogenesis. To conditionally manipulate -catenin or c-myc gene expression in adult skeletal muscle we generated the HSA-MerCreMer mouse. Aim 1 will determine if -catenin expression is necessary for skeletal muscle hypertrophy using a mechanical overload model of the plantaris muscle following catenin gene inactivation. Aim 2 will determine if increased expression of -catenin is sufficient to stimulate skeletal muscle hypertrophy. -catenin will be over-expressed in adult skeletal muscle by using the HSA- MerCreMer strain to generate a stabilized form of -catenin. Aim 3 will determine if c-myc expression is necessary for skeletal muscle hypertrophy following the conditional inactivation of c-myc in adult skeletal muscle using the HSA-MerCreMer strain. The effect of gene inactivation on the hypertrophic response will be assessed by measuring morphometric (muscle weight fiber CSA) biochemical (total protein RNA and DNA) molecular (Western blot RT-PCR promoter analysis chromatin immunoprecipitation (ChIP) and electrophorectic mobility shift assay (EMSA)) and metabolic (rates of protein synthesis and degradation) variables. The results of the proposed studies are expected to have important clinical implications by identifying new molecular targets for promoting skeletal muscle protein synthesis and hypertrophy. In the long- term the ability to manipulate ribosome biogenesis represents a promising novel strategy to attenuate or ameliorate muscle atrophy associated with aging bed rest and cachexia.

project_terms:
Adult;Aging;Atrophic;Attenuated;Bed rest;Biochemical;Biogenesis;Biology;Body Weight;Cachexia;Cartoons;Catabolism;Cells;Clinical;Complement;DNA;DNA Polymerase I;DNA-Directed RNA Polymerase;Electrophoretic Mobility Shift Assay;Event;Fiber;Gene Expression;Gene Silencing;Genes;Genetic Transcription;Growth;Health;Hindlimb Suspension;Housing;Human;Hypertrophy;In Vitro;Insulin-Like Growth Factor I;Knowledge;Laboratories;Malignant Neoplasms;Measurement;Measures;Mechanics;Modeling;Molecular;Molecular Target;Morbidity - disease rate;Mus;Muscle;Muscle Cells;Muscle Fibers;Muscle Proteins;Muscular Atrophy;Outcome;Pathway interactions;Plantaris muscle;Protein Biosynthesis;Proteins;Publishing;Quality of life;RNA;Regulation;Research;Reverse Transcriptase Polymerase Chain Reaction;Ribosomal RNA;Ribosomes;Rodent;Role;Skeletal Muscle;Stimulus;System;Testing;Translations;Weight;Western Blotting;Work;c-myc Genes;cell growth;chromatin immunoprecipitation;in vitro Model;in vivo;macromolecule;metabolic rate;mortality;muscle form;muscle hypertrophy;muscle strength;novel;novel strategies;overexpression;prevent;promoter;protein degradation;research study;response;sedentary;skeletal

public_health_relevance:
Skeletal muscle mass makes up almost 50% of the total body weight in healthy adults and it is now recognized as an important health factor. The findings from the proposed research are expected to reveal whether or not b-catenin regulation of protein synthesis is necessary for muscle growth. If confirmed such results will be of medicinal value by providing new targets for promoting muscle growth during periods of muscle loss associated with inactivity cancer and aging.


application_id: 9118883
project_number: 5R01AR067667-02
project_title: Mitigating mitochondrial epigenetics in bone remodeling by hydrogen sulfide
administering_ic: NIAMS
award_notice_date: 2016-08-12
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AR
serial_number: 067667
program_official: CHEN, FAYE H
project_start_date: 2015-09-01
project_end_date: 2020-08-31
study_section: Special Emphasis Panel[ZRG1-MOSS-U(90)S]
contact_pi_person_id: 9959914
contact_pi: TYAGI, NEETU
other_pis: TYAGI, SURESH C.
congressional_district: 03
department: PHYSIOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Affect;Alkaline Phosphatase;Antibodies;Attenuated;Azacitidine;Biomechanics;Blood Vessels;Blood flow;Bone Density;Bone Diseases;Bone Matrix;Bone Mineral Contents;Bone Resorption;Bone remodeling;C-terminal;Child;Chimeric Proteins;Clinical Research;Co-Immunoprecipitations;Collagen;Collagen Type I;Consumption;Cyclophosphamide;Cystathionine;DNA Methylation;Data;Deformity;Elastin;Enzyme-Linked Immunosorbent Assay;Epigenetic Process;Event;Gel;Gelatin;Gelatinase B;Generations;Genes;Genetic;Goals;Health;Homocysteine;Homocystine;Hydrogen Sulfide;Hyperhomocysteinemia;Immunohistochemistry;Impairment;In Situ;Interstitial Collagenase;Knock-out;Knockout Mice;Lasers;MMP9 gene;MTHFR gene;Matrix Metalloproteinases;Measures;Mechanics;Metabolism;Mitochondria;Mitochondrial DNA;Molecular;Mus;Osteoblasts;Osteocalcin;Osteoclasts;Osteocytes;Osteogenesis;Oxidation-Reduction;Oxidative Stress;Pathology;Pathway interactions;Peptides;Plasma;Process;Proteins;Proteome;Pyridoxal Phosphate;Reporting;Reverse Transcriptase Polymerase Chain Reaction;Role;Staining method;Stains;Stress;Structure;Testing;Therapeutic;Therapeutic Agents;Weight-Bearing state;Western Blotting;Wild Type Mouse;blood lead;bone;bone cell;bone loss;bone strength;bone turnover;crosslink;density;femoral artery;inhibitor/antagonist;innovation;malformation;microCT;mitochondrial dysfunction;novel;osteoblast differentiation;skeletal;tibia


application_id: 9117734
project_number: 3U54CA153604-05S2
project_title: Appalachia Community Cancer Network
administering_ic: NCI
award_notice_date: 2015-08-28
opportunity_number: RFA-CA-09-032
application_type: 3
activity_code: U54
ic: CA
serial_number: 153604
suffix: S2
program_official: PERRUCCIO, ELIZABETH M
project_start_date: 2010-09-01
project_end_date: 2016-08-31
study_section: ZCA1-PCRB-G(M1)
contact_pi_person_id: 1871398
contact_pi: DIGNAN, MARK B
other_pis: Not Applicable
congressional_district: 06
department: INTERNAL MEDICINE/MEDICINE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
The Appalachian region has long been considered an area with pronounced health disparities particularly related to cancer. A transdisciplinary team of community partners and academic collaborators from Kentucky Ohio Pennsylvania Virginia and West Virginia propose to build on the strong foundation of community based participatory research (CBPR) and implement the next generation of cancer disparities reduction efforts for the low income medically underserved population of Appalachia. This proposed National Community Network Program will consist of a headquarters site at the University of Kentucky and regional sites at the Ohio State University Pennsylvania State University Virginia Polytechnic Institute and State University (Virginia Tech) West Virginia University and the University of Kentucky and will address cancer disparities in a five-state region. Each partnering institution includes a constellation of regional community and academic partners who collectively have built strong CBPR models for cancer research and intervention. Plans for this proposed Community Networks Program have been developed in collaboration with community partners and is structured to include community participation. The ACCN will include an Administrative Core at the University of Kentucky and programs in Research Training and Community Outreach. The Research Program will include a full research project that will test a faith-based intervention to reduce cancer risks by addressing the problem of obesity which occurs in epidemic proportions in Appalachia. The full research project will be implemented in all ACCN regions. A pilot project on health communications related to participation in clinical trials is proposed by a promising junior investigator with mentorship by ACCN senior investigators at two universities. The Training program proposes an initiative that will provide structured mentored experiences for junior investigators and postdoctoral trainees. The Community Outreach program will continue to develop infrastructure and support for community interactions and will include a Community Health Educator to work jointly with the ACCN and CRCHD.

project_terms:
Achievement;Action Research;Address;Appalachian Region;Area;Attention;Award;Cancer Burden;Cancer Intervention;Clinical Sciences;Clinical Trials;Collaborations;Colorectal Cancer;Communities;Community Health;Community Networks;Community Outreach;Community Participation;Distress;Economically Deprived Population;Education and Outreach;Epidemic;Foundations;Funding;Goals;Health Communication;Health Educators;Health Priorities;Incidence;Institutes;Institution;Instruction;Intervention;Intervention Trial;Kentucky;Knowledge;Life Style;Link;Low income;Malignant Neoplasms;Malignant neoplasm of cervix uteri;Malignant neoplasm of lung;Mentors;Mentorship;Mission;Modeling;Morbidity - disease rate;Mortality Vital Statistics;National Center for Research Resources;Obesity;Ohio;Outcome;Pennsylvania;Pilot Projects;Population;Prevention Measures;Primary Prevention;Process;Program Development;Randomized;Research;Research Infrastructure;Research Personnel;Research Project Grants;Research Training;Resources;Risk Factors;Site;Structure;Testing;Training;Training Programs;Translational Research;United States;Universities;Virginia;Vision;West Virginia;Work;anticancer research;base;burden of illness;cancer health disparity;cancer risk;cancer type;community based participatory research;community planning;design;experience;faith-based intervention;health disparity;interest;medically underserved;medically underserved population;member;next generation;outreach program;postdoctoral investigator;prevent;programs;social;therapeutic target

public_health_relevance:
RELEVANCE (See instructions): This proposed project focuses on reducing cancer health disparities in Appalachia a population with high rates of several types of cancer. The project will be planned and carried out with community partners and will be designed with a clear vision of the needs interests and values of the community. The research will be carried out in partnership with the faith community and will focus on obesity which increases cancer risk.


application_id: 9117290
project_number: 5P01HD071875-03
project_title: Administrative Core
administering_ic: NICHD
award_notice_date: 2016-08-02
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
study_section: ZHD1-DRG-D
subproject_number: 7822
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
PROJECT SUMMARY (See instructions): The Administrative Core is the operational center behind the entire P01 program. The Core will facilitate the research goals of the program by:  * providing the organizational and administrative structure that insures maximally efficient use of resources among all investigators * providing a centralized location for the tracking of expenditures and compilation of budgets * insuring optimal dissemination of information among all investigators * overseeing usage of the Tissue Repository Core to insure efficient distribution of human  macaque and rat tissues to all investigators * directing usage of the Tissue Repository Core so that minimal numbers of animals are  utilized * funding new pilot projects in promising areas of research that complement the existing  P01 projects while also opening additional avenues of research collaboration or expertise arranging and coordinating the annual scientific retreat for the P01 program investigators * assisting with the preparation and submission of manuscripts reporting P01 program scientific advances and also providing for page charges to support publication of these manuscripts * interacting with NICHD and the Office of Sponsored Projects Administration at the University of Kentucky to ensure compliance with all federal regulations * insuring that each scientific project maintains regulatory compliance by coordinating and accounting for all aspects of personnel training protocol submission approval revision and continuing review (IACUC recombinant DNA biohazardous materials)

project_terms:
Accounting;Advisory Committees;Animals;Area;Budgets;Charge;Collaborations;Complement;Ensure;Expenditure;Faculty;Funding;Goals;Human;Human Resources;IACUC;Individual;Information Dissemination;Information Distribution;Institutional Review Boards;Instruction;Kentucky;Laboratories;Letters;Location;Macaca;Manuscripts;Monitor;Monkeys;National Institute of Child Health and Human Development;Ovulation;Pilot Projects;Preparation;Program Research Project Grants;Protocols documentation;Publications;Rattus;Recombinant DNA;Regulation;Reporting;Research;Research Personnel;Resources;Rodent;Scientific Advances and Accomplishments;Secondary to;Services;Structure;Tissues;Training;Universities;Visit;Woman;Work;meetings;member;operation;programs;repository;success;web page

public_health_relevance:
RELEVANCE (See instructions): The Administrative core is responsible for carefully and closely monitoring the entire operation of the P01 program which is a multi-institutional program with 6 investigators at 3 different Universities. This core is the "command central" that deals with the day to day problems as well as insures that the long term research goals of the program are achieved.


application_id: 9117288
project_number: 5P01HD071875-03
project_title: CIPAR1 A Novel Modulator of Progesterone Accumulation in Periovulatory Follicle
administering_ic: NICHD
award_notice_date: 2016-08-02
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
study_section: ZHD1-DRG-D
subproject_number: 7820
contact_pi_person_id: 8244639
contact_pi: JO, MISUNG
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
PROJECT SUMMARY (See instructions): In response to the preovulatory LH surge the preovulatory follicle rapidly increases progesterone production which is essential for ovulation and/or corpus luteum formation. Although this rise in progesterone level has been mainly linked to a few LH-induced genes involved in steroidogenesis (e.g. StAR Cypi 1 a l  and HSD3b) but there are many gaps in our understanding of periovulatory accumulation of progesterone. In this proposal we put forward a novel protein CIPAR1 (castration-induced prostatic apoptosis-related protein 1) as a vital mediator of progesterone accumulation in the periovulatory follicle. We have recently demonstrated the LH surge increases the expression of Ciparl in periovulatory follicles of rodent ovaries. More importantly our preliminary study using granulosa cell cultures showed that knockdown of Ciparl expression resulted in significant reduction of progesterone levels. Based on these novel findings we hypothesize that induction of CIPAR1 by the LH surge is crucial for progesterone accumulation in periovulatory follicles thus ovulation and luteinization. In specific Aim#1 we will demonstrate that the alteration of Ciparl expression by silencing or over-expression affects progesterone production in rat periovulatory follicles using both in vivo and in vitro models. As the first approach to pinpoint the functional contribution of C1PAR1 in periovulatory follicles we will identify the genes and proteins that are differentially expressed when Ciparl expression is silenced or over-expressed in periovulatory follicles. Because littie is known about cellular function of CIPAR1 Specific Aim #2 focuses on first determining the cellular location of CIPAR1 in periovulatory granulosa cells using confocal co-localization and/or subcellular fractionated protein analyses and then identifying CIPAR1 interacting proteins in periovulatory granulosa cells using immunoprecipitation followed by a proteomic approach. Other than our preliminary data detecting Ciparl expression in human granulosa cells nothing is known about CIPAR1 in human tissues. In collaboration with Drs. Brannstrum and Duffy specific Aim #3 will determine whether Ciparl expression is hormonally regulated during the periovulatory period and critical for LH-induced progesterone production in humans and/or macaques. Data obtain from the proposed studies will unravel the role of C1PAR1 as a novel and critical mediator of progesterone accumulation in periovulatory follicles of primates as well as rodents.

project_terms:
Affect;Antibodies;Apoptosis;Castration;Cell Culture Techniques;Cell Differentiation process;Cell physiology;Cells;Collaborations;Cytoprotection;Data;Development;Enzymes;Experimental Models;Female;Fertility;Future;Gene Proteins;Genes;Goals;Gonadotropins;Hormones;Human;Immunoprecipitation;In Vitro;Instruction;Link;Location;Luteinization;Macaca;Mediating;Mediator of activation protein;Molecular;Monkeys;Ovary;Ovulation;Physiological;Play;Primates;Production;Progesterone;Prostaglandins;Prostate;Proteins;Proteomics;Rattus;Reproduction;Rodent;Role;Steroid biosynthesis;Testing;Tissues;Woman;base;corpus luteum;critical period;differential expression;granulosa cell;hormone regulation;human tissue;improved;in vitro Model;in vivo;knock-down;novel;overexpression;research study;response

public_health_relevance:
RELEVANCE (See instructions): Progesterone plays a vital role in many aspects of reproduction including ovulation and corpus function therefore female fertility. Identifying the cellular function of CIPAR1 will improve our understanding of mechanisms controlling progesterone production and may suggest a novel target for managing female fertility.


application_id: 9117287
project_number: 5P01HD071875-03
project_title: Mechanism of Periovulatory Leukocyte Infiltration into the Ovary
administering_ic: NICHD
award_notice_date: 2016-08-02
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
study_section: ZHD1-DRG-D
subproject_number: 7819
contact_pi_person_id: 7351245
contact_pi: KO, CHEMYONG JAY
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
PROJECT SUMMARY (See instructions): Crosstalk between the immune and reproductive systems dramatically impacts fertility. In particular studies have shown that a tight spatiotemporal control of leukocyte infiltration into the ovary is pivotal for successful ovulation. Once infiltrated the leukocytes differentiate into a cohort of pro- or anti-infiammatory cells in the preovulatory ovary and play critical roles in ovulation and luteal formation. In this study we will test the hypothesis that progesterone (P4) and prostaglandins (PG) play pivotal roles in recruiting leukocytes into the preovulatory ovary. Aim 1. To determine the mechanism(s) by which P4 and PG regulate WBC infiltration. We will first determine the roles of P4 and PG on WBC infiltration by treating cycling adult rats with RU486 indomethacin and vehicle and measuring the effect on the numbers populations and localization of infiltrating WBC by flow cytometry and immunohistochemistry together with a functional analysis of the expression of chemokines cytokines their receptors and cell adhesion molecules (CAMs) in serum on ovarian cells and WBC by ELISA and qPCR. Aim 2. To determine whether P4 and PG regulate WBC infiltration in primate ovary. In this Aim we will investigate P4 and PG regulated WBC infiltration in primates. Similar to rodents primates including humans also require P4 and PG for normal ovulation. Therefore we hypothesize that P4 and PG will regulate WBC infiltration in the primate ovary. The actions of P4 and PG will be inhibited by treating primates (Cynomolgous monkeys) with trilostane (3|3HSD inhibitor; inhibits progesterone synthesis) celecoxib (selective COX-2 inhibitor) or vehicle under ovarian stimulation. The effects on the numbers populations and localization of WBC together with the expression of infiammatory mediators will be determined. Upon the identification of the P4- and PG-regulated WBC subtypes and infiammatory mediators in the monkey the localization and expression patterns of their homologs will be determined in the human ovary. Aim 3. To determine the regulatory mechanism of preovulatory splenic WBC release. We will identify the trigger(s) and the mechanism of action of splenic WBC release from spleen. We hypothesize that either LH decreased concentration of circulating WBC or angiotensin-ll (the only known trigger of splenic leukocyte release) act as the trigger. To identify the trigger(s) ovariectomized rats will be treated with candidate triggers (LH and angiotensin-ll) or artificially reduce the concentration of circulating WBC by perfusing rats with plasma. The effects on splenic WBC release will be measured by counting WBC numbers in spleen and peripheral blood.

project_terms:
Accounting;Adhesions;Adult;Affect;Age;Angiotensins;Animals;Anovulation;Biological Assay;Biological Process;Blood Circulation;Cell Adhesion Molecules;Cell-Adhesion Molecule Receptors;Cells;Chronic;Clinical Treatment;Cytokine Receptors;Cytometry;Data;Defect;Diagnosis;Disease;Endothelial Cells;Enzyme-Linked Immunosorbent Assay;Failure;Female;Fertility;Flow Cytometry;Homologous Gene;Human;Immune system;Immunohistochemistry;In Vitro;Indomethacin;Infiltration;Inflammation;Inflammation Mediators;Instruction;Knockout Mice;Lead;Leukocyte Trafficking;Leukocytes;Measures;Mediator of activation protein;Mifepristone;Migration Assay;Monitor;Monkeys;Ovarian;Ovarian Stimulations;Ovary;Ovulation;PTGS2 gene;Pathway interactions;Pattern;Plasma;Play;Population;Primates;Procedures;Progesterone;Prostaglandins;Rattus;Receptor Cell;Recruitment Activity;Reproductive system;Rodent;Role;Serum;Signal Pathway;Spleen;Testing;Woman;celecoxib;chemokine;cohort;cytokine;inhibitor/antagonist;nonhuman primate;novel;novel strategies;peripheral blood;receptor;reproductive;spatiotemporal

public_health_relevance:
RELEVANCE (See instructions): Chronic anovulation affects up to 15% of the female US population many of the causes not being accounted for. This study will identify a novel cause of anovulation resulting from defective ovarian inflammation which will lead to develop a better treatment option for an ovulatory disorder.


application_id: 9117286
project_number: 5P01HD071875-03
project_title: Angiogenesis in the Primate Ovulatory Follicle
administering_ic: NICHD
award_notice_date: 2016-08-02
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
study_section: ZHD1-DRG-D
subproject_number: 7818
contact_pi_person_id: 1919355
contact_pi: DUFFY, DIANE M
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
Ovulation is essential for successful reproduction. The ovulatory luteinizing hormone (LH) surge stimulates periovulatory follicles to produce prostaglandin E2 (PGE2). Blockade of PGE2 production causes ovulation failure. LH-stimulated neovascularization of the follicle is also essential for ovulation as inhibition of follicular angiogenesis prevents ovulation. This proposal puts for the overall hypothesis that PGE2 mediates the ability of the ovulatory LH surge to regulate angiogenesis within the ovulatory follicle. Angiogenesis is regulated via vascular growth factors. In Aim 1 we will determine if LH acts at follicular granulosa cells to regulate production of vascular growth factors in a PGE2-dependent manner. Monkey ovaries with multiple follicles will be obtained before and after administration of an ovulatory dose of the LH-like hormone hCG; some monkeys will also receive concomitant administration of a prostaglandin (PG) synthesis inhibitor. Granulosa cells follicular fluid and whole ovaries will be assessed for vascular growth factor mRNAs by qPCR and proteins by western blotting ELISA and immunofiuorescent detection on tissue sections. In vitro studies will be performed to determine if PGE2 acts directiy at granulosa cells to regulate vascular growth factor mRNA and proteins. Vascular growth factors act at endothelial cells to promote the formation of new blood vessels. In Aim 2 we will determine if PGE2 and vascular growth factors act at endothelial cells of the follicle to stimulate angiogenesis. Using a novel proliferating population of monkey ovarian endothelial cells we will determine if PGE2 stimulates endothelial cell proliferation migration and formation of new capillaries. Similarly vascular growth factors produced by granulosa cells granulosa cell-conditioned media and coculture with granulosa cells will be used to determine if vascular growth factors stimulate endothelial cell functions necessary for angiogenesis. Finally monkey ovaries obtained after treatment in vivo with hCG hCG+PG synthesis inhibitor or hCG+PG synthesis inhibitor+PGE2 will be assessed histologically for neovascularization of the ovulatory follicle. The proposed studies will likely demonstrate that PGE2 and vascular growth factors act directly at endothelial cells to promote the neovascularization of the primate ovulatory follicle. Modulation of follicular PGE2 levels or PGE2 receptor activity may provide effective treatments for infertility or suggest targets for the development of novel contraceptives.

project_terms:
Aftercare;Antibodies;Area;Biopsy;Blood Vessels;Blood capillaries;Cell Count;Cell Proliferation;Cell physiology;Cells;Coculture Techniques;Conditioned Culture Media;Contraceptive Agents;Data;Detection;Development;Diagnosis;Dinoprostone;Dose;Endothelial Cells;Endothelial Growth Factors Receptor;Enzyme-Linked Immunosorbent Assay;Exposure to;Failure;Fertility;Follicular Fluid;Gonadotropins;Growth;Histologic;Hormones;Human;Human Chorionic Gonadotropin;In Vitro;Infertility;Instruction;Laboratories;Lead;Luteinizing Hormone;Macaca;Mediating;Mediator of activation protein;Messenger RNA;Modeling;Monkeys;Ovarian;Ovarian Follicle;Ovarian Hyperstimulation Syndrome;Ovary;Ovulation;Population;Pregnancy;Primates;Production;Proliferating;Prostaglandin Inhibition;Prostaglandins;Proteins;Reproduction;Rodent;Structure;Testing;Time;Tissues;Vascular Endothelial Growth Factors;Western Blotting;Woman;angiogenesis;capillary;effective therapy;granulosa cell;in vivo;infertility treatment;inhibitor/antagonist;migration;neovascularization;novel;prevent;receptor;research study;response

public_health_relevance:
RELEVANCE (See instructions): Formation of new blood vessels In the ovarian follicle is essential for ovulation and therefore fertility. Understanding how prostaglandins regulate angiogenesis in the ovarian follicle may identify new treatments for infertility or suggest targets for the development of novel contraceptives.


application_id: 9117285
project_number: 5P01HD071875-03
project_title: EMMPRIN: A Regulator of Angiogenesis and Leukocyte Trafficking During Ovulation
administering_ic: NICHD
award_notice_date: 2016-08-02
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
study_section: ZHD1-DRG-D
subproject_number: 7817
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: Unavailable
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: Domestic Higher Education
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-07-01
budget_end_date: 2017-06-30
project_abstract:
PROJECT SUMMARY (See instructions): The preovulatory LH surge stimulates an increase in ovarian extracellular matrix metalloproteinase inducer (EMMPRIN) which is known as a classic regulator o fthe matrix metalloproteinases (MMPs). The paramount role of EMMPRIN in ovulation is evident from experiments in mice lacking EMMPRIN that display a decrease in oocyte release and fertilization. Yet other than our preliminary data nothing is known as to temporal expression patterns the regulation and potential function of EMMPRIN in the ovulatory process in the human. This question will be addressed in the proposed POI program through a collaborative approach utilizing the exceptional backgrounds technical expertise and models ofthe PIs. We will make use of a unique model where the granulosa and theca from human periovulatory follicles will be collected prior to and at three designated times after hCG (early late and postovulatory). The expression patterns of EMMPRIN in the human will be illuminated in Aim #1. Specific Aim #2 will build upon these findings to elucidate the role of EMMPRIN in ovarian angiogenesis in the human macaque and rat. The ability of EMMPRIN to stimulate proliferation migration and spouting of new vessels will be determined. To further characterize EMMPRIN's action. Specific Aim #3 will investigate the role of EMMPRIN in immune cell trafficking' Specifically studies will explore the impact of EMMPRIN on leukocyte expression of the MMP system and EMMPRIN's ability to regulate the invasive capacity of leukocytes. One novel aspect of this study is the use of well characterized human preovulatory follicles as a foundation to explore the expression and function of EMMPRIN in the process of human ovulation which has never been accomplished. Another major strength of this proposal is the collaborative interactions between different investigators to address the function of EMMPRIN in periovulatory events across multiple species. As such the proposed studies are extremely timely to elucidate the role that this exquisite proteolytic system plays in the coordinated processes of follicular rupture and oocyte release which are key aspects of normal human ovarian physiology.

project_terms:
Address;Blood Vessels;Cells;Data;Defect;Dinoprostone;EGF gene;Endothelial Cells;Event;Extracellular Matrix;Fertilization;Foundations;Gene Expression Profile;Genes;Glycoproteins;Human;Human Chorionic Gonadotropin;Immune;In Vitro;Infertility;Inflammatory;Instruction;Leukocyte Chemotaxis;Leukocyte Trafficking;Leukocytes;Macaca;Matrix Metalloproteinases;Mediator of activation protein;Modeling;Molecular Profiling;Monkeys;Motion;Mus;Oocytes;Ovarian;Ovarian Tissue;Ovary;Ovulation;Pattern;Peptide Hydrolases;Physiology;Play;Primates;Process;Production;Progesterone;Prostaglandins;Rattus;Regulation;Reporting;Research Personnel;Rodent;Rodent Model;Role;Rupture;Signal Pathway;Stimulus;System;Technical Expertise;Time;Tissues;Vascular Endothelial Growth Factors;Woman;angiogenesis;granulosa cell;human tissue;implantation;in vitro Model;in vivo;migration;neoplastic cell;neovascularization;novel;programs;reproductive function;research study;trafficking;tumor

public_health_relevance:
The proposed studies will use human tissues collected at carefully defined times prior to and immediately after ovulation to investigate the changes in gene expression patterns that may impact oocyte release. The changes in these genes and their regulation will be studied using both human tissues and rodent models to mimic the human. These studies will expand our understanding of ovulation in the human.


application_id: 9117282
project_number: 5P01HD071875-03
project_title: Ovulation and Luteal Formation in Rodents Monkeys and Women
administering_ic: NICHD
award_notice_date: 2016-08-02
opportunity_number: PAR-10-245
application_type: 5
activity_code: P01
ic: HD
serial_number: 071875
program_official: TAYMANS, SUSAN
project_start_date: 2014-09-19
project_end_date: 2019-06-30
study_section: ZHD1-DRG-D(41)
contact_pi_person_id: 1896366
contact_pi: CURRY, THOMAS E
other_pis: Not Applicable
congressional_district: 06
department: OBSTETRICS & GYNECOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The unifying theme of this P01 proposal is to investigate one of the cornerstones of female fertility ovulation. Through this P01 project we will address key questions of the mechanisms associated with follicular rupture and the subsequent early changes in the postovulatory follicle. This will be accomplished through the scientific integration both experimentally and technically of 4 separate projects involving 5 investigators that will utilize ovarian tissues from women macaques and rodents. Project 1 (Curry/Brannstrom) will make use of an extremely novel model where human follicles are collected across the periovulatory period to examine the changes in the expression of extracellular matrix metalloproteinase inducer (EMMPRIN). Project #2 (Duffy) will take advantage of Dr. Duffy's extensive experience with macaques to investigate the role of PGE2 in angiogenesis of the nonhuman primate periovulatory follicle. Project #3 (Ko) will study the mechanisms by which progesterone regulates leukocyte infiltration in the preovulatory ovary. Project #4 (Jo) will elucidate the cellular action of CIPAR1 in regulating the LH mediated induction of progesterone production. Translational interactions across the projects are readily evident as tissues from women (Project #1) and macaques (Project #2) will be available to extrapolate to rodent models (Projects 1 3 4). An Administrative core provides support for the research teams by overseeing the overall functioning of the program as well as coordinating shared tissues from women macaques and rodents across the different projects. A pilot project will also be supported to open additional avenues of research collaboration and expertise. The significance of this proposal lies in its truly unique translational potential to further our understanding of the pathways that are critical for ovulation and early luteal formation in the human. There can be no stronger translational potential than to use human follicles collected at defined times after hCG to truly comprehend the mechanisms of ovulation and luteinization. The proposed studies in both the human and macaque will make significant strides towards advancing our understanding and treatment of ovulatory associated infertility as well as providing therapeutic modalities to manipulate the ovulatory process in the human thereby providing an important relevance to human health.

project_terms:
Address;Collaborations;Contraceptive methods;Critical Pathways;Dinoprostone;Extracellular Matrix;Female;Fertility;Health;Human;Human Chorionic Gonadotropin;Infertility;Infiltration;Leukocytes;Luteinization;Macaca;Matrix Metalloproteinases;Mediating;Methods;Modality;Modeling;Monkeys;Oocytes;Ovarian Tissue;Ovary;Ovulation;Pilot Projects;Process;Production;Progesterone;Research;Research Personnel;Research Support;Rodent;Rodent Model;Role;Rupture;Therapeutic;Time;Tissue Model;Tissues;Woman;angiogenesis;experience;nonhuman primate;novel;programs

public_health_relevance:
RELEVANCE: The proposed studies will examine the process of oocyte release using unique models and tissues from women monkeys and rodents. This will be accomplished by the integration of 4 synergistic and interactive research programs that will together provide a broader more comprehensive picture of the interrelated mechanisms of ovulation and luteal formation. This information can be used to treat infertility or conversely to explore novel methods of contraception.


application_id: 9116287
project_number: 4U01HL121807-04
project_title: The Impact of Oxidative Stress on HIV-induced Lung Disease
administering_ic: NHLBI
award_notice_date: 2016-07-21
opportunity_number: RFA-HL-13-026
application_type: 4
activity_code: U01
ic: HL
serial_number: 121807
program_official: CALER, ELISABET V
project_start_date: 2013-09-26
project_end_date: 2018-07-31
study_section: ZHL1-CSR-S(S1)
contact_pi_person_id: 8816315
contact_pi: RAMIREZ, JULIO ALBERTO
other_pis: ROMAN, JESSE
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): Lung diseases are major causes of morbidity and mortality in patients infected with the Human Immunodeficiency Virus (HIV). Currently antiretroviral therapy (ART) has changed HIV into a chronic disease. In the pre-ART era pulmonary infections were very common. In patients with ART however pulmonary infections are less frequent and noninfectious lung disorders such as COPD pulmonary hypertension lung cancer and pulmonary fibrosis are emerging as important causes of illness. These are important cause of morbidity and mortality yet the mechanisms responsible for these disorders in HIV patients are unknown. All pulmonary disorders mentioned above are associated with among other things lung inflammation and tissue remodeling characterized by alterations in matrix expression deposition and degradation. Interestingly HIV infection is also associated with oxidant stress caused by oxidation of the thiol disulfide couple cysteine (Cys)/cysteine (CySS) redox potential (Eh); also termed Eh Cys/CySS. This is important because in vitro studies show that an oxidized Eh Cys/CySS stimulates lung cells to produce more fibronectin (a matrix glycoprotein implicated in tissue injury and repair) transforming growth factor b (a pro-fibrotic growth factor) and pro-inflammatory cytokines like interleukin-1b. It also stimulates theproliferation and epithelial- mesenchymal transformation of lung fibroblasts processes implicated in tissue remodeling. These data suggest that HIV-related oxidation of Eh Cys/CySS may promote lung tissue remodeling. We have shown that one mechanism by which oxidation of Eh Cys/CySS stimulates tissue remodeling is through the activation of nicotinic acetylcholine receptors (nAChRs). This is intriguing considering that HIV-1 proteins like gp120 bind and increase the expression and signaling of nAChRs expressed in brain and this mechanism has been implicated in HIV-related dementia. We hypothesize that patients with HIV infection have oxidation of the Eh Cys/CySS which together with gp120 activates nAChR-mediated signaling in lung cells and leads to their expression of cellular products with pro-inflammatory and pro-fibrotic effects such as cytokines and growth factors matrix glycoproteins and tissue proteases. The persistent and exaggerated production of these factors activates lung tissue remodeling thereby promoting HIV-related lung disease. The type of disease developed (e.g. COPD versus pulmonary hypertension) however is dependent on both the genetic makeup of the subject and external factors such as smoking and infection. It is important that this hypothesis be tested considering that diet and other interventions have been shown to influence Eh Cys/CySS (9). If found to be causal Eh Cys/CySS and nAChRs can be targeted for intervention in the hope of reducing the incidence and/or severity of HIV-related non-infectious lung disease.

project_terms:
Address;Binding;Blood;Brain;Bronchoalveolar Lavage Fluid;Cause of Death;Cells;Chronic Disease;Chronic Obstructive Airway Disease;Chronic lung disease;Clinical Research;Cysteine;Data;Data Analyses;Databases;Dementia;Deposition;Deterioration;Diet;Disease;Disulfides;Epidemiologic Studies;Epithelial;Fibroblasts;Fibronectins;Glycoproteins;Goals;Growth;HIV;HIV Envelope Protein gp120;HIV-1;Health;Immunologist;In Vitro;Incidence;Individual;Infection;Inflammatory;Interleukin-1 beta;Interleukins;Intervention;Lung;Lung Inflammation;Lung diseases;Malignant neoplasm of lung;Mediating;Mesenchymal;Morbidity - disease rate;Myofibroblast;Nicotinic Receptors;Oxidation-Reduction;Oxidative Stress;Patients;Peptide Hydrolases;Physicians;Process;Production;Proteins;Pulmonary Fibrosis;Pulmonary Hypertension;Research Personnel;Scientist;Severities;Signal Transduction;Smoking;Structure of parenchyma of lung;Sulfhydryl Compounds;Testing;Tissues;Transforming Growth Factors;Universities;Virus Diseases;antiretroviral therapy;base;clinical investigation;cytokine;design;env Gene Products;follow-up;genetic makeup;injury and repair;mortality;oxidant stress;oxidation;prevent;programs;pulmonary function;research and development;transdifferentiation

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Lung diseases are major causes of death in patients with HIV infection. We are investigating what damages the lung in HIV infected patients compared to patients without HIV. Our ultimate goal is develop treatments to prevent lung diseases in these patients.


application_id: 9116278
project_number: 5R01HL128592-02
administering_ic: NHLBI
award_notice_date: 2016-04-30
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 128592
program_official: DESVIGNE-NICKENS, PATRICE
project_start_date: 2015-08-01
project_end_date: 2016-12-31
study_section: Special Emphasis Panel[ZRG1-DTCS-A(81)S]
contact_pi_person_id: 11817133
contact_pi: VANDSBURGER, MORIEL
other_pis: Not Applicable
congressional_district: 06
department: PHYSIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-05-01
project_title:
Novel MRI techniques for imaging cardiac fibrosis to improve clinical practice in patients with renal failure

project_abstract:
DESCRIPTION (provided by applicant): Cardiovascular disease affects millions of Americans with heart failure as a common endpoint. The development of cardiac fibrosis occurs early in cardiovascular disease promotes heart failure and provides arrhythmogenic substrate leading to increased frequency of adverse cardiac events and higher mortality. Cardiac magnetic resonance imaging (CMR) is routinely used to measure changes in ventricular structure and function with balanced steady state free precession (bSSFP) imaging. With intravenously delivered gadolinium contrast agents late gadolinium enhancement (LGE) CMR is the clinical standard for identifying focal fibrosis and quantifying fibrotic burden and when combined with mapping of T1-relaxation times can quantify diffuse fibrosis through measurement of increased extracellular volume fraction (ECV). In individuals with chronic kidney disease a strong link exists between cardiac fibrosis and adverse cardiac events however LGE is contraindicated due to the danger of nephrogenic systemic fibrosis. Emerging studies suggest that specific circulating hormones and peptides may be biomarkers of cardiac fibrosis and potential therapeutic targets in chronic kidney disease. However the inability to measure fibrosis in such patients represents a major gap to the discovery of potential biomarkers and leaves most studies measuring cardiac hypertrophy as an insensitive surrogate of fibrosis. This proposal seeks to develop a gadolinium free MRI method to measure fibrotic burden via reduced magnetization transfer (MT) in areas fibrotic tissue. This method termed 2-point bSSFP exploits an endogenous contrast mechanism in bSSFP imaging to identify fibrotic and edematous tissue. The proposed aims will validate 2-point bSSFP against standard of care LGE and measurement of diffuse fibrosis through ECV mapping. Finally comparison of fibrotic burden (measured with 2-point bSSFP) to blood chemical workup in CKD patients will examine the correlation between fibrosis and potential biomarkes. The successful completion of these aims will enable rapid and gadolinium free imaging of cardiac fibrosis over the entire heart. Further correlation of cardiac fibrosis with blood serum biomarkers in chronic kidney disease patients can help identify potential therapeutic targets to halt or reverse fibrosis the efficacy f which can be serially monitored using 2-point bSSFP.

project_terms:
Affect;Age;Agreement;American;Area;Biological Markers;Blood;Cardiac;Cardiovascular Diseases;Cause of Death;Chemicals;Chronic Kidney Failure;Cicatrix;Clinical;Clinical Research;Comorbidity;Contrast Media;Coronary Arteriosclerosis;Defibrillators;Development;Diagnostic;Diffuse;Disease;Edema;Equilibrium;Evaluation;Event;Fibrosis;Frequencies;Funding;Gadolinium;Gold;Health;Heart;Heart Hypertrophy;Heart failure;Hormones;Image;Image Enhancement;Imaging Techniques;Individual;Intraobserver Variability;Kentucky;Kidney Failure;Left ventricular structure;Link;Magnetic Resonance Imaging;Maps;Measurement;Measures;Methods;Monitor;Morbidity - disease rate;Motion;Myocardial Infarction;Non-Insulin-Dependent Diabetes Mellitus;PTH gene;Pathway interactions;Patients;Recruitment Activity;Relaxation;Renal function;Risk;Sensitivity and Specificity;Serum;Serum Markers;Signal Transduction;Slice;Structure;Testing;Therapeutic Intervention;Time;Tissues;Treatment Efficacy;Universities;Ventricular;Ventricular septum;Weight;Work;base;clinical practice;coronary fibrosis;density;design;extracellular;fibroblast growth factor 23;follow-up;gadolinium oxide;imaging modality;improved;mortality;non-invasive monitor;novel;novel therapeutics;peptide hormone;potential biomarker;standard of care;targeted treatment;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cardiovascular disease remains the leading cause of death amongst Americans particularly for patients with chronic kidney disease. The emerging link between fibrosis and adverse cardiac events has motivated development of gadolinium contrast agent based diagnostics of cardiac fibrosis that are not suitable for patients with compromised renal function. The proposed work fully validates a completely non-invasive and gadolinium free fibrosis imaging technique and applies this method to the identification of novel blood biomarkers of cardiac fibrosis in chronic kidney disease patients.


application_id: 9116041
project_number: 5R01AR060701-07
project_title: Novel Roles for Satellite Cells in Adult Skeletal Muscle Adaptation
administering_ic: NIAMS
award_notice_date: 2016-06-18
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AR
serial_number: 060701
program_official: BOYCE, AMANDA T
project_start_date: 2010-09-17
project_end_date: 2020-06-30
study_section: Skeletal Muscle and Exercise Physiology Study Section[SMEP]
contact_pi_person_id: 1878115
contact_pi: PETERSON, CHARLOTTE A.
other_pis: MCCARTHY, JOHN JOSEPH
congressional_district: 06
department: PHYSICAL MEDICINE & REHAB
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCH ALLIED HEALTH PROFESSIONS
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Ablation;Acquired Immunodeficiency Syndrome;Address;Adult;Affect;Age;Aging;Area;Atrophic;Attenuated;Award;Cell Culture Techniques;Cell Therapy;Cell fusion;Cell physiology;Clinical;Coculture Techniques;Collagen;Congestive Heart Failure;Data;Deterioration;Environment;Extracellular Matrix;Fiber;Fibroblasts;Fibronectins;Fibrosis;Foundations;Gene Expression;Gene Targeting;Genes;Genetic;Grant;Growth;HIV;Health;Hypertrophy;Immobilization;In Vitro;Individual;Knockout Mice;Knowledge;Limb structure;Maintenance;Malignant Neoplasms;Mediating;MicroRNAs;Molecular;Molecular Profiling;Morbidity - disease rate;Mouse Strains;Mus;Muscle;Muscle Fibers;Muscle function;Operative Surgical Procedures;Phenotype;Plantaris muscle;Process;Production;Publishing;Quality of life;Regulation;Rehabilitation therapy;Reporter;Reporting;Rheumatoid Arthritis;Role;Sepsis;Series;Skeletal Muscle;Skeletal Muscle Satellite Cells;Stem cells;Systemic disease;Tamoxifen;Testing;Therapeutic Agents;Therapeutic Uses;Time;Untranslated Regions;Wasps;Weight;Work;base;cell growth;exosome;extracellular;flexibility;in vitro Assay;in vivo;loss of function;mortality;mouse model;muscle form;muscle hypertrophy;novel;patient population;physical inactivity;prevent;research study;response;sarcopenia;satellite cell;skeletal;skeletal muscle plasticity;stem


application_id: 9115755
project_number: 1R56DA036635-01A1
project_title: Exploring New Drug Signals of Abuse in the Human Laboratory
administering_ic: NIDA
award_notice_date: 2015-08-28
opportunity_number: PA-13-302
application_type: 1
activity_code: R56
ic: DA
serial_number: 036635
suffix: A1
program_official: KAUTZ, MARY A
project_start_date: 2015-09-01
project_end_date: 2018-08-31
study_section: Risk, Prevention and Intervention for Addictions Study Section[RPIA]
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): A limited number of pharmacological classes are widely recognized for being associated with abuse potential and these are typically regulated under the Controlled Substances Act before marketing. However drugs from non-prototype pharmacological classes may be abused after introduction into the market posing new public health challenges and prompting a need for evaluation after marketing. The aim of this project is to evaluate and characterize the risks associated with two agents quetiapine and gabapentin both of which are marketed widely prescribed off-label unscheduled and for which clear signals of abuse and misuse have emerged in the U.S. and abroad. Two studies employing randomized placebo-controlled inpatient within- subject designs will be conducted with otherwise healthy recreational drug abusing volunteers who report a history of recreational sedative use. Participants will undergo a qualification test session during which the response to a test dose of triazolam is determined. Study 1 will examine a range of doses of quetiapine (50 100 and 200 mg p.o.) in comparison to triazolam and placebo Study 2 will examine a range of gabapentin doses (600 1200 1800 mg p.o.) compared to triazolam oxycodone and placebo. For each drug condition experimental sessions will include 1) a Sample Session during which standard abuse liability safety and simulated driving data will be collected to capture the pharmacodynamic profile and time-action curve for each drug condition and 2) a Self-Administration Session during which the reinforcing efficacy of each drug will be directly assessed using a progressive ratio procedure. One innovative feature of these studies is that driving simulation testing in the laboratory will be incorporated into the experimental design to evaluate psychomotor effects as they relate to impaired or "drugged driving"- a national public health concern that has been identified as a priority by the National Institute on Drug Abuse and the White House Office of National Drug Control Policy. These studies will provide important new information on the abuse liability characteristics of two widely prescribed agents quetiapine and gabapentin that may inform regulatory decision making and will provide important public health information regarding the risks related to impairment after use of these commonly prescribed and abused drugs.

project_terms:
Abuse Reporting;Acute;Adult;Affective;Amphetamines;Analgesics;Anxiety Disorders;Area;Automobile Driving;Barbiturates;Belief;Benzodiazepines;Cannabinoids;Case Study;Categories;Characteristics;Cocaine;Communities;Complex;Crossover Design;Data;Deception;Decision Making;Dose;Drug Controls;Drug abuser;Drug usage;Enrollment;Epilepsy;Europe;Evaluation;Experimental Designs;Gold;Hallucinogens;Health;Housing;Human;Impairment;Inpatients;Institution;Intravenous;Label;Laboratories;Manic;Marketing;Mental Depression;National Institute of Drug Abuse;Opioid;Oxycodone;Pain;Participant;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Physiological;Placebo Control;Placebos;Policies;Population;Procedures;Property;Randomized;Recording of previous events;Recreational Drugs;Regulation;Relative (related person);Reporting;Research;Research Priority;Risk;Route;Safety;Sampling;Schizophrenia;Self Administration;Signal Transduction;Sleep Disorders;Sleeplessness;Substance Use Disorder;Testing;Time;Triazolam;United States Food and Drug Administration;alpha-adrenergic receptor;analog;atypical antipsychotic;base;clinical practice;computerized;design;driving behavior;drug driving;drug of abuse;functional disability;gabapentin;gamma-Aminobutyric Acid;innovation;non-drug;novel;public health medicine (field);quetiapine;receptor;recreational drug abuse;research study;response;secondary outcome;sedative;simulation;substance abuser;volunteer

public_health_relevance:
PUBLIC HEALTH RELEVANCE: This research will provide important information regarding the abuse potential of two widely used drugs quetiapine and gabapentin which are not presently controlled by the Drug Enforcement Agency but for which signals of abuse have emerged. Moreover the risks of using these drugs and others (triazolam oxycodone) on driving will be assessed and will inform prescribing practices and public safety.


application_id: 9115730
project_number: 5R13OD021318-02
project_title: Comparative Medicine Resource Directors Meetings
administering_ic: OD
award_notice_date: 2016-08-12
opportunity_number: PA-13-347
application_type: 5
activity_code: R13
ic: OD
serial_number: 021318
program_official: MURPHY, STEPHANIE
project_start_date: 2015-09-01
project_end_date: 2020-08-31
study_section: Special Emphasis Panel[ZRG1-IMST-C(90)S]
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_terms:
Address;Biocompatible Materials;Biomedical Research;Collaborations;Development;Face;Fostering;Funding;Grant;Health;Location;Medicine;Mission;Request for Applications;Request for Proposals;Research Infrastructure;Resources;Scientist;Strategic Planning;United States National Institutes of Health;comparative;design;innovation;meetings;posters;programs;symposium;working group


application_id: 9115058
project_number: 5R01CA185972-03
project_title: Chemoprevention of metastatic colorectal cancer
administering_ic: NCI
award_notice_date: 2016-07-18
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: CA
serial_number: 185972
program_official: CHEN, WEIWEI
project_start_date: 2014-08-01
project_end_date: 2019-07-31
study_section: Chemo/Dietary Prevention Study Section[CDP]
contact_pi_person_id: 7649061
contact_pi: DAMODARAN, CHENDIL
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 MEDICINE
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Colon cancer metastasis remains the leading cause of death due to this disease. It is important to identify the cause of events maneuvering it to a more advanced stage and metastasis. In the proposed study we have hypothesized that high level of AKT expression is CRC is responsible for developing an aggressive and metastatic disease by influencing epithelial-mesenchymal transitions (EMT) endowing cells with migratory and invasive phenotype hence targeting AKT activation can prevent metastasis in CRC. To prove the hypothesis we have checked the status of AKT in CRC cell lines and patient samples revealing high expression of AKT. In our cell culture and colon cancer xenograft models we have shown that overexpression of AKT leads to aggressive cell and tumor growth angiogenesis in tumors and EMT phenotype in tumor cells. The goal of the current project is to characterize and generate preclinical data on withaferin-A (WA) or ita potent analog as an oral agent for the prevention of colon cancer metastasis. To inhibit AKT signaling we have employed Withaferin-A (WA) an herbal molecule that overcomes AKT-mediated EMT in preclinical models of CRC. Based on these finding we hypothesize that CRC cells have adapted for the high-level of AKT expression to develop an aggressive phenotypes hence targeting AKT activation can prevent the development of aggressive CRC growth by inhibiting epithelial mesenchymal transition (EMT). We have proposed to identify and synthesize more potent molecules derived from WA which bind more strongly to AKT. These derivatives will be further characterized in cell culture and animal (metastatic xenograft and an APC mimicking advanced and metastatic human CRC) models. Preventing colon cancer using potent biomolecules targeting AKT specifically is a novel approach and may have significant impact on high-risk patients. In addition for the first time we have shown that AKT accumulation is a critical step towards EMT and we have proposed to develop biotin-labeled compounds to target AKT specifically. Chemoprevention of CRC by using these novel potent compounds may have a significant impact in high-risk patients or clinically relapsing patients by inhibiting AKT- induced EMT signaling and hence metastasis.

project_terms:
AKT Signaling Pathway;AKT inhibition;Affinity;Animal Model;Animals;Apoptosis;Ashwagandha;BCL2 gene;Binding;Biological Assay;Biotin;Cancer Etiology;Cause of Death;Cell Culture Techniques;Cell Line;Cell Proliferation;Cells;Cessation of life;Chemoprevention;Chemopreventive Agent;Clinical;Clinical Trials;Colon Carcinoma;Colonic Neoplasms;Colorectal Cancer;Data;Development;Diagnosis;Disease;Disseminated Malignant Neoplasm;Docking;E-Cadherin;Epithelial;Event;Fluorouracil;Goals;Growth;HCT116 Cells;Health;Human;In Vitro;Investigation;Label;Laboratories;Large Intestine Carcinoma;Lead;Malignant Epithelial Cell;Mediating;Mesenchymal;Modeling;Molecular;Neoplasm Metastasis;Oral;Oral Administration;Patients;Pattern;Phenotype;Phosphotransferases;Polyps;Pre-Clinical Model;Prevention;Proteins;Proto-Oncogene Proteins c-akt;Radiosurgery;Regimen;Relapse;Research Personnel;Role;SW620;Sampling;Signal Transduction;Snails;Staging;Survival Rate;Therapeutic;Time;Tumor Tissue;Woman;Xenograft Model;Xenograft procedure;analog;angiogenesis;base;cell growth;chemotherapy;dietary supplements;high risk;insight;interest;meetings;men;metastatic colorectal;migration;neoplastic cell;novel;novel strategies;overexpression;pre-clinical;prevent;relapse patients;slug;survivin;transcription factor;tumor;tumor growth;tumor progression

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The survival rate of metastatic colorectal carcinoma (CRC) is less than 5%. Use of 5-fluorouracil (5-FU) radiation and surgery are the primary treatments; however most metastatic cancers eventually cause death. Developing approaches to prevent progression to metastasis could therefore be part of an important therapeutic strategy especially for high-risk patients including those patients already diagnosed with high grade polyps or localized colon cancer. The goal of the current project is to characterize and generate preclinical data on withaferin-A (WA) as an oral agent for the prevention of colon cancer metastasis which is the third leading cause of cancer-related death for both men and women. The proposed study of the dietary supplement Withaferin-A (WA) the major bioactive compound from Withania somnifera) and its potent analog will provide molecular level insight into the mechanism of action of this agents against metastatic colon cancer and clarify the clinical potential of WA or its potent analog with respect to the chemoprevention and/ or chemotherapy of colon cancer.


application_id: 9114484
project_number: 5R01AI119022-02
project_title: Structure and mechanism of the ESX secretion system from pathogenic mycobacteria
administering_ic: NIAID
award_notice_date: 2015-12-08
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: AI
serial_number: 119022
program_official: KRAIGSLEY, ALISON
project_start_date: 2015-07-25
project_end_date: 2019-12-31
study_section: Bacterial Pathogenesis Study Section[BACP]
contact_pi_person_id: 11365624
contact_pi: KOROTKOV, KONSTANTIN V
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_terms:
Affect;Amino Acids;Antigens;Architecture;Binding;Biochemical;Biological;Biological Process;C-terminal;Cell Wall;Cell physiology;Cell surface;Cessation of life;Communicable Diseases;Complex;Data;Development;Diagnostic;Diagnostic Reagent;ELF3 gene;Environment;Enzymes;Essential Amino Acids;Family;Future;Genetic;Genus Mycobacterium;Goals;Growth;Health;Homologous Gene;Human;Immune;Individual;Infection;Investigation;Knowledge;Macromolecular Complexes;Mass Spectrum Analysis;Membrane;Methods;Modeling;Molecular;Molecular Chaperones;Multi-Drug Resistance;Mutation;Mycobacterium tuberculosis;Pathogenesis;Pathway interactions;Peptide Hydrolases;Pilum;Play;Process;Protein Family;Protein Secretion;Proteins;Role;Specificity;Staging;Structure;Surface;System;Testing;Therapeutic;Tuberculosis;Vaccines;Virulence;Work;X-Ray Crystallography;base;design;dimer;drug development;drug discovery;extensive drug resistance;extracellular;improved;inhibitor/antagonist;insight;mycobacterial;new therapeutic target;novel therapeutics;pathogen;protein aggregation;protein protein interaction;protein transport;research study;resistant strain;tool;tuberculosis drugs;vaccine candidate;vaccine development


application_id: 9114456
project_number: 4R01AA021722-04
project_title: Behavioral Dysregulation and Alcohol Sensitivity in Risky Drivers
administering_ic: NIAAA
award_notice_date: 2016-07-13
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: AA
serial_number: 021722
program_official: BLOSS, GREGORY
project_start_date: 2013-08-05
project_end_date: 2019-07-31
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 6368360
contact_pi: FILLMORE, MARK T
other_pis: Not Applicable
congressional_district: 06
department: PSYCHOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Alcohol-related traffic fatality and injury continue to be a major public health problem prompting the need for research aimed at identifying characteristics of DUI drivers in efforts to improve treatment and prevention. Although DUI offenders report traits of impulsivity suggesting poor inhibitory control and heightened reward sensitivity the specific cognitive characteristics underlying such behavioral dysregulation have not been systematically studied in the laboratory. The over-arching hypothesis of this application is that deficient inhibitory control and increased sensitivity to the disinhibiting effects of alcool contribute to the risk of DUI and possibly to its recidivism. The proposed project views DUI offenders from a cognitive dysfunction perspective that targets deficits in specific mechanisms of behavioral regulation. The research will directly evaluate driving performance and mechanisms of self-regulation (e.g. inhibitory control reward-seeking) in recidivist DUI offenders and will test hypotheses that these high-risk drivers respond differently to alcohol wit increased disinhibition and risk-taking and that these factors contribute to their decisions to drive after drinking. The application represents an innovative application of state-of-the-art assessments and techniques to identify the specific neurocognitive characteristics that underlie risky driving behavior and which could be candidate mechanisms for treatment and prevention. The project aims fit well with the recent NIH Funding Opportunity Announcement (PA-10-255) Behavioral Regulation Mechanisms of Alcohol Dependence and Related Phenotypes aimed at promoting research on the effects of alcohol on neurocognitive mechanisms implicated in impulse control.

project_terms:
Acute;Address;Alcohol dependence;Alcohols;Attention deficit hyperactivity disorder;Automobile Driving;Awareness;Behavior;Behavioral;Behavioral Mechanisms;Blood;Blood alcohol level measurement;Characteristics;Cognitive;Cognitive deficits;Counseling;Data;Disinhibition;Dose;Environment;Environmental Risk Factor;Funding Opportunities;Health;Impaired cognition;Impairment;Impulsivity;Incentives;Incidence;Informal Social Control;Injury;Intervention;Laboratories;Legal;Licensing;Link;Neurocognitive;Patient Self-Report;Performance;Personality inventories;Phase;Phenotype;Prevention;Public Health;Regulation;Reporting;Research;Rewards;Risk;Risk-Taking;Speed;Techniques;Testing;United States;United States National Institutes of Health;Vehicle crash;Wit;addiction;alcohol effect;alcohol response;alcohol sensitivity;distraction;drinking;driving behavior;driving under influence;high risk;impaired driving performance;improved;innovation;offender;programs;recidivism;response;success;theories;trafficking;trait impulsivity;treatment program;willingness

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  One in every 127 licensed drivers is arrested for driving under the influence (DUI) and recidivism rates are high with over one-third of DUI offenders re-offending within three years. The proposed project examines DUI drivers from a cognitive dysfunction perspective that targets deficits in specific mechanisms of behavioral regulation. Identification of specific cognitive deficits in DUI offenders is critical for guiding new interventions that will move treatment beyond general addiction counseling. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page


application_id: 9114402
project_number: 5U18FD004433-05
project_title: Kentucky Department for Public Health DPHPS Food Safety Branch Conformance with t
administering_ic: FDA
award_notice_date: 2016-07-25
opportunity_number: RFA-FD-12-007
application_type: 5
activity_code: U18
ic: FD
serial_number: 004433
program_official: WEED, BRETT
project_start_date: 2012-08-15
project_end_date: 2017-07-31
study_section: Special Emphasis Panel[ZRG1-SRC(99)]
contact_pi_person_id: 14929079
contact_pi: GILLIS, REBECCA
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
Kentucky Department for Public Health-DPHPS Food Safety Branch Cooperative Agreement AbstractConformance with the Manufactured Food Regulatory Program Standards (MFRPS) (U18) Funding Opportunity Announcement (FOA) Number: RFA-FD-12-007 April 16 2012Abstract:Our agency's enrollment in the MFRPS program started in July 2011. Many gaps alreadyidentified in our program include lack of a solid regulatory platform equivalent to that of FDA'sin which to enforce uniform standards as part of a nationally integrated food protection system.A key gap with regards to fulfilling most if not all of the MFRPS program standards includes thelack of human resources (including a training officer compliance officer and a MFRPS ProjectCoordinator). The intended outcome of this Cooperative Agreement Funding Application is toadvance efforts for a nationally integrated food safety system by utilizing available federal (FDA)funding assistance to allow Kentucky's State Manufactured Food Regulatory Program toachieve and maintain significant to full conformance with the Manufactured Food RegulatoryProgram Standards (MFRPS). This Cooperative Funding Application if successful will allowour state food protection program to address many intra-agency identified gaps and obstaclesand will allow all the Food Safety Branch to implement a fully-functional MFRPS program inKentucky.The intent of this Cooperative Agreement application is to fund two (2) MFRPS-dedicatedpersonnel as part of our Food Protection Team. The addition of these two additional employeesto our staff one of whom will be designated as the MFRPS Project Coordinator will provide theKentucky DPH-Food Safety Branch the human resource capability to develop and implement acomprehensive strategic plan that will result in significant to full conformance with the MFRPSand program equivalency with our federal (FDA) partners; a key component of advance ourKentucky Food Protection program forward as a key partner in a nationally integrated foodsafety system.

public_health_relevance:
Kentucky Department for Public Health-DPHPS Food Safety Branch Cooperative Agreement Summary for Funding Opportunity:Conformance with the Manufactured Food Regulatory Program Standards (MFRPS) (U18) Funding Opportunity Announcement (FOA) Number: RFA-FD-12-007 April 16 2012Summary:The Kentucky DPH-Food Safety Branch's enrollment in the MFRPS program started in July2011. Though our initial program self-assessment has not been completed as of the date of thisapplication we know and expect that we will fall short in many of the program standards. A keygap with regards to fulfilling most if not all of the MFRPS program standards includes the lackof human resources (including a training officer compliance officer and a MFRPS ProjectCoordinator). If successful this federal funding opportunity will allow our state food protectionprogram to address many of the identified gaps and obstacles and will allow our agency toimplement a fully-functional MFRPS program in Kentucky. The intent of this CooperativeAgreement application is to fund two (2) MFRPS-dedicated personnel as part of our FoodProtection Team. The addition of these two additional employees will provide the humanresource capability to develop and implement a comprehensive strategic plan that will result insignificant to full conformance with the MFRPS and sustainability after the cooperativeagreement.


application_id: 9114124
project_number: 5R01EY023561-03
project_title: Mid-level mechanisms of surface and binocular perception
administering_ic: NEI
award_notice_date: 2016-08-08
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: EY
serial_number: 023561
program_official: WIGGS, CHERI
project_start_date: 2014-08-01
project_end_date: 2019-07-31
study_section: Cognition and Perception Study Section[CP]
contact_pi_person_id: 1965646
contact_pi: HE, ZIJIANG
other_pis: Not Applicable
congressional_district: 03
department: PSYCHOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Retinal images are inherently fragmentary and ambiguous because images of separate entities overlap. But the early visual mechanisms are not equipped to parse the overlapping 2-D retinal images into distinct 3-D entities. The job of parsing these images falls on the mid-level mechanisms whose main role is to represent the distinct entities as separate surfaces. The represented surface information then serves as inputs to the WHAT and WHERE systems that underlie our 3-D perception of objects and space respectively. As such the mid-level mechanisms are not just simple "conduits" of information between early and late level visual mechanisms but play a crucial role in determining the quality and reliability of the visual information conveyed. Compared to other aspects of visual processing less is known about the mid-level mechanisms. One of the biggest challenges is to discover how the often fragmentary and ambiguous retinal information is transformed into reliable surface representations presumably through a spreading-in operation. At times when an image belonging to the same entity is broken into parts due to occlusion a surface interpolation operation is required to integrate the parts into a global surface. Moreover inputs from the two eyes that contribute to these operations can be disparate in content and location. In the face of the myriad complexities of the visual inputs it is further proposed that the mid-level mechanisms must rely on internal assumptions (perceptual rules) and feedbacks from the higher visual levels for guidance in representing surfaces. But how these operations are accomplished is still unclear. Remedying it this proposal uses the human psychophysical approach to investigate the above issues by focusing on three specific aims. Aim 1 investigates how the spreading-in operation represents surfaces with texture patterns which is more complex than representing texture-free surfaces. It is proposed the principle of reducing coding redundancy that governs the spreading-in operation causes the global surface representation operation to be efficient but prone to poor resolution. The latter could be one basis of the well-known "crowding effect" phenomenon. Aim 2 investigates the texture-surface interpolation operation. Cognizant of the roles of attention and object knowledge the research investigates how these top-down factors influence surface integration. Aim 3 investigates the long-term plasticity of the mid-level mechanisms. Perceptual learning experiments will be conducted to reveal how extensive training modifies the perceptual rules implemented at the mid-level. The long-term goal of this proposal is to advance our knowledge of how visual information is processed and represented by the mid-level mechanisms. This knowledge helps us better understand how humans perceive the visual world and provides a clinical basis for behavioral diagnoses and treatments of visual dysfunctions related to amblyopia strabismus and aging.

project_terms:
3-Dimensional;Affect;Aging;Amblyopia;Attention;Behavioral;Clinical;Code;Color;Complex;Crowding;Diagnosis;Ensure;Environment;Eye;Feedback;Frequencies;Functional disorder;Goals;Grant;Health;Human;Image;Knowledge;Link;Location;Measurement;Motion;Occupations;Ownership;Pattern;Perception;Perceptual learning;Play;Process;Property;Protocols documentation;Psychophysics;Research;Resolution;Retinal;Role;Space Perception;Strabismus;Surface;System;Testing;Texture;Time;Training;Visual;Visual Perception;Visual system structure;base;detector;falls;feeding;improved;luminance;neurophysiology;object perception;object shape;operation;research study;visual information;visual process;visual processing;visual stimulus

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Early level visual information is often fragmentary and ambiguous because images of distinct entities overlap. A role of the mid-level mechanisms is to "make sense" of this information by representing the distinct entities as separate surfaces. Discovering how this is achieved leads to better scientific understanding of how humans perceive the visual world and provides a clinical basis for non-invasive diagnoses and treatments of visual dysfunctions related to amblyopia and strabismus.


application_id: 9113975
project_number: 5R01NR012967-03
administering_ic: NINR
award_notice_date: 2016-08-08
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: NR
serial_number: 012967
program_official: HUSS, KAREN
project_start_date: 2014-09-26
project_end_date: 2019-07-31
study_section: Behavioral Medicine, Interventions and Outcomes Study Section[BMIO]
contact_pi_person_id: 8446344
contact_pi: CHUNG, MISOOK LEE
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2016-08-09
project_title:
Effects of Family Sodium Watchers Program on Outcomes in Heart Failure Patient-Family Caregiver Dyads

project_abstract:
DESCRIPTION (provided by applicant): Heart failure (HF) emerged as a significant public health threat in the 1990s and has now reached epidemic proportions. Despite advances in the medical treatment of HF patients with HF face frequent hospitalizations for acute exacerbations. Inadequate self-care strategies in particular non-adherence to a sodium restricted diet (SRD) are a main cause of these hospitalizations. Prior interventions to increase adherence have focused on increasing knowledge about restricting sodium in the diet have met with limited success. Unaddressed by these interventions are the major barriers of measuring and tracking daily sodium intake family members who continue to eat high sodium diets and a preference for salty foods-particularly in the elderly who have a decreased sense of taste. It is possible to retrain the taste buds to enjoy low salt foods by gradually reducing the amount of sodium in foods over the course of 16 weeks. This retraining works best with direct involvement and support from family members. The Family Sodium Watcher Program (Family Swap) proposed in this study incorporates the use of a unique electronic salt monitoring device that easily measures salt content in food-the major source of sodium. The intervention is designed to improve adherence to a SRDby both patients and family caregivers through education and strategies for gradual taste adaptation to low salt foods. The purpose of this 2-group randomized controlled repeated measures (baseline 4-month and 12-month) study is to examine effects of Family Swap on adherence (24-hour urine sodium excretion) to a SRD; knowledge attitudes and barriers about SRD; perceived control and perceived social support (in patient- caregiver dyads); caregiving burden (in caregivers only); and symptom distress and hospitalizations (in patients only). We will enroll a total of 220 patient-caregiver dyads. Dyads will be stratified as adherent and non-adherent using baseline patients' 24-hour urine sodium excretion (cut point = 3000 mg) and then randomly assigned to Family Swap intervention group or a usual care control group. The Family Swap intervention (6 weekly 45-minute sessions followed by 5 bi-weekly booster sessions) will be delivered remotely using a video- conferencing program on an iPad tablet. Patient-caregiver dyads will complete questionnaires (knowledge attitudes and barriers about diet; symptoms distress; perceived control; perceived social support; caregiving burden; and quality of life) and collect a 24-hour urine for sodium excretion at each assessment. Data will be analyzed using repeated measures ANOVA Cox regression and an innovative actor-partner interdependence model dyadic analysis for longitudinal data. This dyadic intervention study will provide rich data on the complex interpersonal relationships within patient-caregiver dyads that affect adherence and health outcomes in patients with HF and family caregivers. Given the recommendation that all individuals should consume a sodium restricted diet the intervention has the potential for expanded application beyond patients who need to follow a sodium restricted diet for cardiovascular reasons to everyone consuming a diet high in sodium.

project_terms:
Acute;Address;Adherence;Adult;Affect;Age;Analysis of Variance;Attitude;Behavior;Cardiovascular system;Caregivers;Caring;Chronic;Chronically Ill;Complex;Control Groups;Data;Desire for food;Diet;Dietary Intervention;Dietary Sodium;Distress;Eating;Education;Educational Intervention;Educational process of instructing;Elderly;Electronics;Enrollment;Epidemic;Excretory function;Face;Family;Family Caregiver;Family member;Feeling;Food;Food Labeling;Food Preferences;Goals;Health;Health Care Costs;Health Status;Heart failure;Hospitalization;Hour;Individual;Intake;Interpersonal Relations;Intervention;Intervention Studies;Knowledge;Lead;Long-Term Effects;Measures;Medical;Modeling;Monitor;Outcome;Patients;Perception;Physiological;Play;Prevalence;Public Health;Quality of life;Questionnaires;Randomized;Randomized Controlled Trials;Reading;Recommendation;Research;Research Personnel;Resources;Role;Self Care;Self Management;Sensory;Social support;Sodium;Sodium Chloride;Sodium-Restricted Diet;Source;Symptoms;Tablets;Taste Buds;Taste Perception;Testing;Time;Urine;Videoconferences;Videoconferencing;Wit;Work;base;care giving burden;caregiving;design;follow-up;group intervention;hedonic;high salt diet;improved;improved outcome;innovation;intervention program;longitudinal analysis;meetings;member;monitoring device;outcome forecast;preference;prevent;programs;reduce symptoms;skills;success;treatment as usual;urinary

public_health_relevance:
PUBLIC HEALTH RELEVANCE: With the rising costs of health care family members are playing a greater role in the care of chronically ill patients. This family-based intervention addresses the public health goal of improving the health status and quality of life of patients wit heart failure and their family caregivers through an innovative educational program focused on the self-care of sodium restricted diet.


application_id: 9113937
project_number: 5F30DE025543-02
project_title: Characterization of P. gingivalis minor fimbrial accessory proteins
administering_ic: NIDCR
award_notice_date: 2016-04-04
opportunity_number: PA-14-150
application_type: 5
activity_code: F30
ic: DE
serial_number: 025543
program_official: FRIEDEN, LESLIE A
project_start_date: 2015-06-01
project_end_date: 2019-05-31
study_section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR]
contact_pi_person_id: 11948429
contact_pi: LEE, JAE YONG
other_pis: Not Applicable
congressional_district: 03
department: DENTISTRY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF DENTISTRY/ORAL HYGN
organization_zip: 402920001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): Periodontitis is a chronic inflammatory disease affecting around half the adults over 35 in the United States. Clinical outcomes include damage to periodontal tissues and alveolar bone loss with eventually exfoliation of the teeth. Porphyromonas gingivalis is a keystone pathogen in adult periodontitis and the organism possesses a number of virulence factors that enable colonization of the periodontal area confer resistance to host immunity and mediate destruction of periodontal tissues. P. gingivalis colonization of antecedent oral communities is facilitated by binding to common oral bacteria such as S. gordonii. Attachment of P. gingivalis to S. gordonii is mediated by the short/minor fimbriae of P. gingivalis which interact with the SspA/B streptococcal surface proteins. Communities of P. gingivalis and S. gordonii are more pathogenic in a mouse model of alveolar bone loss compared to either organism alone. The minor/short fimbriae are comprised of the Mfa1 structural subunit and the mfa1 gene is part of a cluster that contains mfa1 mfa2 mfa3 pgn0290 and pgn0291. Mfa2 is an anchoring and length regulating protein. Mfa3 is an accessory protein localized to the fimbrial tip and necessary for the integration of proteins derived from pgn0290 and pgn0291 (which we designate Mfa4 and Mfa5 respectively) into the fimbrial structure. Beyond this however little is known regarding protein interactions supramolecular structure and the functions of Mfa3 4 and 5. We propose 3 specific aims to address these topics: To determine the location of Mfa4 and Mfa5 on the Mfa fimbriae and characterize the binding interactions among Mfa3 4 and 5; to determine the role of Mfa3 Mfa4 and Mfa5 in P. gingivalis co-adhesion to S. gordonii; and to determine the role of Mfa3 Mfa4 and Mfa5 in polymicrobial synergy in vivo. The findings from this study will provide novel structural and functional detail of an important virulence factor of P. gingivalis. This has the potential to lead to the design of new therapeutics to target the effector molecules of P. gingivalis colonization and prevent the accumulation of P. gingivalis into polymicrobially synergistic communities.

project_terms:
Address;Adhesions;Adult;Affect;Alveolar Bone Loss;Anaerobic Bacteria;Animals;Area;Binding;Binding Proteins;Biogenesis;Biological Assay;Cell surface;Chronic;Chronic Disease;Clinical;Communities;Complement;Complex;Development;Disease;Electron Microscopy;Epithelial Cells;Exhibits;Filament;Gene Cluster;Genes;Goals;Homeostasis;Immune;Immune response;Immunity;Individual;Infection;Inflammatory;Lead;Left;Length;Location;Mediating;Membrane Proteins;Minor;Molecular;Mouth Diseases;Oral;Oral cavity;Oral health;Organism;Outcome;Pathogenesis;Pathogenicity;Periodontitis;Population;Porphyromonas gingivalis;Process;Properdin;Protein Subunits;Proteins;Recombinant Proteins;Research;Resistance;Role;Severities;Streptococcus gordonii;Structure;Surface;Testing;Therapeutic Studies;Tissues;Tooth Exfoliation;Tooth Loss;United States;Virulence Factors;bone loss;co-infection;design;fimbria;immunoregulation;improved;in vivo;mouse model;mutant;new therapeutic target;novel;novel therapeutics;oral bacteria;pathogen;prevent;protein complex;protein structure;public health relevance;targeted treatment;therapeutic target

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Periodontitis is a prevalent oral disease that can ultimately lead to tooth loss. In this project we shall study the means by which one of major causative agents of periodontitis establishes itself in the mouth. This has the potential to identify therapeutic targets which in turn can be included in oral health products designed to mitigate the severity of periodontitis.


application_id: 9113697
project_number: 3R01AA024405-02S1
project_title: SAM Deficiency Mediated Epigenetic Mechanisms in Alcohol induced Immunosuppression
administering_ic: NIAAA
award_notice_date: 2016-04-29
opportunity_number: PA-14-077
application_type: 3
activity_code: R01
ic: AA
serial_number: 024405
suffix: S1
program_official: WANG, JOE
project_start_date: 2015-03-10
project_end_date: 2020-02-29
study_section: ZAA1(50)-P
contact_pi_person_id: 1878178
contact_pi: BARVE, SHIRISH S
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:
Alcohol abuse;Alcohol consumption;Alcohols;Apoptotic;CD4 Positive T Lymphocytes;Candidate Disease Gene;Cell Death;Cell Death Signaling Process;Cell Survival;Cessation of life;Chronic;Clinical;Cytosine;DNA;DNA Modification Process;Data;Depressed mood;Epigenetic Process;Ethanol;Gene Expression;Genes;HIV;Healthcare Systems;Hepatic;Histones;Human;Immune System Diseases;Immune system;In Vitro;Instruction;Lymphocyte;Mass Spectrum Analysis;Mediating;Metabolism;Modification;Molecular;Natural immunosuppression;Patients;Proteomics;Research;Role;S-Adenosylmethionine;Signal Transduction;Supplementation;T-Cell Depletion;Transcriptional Activation;Work;alcohol abuser;alcohol effect;alcohol exposure;alcohol response;base;chronic alcohol ingestion;epigenetic regulation;genome-wide;histone modification;immune function;immunotoxicity;insight;mRNA Expression;methionine adenosyltransferase;prevent;problem drinker;promoter


application_id: 9113195
project_number: 3R24OD010435-15S1
project_title: Research Resources for Model Amphibians
administering_ic: OD
award_notice_date: 2015-08-13
opportunity_number: PAR-10-289
application_type: 3
activity_code: R24
ic: OD
serial_number: 010435
suffix: S1
program_official: CONTRERAS, MIGUEL A
project_start_date: 2001-10-01
project_end_date: 2016-06-30
study_section: ZRR1-CM-8(01)
contact_pi_person_id: 7876973
contact_pi: VOSS, STEPHEN RANDAL
other_pis: Not Applicable
congressional_district: 06
department: BIOLOGY
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF ARTS AND SCIENCES
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Salamanders are important vertebrate model organisms in biomedical research. The Salamander Genome Project (SGP) is developing applying and making available genomic and bioinformatics resources for salamanders and in particular the Mexican axoloti (Ambystoma mexicanum). This renewal application proposes two objectives to further enhance axoloti genome resources. First a 3x Bacterial Artificial Chromosome (BAC) library will be created and screened to identify clones that contain axoloti genes of interest. This list of clones will be made available via the SGP website (Sal-Site) and 25 BACs will be prioritized by the community for isolation and sequencing. A second objective will innovate an approach to sequence the large axoloti genome. Whole axoloti chromosomes that correspond to the third largest chromosome (Chr3) in the karyotype will be isolated by laser capture microscopy. DNA fragment libraries will be generated from the captured chromosomes and these will be sequenced to yield a Chr3 draft assembly whose contiguity and conceptual context will be increased by integrating paired-end sequences from fosmids protein-coding sequences deriving from expressed sequence tags and markers defining linkage group 3 of the Ambystoma meiotic map. Accomplishment of these objectives will yield resources to enable functional studies of genes and epigenetic mechanisms. Also the project will innovate a 'one-chromosome-at- a time' approach to sequence the large axoloti genome. As a final objective of the application a historically significant collection of axolotis in the Ambystoma Genetic Stock Center (AGSC) will be maintained and distributed to NIH-funded researchers. Since 1969 the AGSC axoloti collection has been supported by funds received from the National Science Foundation. An increasing number of NIH researchers are requesting axoloti living stocks for regeneration research and at the same time there is need to develop a stable long term funding model to maintain this irreplaceable resource. A dual NIH-NSF funding model is proposed where costs associated with the maintenance and distribution of axoloti stocks will be split equally between the NSF and NIH.

project_terms:
Ambystoma;Ambystoma mexicanum;Amphibia;Animal Model;Bacterial Artificial Chromosomes;Bioinformatics;Biological;Biomedical Research;Chromosome Mapping;Chromosomes;Chromosomes Human Pair 3;Code;Collection;Communities;Community Surveys;Complex;Custom;DNA;DNA Sequence;Databases;Development;Embryonic Development;Ensure;Epigenetic Process;Expressed Sequence Tags;Foundations;Funding;Funding Mechanisms;Future;Gene Chips;Genes;Genetic;Genetic Polymorphism;Genome;Genome Mappings;Genomics;Grant;Human;Karyotype;Lasers;Libraries;Life;Location;Maintenance;Maps;Meiosis;Methods;Mexican;Microscopy;Modeling;Natural regeneration;Phenotype;Process;Proteins;Quantitative Trait Loci;Research;Research Personnel;Resources;Salamander;Science;Shotgun Sequencing;Site;Technology;Time;Transcript;Translating;United States National Institutes of Health;Untranslated RNA;Update;comparative;cost;gene function;genetic linkage;genome sequencing;innovation;interest;laser capture microdissection;mutant;organ regeneration;sex;tissue repair;web site

public_health_relevance:
(provided by applicant): Fundamental genome and living stock resources are needed for salamanders so that biomedical researchers can translate biological information to humans. In particular salamanders are primary vertebrate models for organ regeneration tissue repair and post-embryonic development.


application_id: 9113193
project_number: 3U50CK000382-02S1
administering_ic: NCEZID
award_notice_date: 2015-07-31
opportunity_number: RFA-CK-14-1401
application_type: 3
activity_code: U50
ic: CK
serial_number: 000382
suffix: S1
project_start_date: 2014-08-01
project_end_date: 2019-07-31
study_section: ZCK1-SRC(99)
contact_pi_person_id: 9738704
contact_pi: ELLIS, PEGGY
other_pis: Not Applicable
congressional_district: 01
department: Unavailable
primary_duns: 927049767
primary_uei: LECJQDCLHVE5
duns_number: 927049767
uei: LECJQDCLHVE5
fips: US
organization_id: 4242701
organization_name: KY ST CABINET/HEALTH/FAMILY SERVICES
organization_city: FRANKFORT
organization_state: KY
organization_type: Other Domestic Non-Profits
organization_zip: 406012321
organization_country: UNITED STATES
arra_indicator: N
budget_start_date: 2015-08-01
project_title:
Building strengthening and maintenence of capacity for vital programs in the epidemiology laboratory and health information systems in Kentucky state and local health departments.


application_id: 9112029
project_number: 5R44NS083218-04
project_title: SYSTEM FOR AUTOMATED NONINVASIVE MONITORING OF MOUSE SLEEP AND BEHAVIOR
administering_ic: NINDS
award_notice_date: 2016-07-27
opportunity_number: PA-14-071
application_type: 5
activity_code: R44
ic: NS
serial_number: 083218
program_official: FERTIG, STEPHANIE
project_start_date: 2013-04-01
project_end_date: 2018-04-30
study_section: Special Emphasis Panel[ZRG1-ETTN-C(10)B]
contact_pi_person_id: 12510521
contact_pi: LHAMON, MICHAEL E
other_pis: SUNDERAM, SRIDHAR
congressional_district: 06
department: Unavailable
primary_duns: 964938455
primary_uei: D9DRUX8SM4V9
duns_number: 964938455
uei: D9DRUX8SM4V9
fips: US
organization_id: 10032136
organization_name: SIGNAL SOLUTIONS, 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): The basic functions of sleep are still unknown. Abnormal sleep patterns can manifest as a variety of disorders- sleep apnea parasomnias REM (rapid eye movement sleep) behavioral disorder (RBD) narcolepsy-many of which are influenced by heredity. There is an increasing focus on characterizing mouse behaviors for genetic and drug studies. However discovering the genes responsible for sleep and related disorders requires time- consuming large-scale behavioral screening of phenotypes to correlate observed traits with genetics. Behavioral monitoring of mice is usually limited to actigraphic measurements such as video tracking wheel-running and photoelectric beam-breaking. Although many of these methods are noninvasive and have potential for high- throughput (HT) application they monitor mainly locomotor activity without providing information about sleep-wake state and sleep architecture which are important for investigating sleep disorders. While EEG can be used to accurately determine sleep-wake state it is invasive and resource-intensive (surgery recovery etc.) which limits its application in large-scale genetic studies wih rodents. Signal Solutions LLC has developed a sensor cage environment for noninvasive behavioral monitoring that is being used by prominent research groups to identify genes responsible for different traits related to sleep and circadian rhythms. The specific aims of this work are to further improve the capabilities of the piezo system to noninvasively: 1. Discriminate sleep-wake state (sleep/wake REM/NREM) and behavior within wake (e.g. quiet vs. active high activity feeding grooming) to a level comparable to EEG/EMG by classifying piezo signal features with added low-cost video features; 2. Incorporate real-time feedback stimulation for behavior modification 3. Integrate electronics and with new multimodal sensing into a compact system for testing in research laboratories 4. Develop low-cost device for automatic animal welfare monitoring. The envisioned end product is a sensor cage and software interface for HT monitoring of sleep-wake state and behavior in small animals to identify genetic factors responsible for sleep/circadian disorders as well as behavioral effects of pharmacological manipulation sensory stimulation or neural injury (e.g. traumatic brain injury epilepsy). This system will be particularly advantageous for prescreening potentially interesting phenotypes and reserving invasive EEG analysis for further confirmation. Medical targets of interest are sleep/circadian disorders sleep apnea obesity/diabetes REM/NREM sleep deprivation and stress among others. Potential clients include academic research labs as well as industrial labs interested in behavioral monitoring on a large scale (e.g. drug screening).

project_terms:
Affect;Algorithms;Amplifiers;Animal Experimentation;Animal Housing;Animal Welfare;Animals;Behavior;Behavior Disorders;Behavior Therapy;Behavior monitoring;Behavioral;Behavioral Assay;Behavioral Genetics;Behavioral Research;Brain;Circadian Rhythm Sleep Disorders;Circadian Rhythms;Client;Code;Computer Interface;Computer software;Data;Decision Trees;Development;Devices;Diabetes Mellitus;Discrimination;Disease;Electroencephalography;Electronics;Environment;Epilepsy;Evaluation;Event;Feedback;Film;Floor;Genes;Genetic;Genetic Screening;Genetic study;Goals;Government;Grant;Grooming;Health;Heredity;Home environment;Implant;Intervention;Kentucky;Knockout Mice;Label;Laboratory Research;Letters;Measurement;Medical;Methodology;Methods;Modification;Monitor;Motor Activity;Mus;Narcolepsy;Noise;Obesity;Operative Surgical Procedures;Outcome;Pattern;Persons;Pharmaceutical Preparations;Phase;Phenotype;Physiologic pulse;Play;Polysomnography;Power Sources;Preclinical Drug Evaluation;Quantitative Trait Loci;REM Sleep;REM Sleep Parasomnias;Recovery;Research;Resources;Rodent;Role;Running;Sensory;Signal Transduction;Sleep;Sleep Apnea Syndromes;Sleep Architecture;Sleep Deprivation;Sleep Disorders;Sleep Stages;Stress;Structure;System;Systems Integration;Techniques;Testing;Time;Traumatic Brain Injury;Universities;Wakefulness;Work;actigraphy;awake;base;brain research;commercialization;cost;feeding;field study;flexibility;foot;gene discovery;high throughput analysis;improved;interest;meetings;nerve injury;nervous system disorder;novel;pressure;prototype;respiratory;response;screening;sensor;signal processing;somatosensory;success;tool;trait;trend

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Discovery of genes that play a role in sleep and circadian rhythm disorders requires extensive screening of behavior usually in mice preferably with invasive and resource-intensive brain signal (EEG) recordings to score sleep stage (REM NREM) and wake behavior. The goal of this research is to develop and validate a methodology for using a noninvasive pressure-sensitive piezoelectric ("piezo") sensor platform to distinguish different stages of sleep and behavior without the need for EEG making large-scale behavioral screening feasible and limit the need for EEG verification to only the most interesting phenotypes thus identified.


application_id: 9111942
project_number: 5R01GM107586-03
project_title: Light-responsive ruthenium compounds for applications in disease
administering_ic: NIGMS
award_notice_date: 2016-07-28
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: GM
serial_number: 107586
program_official: FABIAN, MILES
project_start_date: 2014-08-01
project_end_date: 2019-07-31
study_section: Synthetic and Biological Chemistry A Study Section[SBCA]
contact_pi_person_id: 8085279
contact_pi: GLAZER, EDITH C
other_pis: Not Applicable
congressional_district: 06
department: CHEMISTRY
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): This proposal seeks to develop a new class of light-responsive inorganic materials as chemotherapeutic agents. Cisplatin and its analogues remain the standard therapy for a variety of cancers despite their nonspecific mechanism of action with nucleic acids resulting in general cytotoxicity and debilitating side-effects. A promising approach that will provide several key advantages is to combine the reactivity of metal- based drugs with the selectivity of photodynamic therapy (PDT) to increase the targeting of malignant tissues and reducing side-effects. We have recently shown that structural distortion can be utilized to promote photochemical reactions to create reactive ruthenium species that are strongly electrophilic and highly photo-toxic in cell based assays. We hypothesize that distortion can be used to control light-activated cytotoxicity for the creation of selective and potent chemotherapeutics. We propose a new class of ruthenium-based compounds that have a readily modifiable modular design to facilitate rapidly incorporation of key molecular components to efficiently develop materials exhibiting selectivity and controlled reactivity. Coordination chemistry will be used to generate a structurally diverse family of three-dimensional chiral ruthenium compounds in a self-assembled manner. The structural variations in the materials will be correlated to cytotoxic efficacy using high-throughput cell survival assays and the most promising compounds will be assessed for Pharmacokinetic (PK) properties Maximum Tolerated Dose (MTD) and efficacy in mouse xenograft models of lung cancer and melanoma. Mechanism of action studies will be used to define the currently unknown process of cell killing. In order to accomplish this aim a novel chemical labeling strategy is proposed to facilitate imaging of the subcellular and potentially sub-organellar localization of active compounds using Electron Microscopy. If successfully validated this approach could be extended to additional imaging applications in tissues. Alternative approaches utilize biotin-labeled ruthenium materials for target pull-down with cellular targets identified through a process of gel electrophoresis chromatography and mass spectrometry. In vitro and in cell transcription and translation assays will support these findings. Cisplatin the benchmark inorganic chemotherapeutic will be used for comparison in all mechanism of action studies. The goal is to determine if the proposed ruthenium materials utilize the same biological target(s) as cisplatin or may be directed to different functional targets via structural modification. Upon completion of these studies we willhave expanded our knowledge of the fundamental photochemistry of ruthenium complexes developed potent and selective cytotoxic chemical entities identified their mechanism of action and developed a new tool for the imaging of small molecules in biological systems. 1

project_terms:
Adverse effects;Animals;Benchmarking;Biological;Biological Assay;Biotin;Cancer cell line;Cell Death;Cell Survival;Cells;Cessation of life;Charge;Chemicals;Chemistry;Chromatography;Cisplatin;Combined Modality Therapy;Complex;DNA;DNA Damage;Development;Disease;Dose-Limiting;Drug Kinetics;Electron Microscopy;Engineering;Exhibits;Family;Genetic Transcription;Goals;Health;Image;Imaging Device;In Vitro;Killings;Knowledge;Label;Lead;Ligands;Light;Malignant - descriptor;Malignant Neoplasms;Malignant neoplasm of lung;Maps;Mass Spectrum Analysis;Maximum Tolerated Dose;Metals;Modality;Modeling;Modification;Molecular;Motivation;Mus;Neutropenia;Nucleic Acids;PUVA Photochemotherapy;Pathway interactions;Patients;Pattern;Pharmaceutical Preparations;Photochemistry;Platinum;Process;Prodrugs;Property;Radiation;Reaction;Resistance;Resistance profile;Resolution;Ruthenium;Ruthenium Compounds;Sampling;Singlet Oxygen;Site;System;Therapeutic;Tissues;Toxic effect;United States;Variant;Xenograft Model;analog;base;biological systems;cancer cell;cancer therapy;cancer type;cell injury;cell killing;cell type;cellular targeting;chemotherapeutic agent;chemotherapy;clinical application;crosslink;cytotoxic;cytotoxicity;design;gel electrophoresis;in vivo;innovation;melanoma;novel;oxidative damage;pre-clinical trial;screening;small molecule;systemic toxicity;targeted agent;translation assay;tumor

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Cisplatin received FDA approval in 1978 for the treatment of cancer and despite producing a wide range of debilitating side-effects; it is still one of the most prescribed chemotherapeutics today. With over 500000 cancer-related deaths in the United States each year it is essential to develop new broadly applicable therapeutic treatments for this disease. This proposal develops ruthenium materials as selective and potent chemotherapeutic agents that reduce off target toxic effects by acting as cytotoxic species only in a spatially controlled manner when "turned on" by light.


application_id: 9111810
project_number: 5R21CA184573-03
project_title: A novel multi-targeted therapy for breast cancer resistance
administering_ic: NCI
award_notice_date: 2016-06-15
opportunity_number: PA-14-078
application_type: 5
activity_code: R21
ic: CA
serial_number: 184573
program_official: YOVANDICH, JASON L
project_start_date: 2016-02-01
project_end_date: 2020-06-30
study_section: ZCA1-RTRB-E(M1)
contact_pi_person_id: 7799129
contact_pi: BROUXHON, SABINE M
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): Over the last decade the most significant revolutionary advances in breast oncology have been the FDA approval of targeted therapies against growth factor receptors including the human epidermal growth factor receptors (HER1 and HER2) and drugs for hormone-receptor-positive disease. However despite such encouraging results patients that are initially responsive to these drugs eventually become resistant within one year of therapy. Multiple mechanisms responsible for resistance have been proposed including compensatory crosstalk with alternate receptor tyrosine kinases (i.e. HER1-4 IGF-1R) hyper-activation of downstream MAPK-PI3K/Akt/mTOR signaling activation of the inhibitor of apoptotic proteins (IAPs) and inactivation of PTEN and p53.  We have identified soluble E-cadherin (sEcad) as a novel therapeutic target and have developed monoclonal antibodies targeting sEcad as an innovative therapy that directly kills cancer cells spares normal cells and overcomes these host resistance pathways. Therefore in this grant application we propose to first narrow down which HER or non-HER receptors (or combinations) are involved in the efficacy of our antibody- based therapy. We then will test whether combinatorial strategies involving HER or non-HER inhibitors that act via different mechanism(s) of action than our antibody may act additively or synergistically to suppress tumor growth and dissect some of the mechanism(s) involved. Lastly we propose to complement our antibody with a panel of PD markers so as to ensure that the antibody is exerting its intended biologic outcome and perform preliminary studies to confirm no off-target effects. Altogether we believe that our innovative therapy will make substantial strides in cure rates and in progression-free survival of patients with HER and non-HER-positive breast cancers that progress beyond targeted or other conventional therapies.

project_terms:
Address;Adjuvant Chemotherapy;Antibodies;Antigens;Antineoplastic Agents;Apoptosis;Apoptotic;Applications Grants;Binding;Breast Cancer Cell;Breast Oncology;Cell Death;Cell Proliferation;Cells;Complement;Data;Disease;Disease-Free Survival;Down-Regulation;E-Cadherin;ERBB2 gene;Endocytosis;Ensure;Epidermal Growth Factor Receptor;Exhibits;FRAP1 gene;Family member;Growth Factor Receptors;Health;Hormone Receptor;Host resistance;Human;In Vitro;Innovative Therapy;Killings;Length;Ligands;Link;MAP Kinase Gene;MCF7 cell;MEKs;Mammary Neoplasms;Mediating;Monoclonal Antibodies;Monoclonal Antibody Therapy;Mouse Mammary Tumor Virus;Mus;Neoplasm Metastasis;Normal Cell;Normal tissue morphology;Oncogenes;Oncogenic;Organ;Outcome;PTEN gene;Pathway interactions;Patients;Pharmaceutical Preparations;Predisposition;Progression-Free Survivals;Proteins;Ras/Raf;Receptor Protein-Tyrosine Kinases;Recurrence;Relapse;Resistance;Resistance development;SKBR3;Safety;Signal Transduction;Signaling Protein;Site;Specimen;TP53 gene;Tamoxifen;Testing;Transgenic Mice;Transmembrane Domain;Trastuzumab;Tumor Burden;Xenograft procedure;base;cancer cell;combinatorial;conventional therapy;crosslink;cytotoxicity;extracellular;hormone therapy;in vivo;ineffective therapies;inhibitor/antagonist;innovation;lapatinib;mTOR Inhibitor;malignant breast neoplasm;migration;neoplastic cell;new therapeutic target;novel;novel anticancer drug;pro-apoptotic protein;receptor;response;targeted treatment;therapeutic development;therapeutic effectiveness;tumor;tumor growth

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The most significant revolutionary advances in breast oncology have been the FDA approval of targeted therapies against the human epidermal growth factor receptors (HER1 and HER2) and therapies for hormone- receptor-positive disease. However despite an initial positive response to these therapies the majority of patient's exhibit resistance - rendering the therapy ineffective within one year of treatment. Thisproject will test an innovative antibody-based therapy that successfully inhibits many of these resistance pathways and kills resistant cells - without exhibiting any untoward cytotoxicity to normal cells.


application_id: 9111785
project_number: 5K01AG040164-05
project_title: Neuroimaging Assessments of Brain Integrity in Aging Mice
administering_ic: NIA
award_notice_date: 2016-07-05
opportunity_number: PA-14-078
application_type: 5
activity_code: K01
ic: AG
serial_number: 040164
program_official: WISE, BRADLEY C
project_start_date: 2014-07-01
project_end_date: 2017-06-30
study_section: Basic Neuroscience of Aging Study Section[NIA-N]
contact_pi_person_id: 10518078
contact_pi: LIN, AI-LING
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 long-term goal of my research career is to use state-of-the-art non-invasive brain imaging methods (magnetic resonance imaging and spectroscopy (MRI/MRS) and positron emission tomography (PET)) to assess brain metabolic hemodynamic and neuronal (structural and functional) integrity and its associations with cognitive function in animal models of healthy aging and of age-related neurodegenerative disorders. The goals of my training program are: 1) to "reversely translate" the neuroimaging methods for assessing hemodynamics and metabolism from humans to rodent models; 2) to receive training in the biology of aging using rodent models with an emphasis on metabolic physiology; 3) to apply these newly found skills to the investigation of the mechanisms of action of aging and potential protective effects of caloric restriction (CR); and 4) to have hands-on training in behavioral testing for rodents and identify the association between imaging and behavioral results. The research objective of this proposal is to use high-field MRI/MRS and PET to investigate the brain integrity of aging mice and identify possible protective effects of CR.  In the brain mitochondrial oxidative phosphorylation of glucose is the predominant source of energy (ATP production) supporting energy demands (maintaining neuronal integrity and basal firing rates). A widely accepted cause of the functional losses that accompany aging both in the brain and in other organs is decreased brain metabolism. In support of this viewpoint a host of neuroimaging studies show that cerebral metabolic rates of oxygen (CMRO2) glucose (CMRGlc) and cerebral blood flow (CBF) decline with age and decline still more rapidly and profoundly in neurodegenerative disorders such as Alzheimer's Disease (AD). It is generally believed therefore that preserving bioenergetics (i.e. glucose oxidative capacity) is critical fr optimizing lifespan and healthspan. Interventions have been introduced to preserve metabolism in aging process. CR perhaps is the most well-studied one for various model organisms of extended longevity including Saccharomyces cerevisiae Caenorhabditis elegans rodents and monkeys. In the neuronal system CR has shown to attenuate age-related metabolic dysfunction and neuromuscular synaptic loss and to enhance cognitive function.  The rationale of the study therefore is to characterize the effect of CR on in vivo brain metabolic hemodynamic and neuronal (structural and functional) integrity in aging using non-invasive multimodal neuroimaging methods and the association of the neuroimaging indices with the cognitive testing. The central hypothesis of this proposal is that cerebral metabolic function will decline i normal aging and consequently reduce brain structural functional and cognitive integrity; mice with CR intervention will demonstrate: preserved CMRO2 CBF CMRGlc total ATP concentration; and thus preserved brain structure functional connectivity and cognition during aging. The hypothesis will be tested by pursuing three specific aims: 1) Determine effects of normal aging on brain metabolic and hemodynamic integrity and possible protective effects of CR; 2) Determine effects of normal aging on neuronal (structural and functional) integrity and possible protective effects of CR; and 3) Determine effects of normal aging on cognitive integrity and possible protective effects of CR. The approach is innovative because it investigates the CR protective effect on in vivo brain metabolism in aging process with non-invasive neuroimaging methods; it uses complementary multi- parametric non-invasive imaging methods (MRI MRS and PET) to explore the physiological effects of mitochondrial alterations for the first time; it uses quantitative imaging techniques (developed by the PI for humans) at ultra-high field (11.7T) and in rodents the first time this has been done; and it willbe the first study to investigate the correlation between cognitive effects (memory and spatial information processing) and brain imaging results in the CR mouse model. The proposed research is significant because 1) physiological effects of metabolic alterations in aging and age-related neuronal disorders disease progression and treatment efficacy can be monitored non-invasively and nondestructively; 2) the interplay between brain metabolic structural and cognitive functions in aging can be identified; and 3) these multi-metric imaging methods can be translated seamlessly from rodents to non-human primates and to humans.  Collectively the training provide by the Career Development Award will place me at the cutting edge of aging research of animal neuroimaging and of their combination: translational neuroimaging of aging. Translational neuroimaging is an emerging field with extraordinary promise. My ambition is to become pioneer in this emerging discipline.

project_terms:
Age;Age-Months;Aging;Aging-Related Process;Alzheimer's Disease;Animal Experimentation;Animal Model;Area;Atrophic;Attenuated;Behavioral;Biochemical Pathway;Bioenergetics;Biological Preservation;Biology of Aging;Brain;Brain imaging;Brain region;Caenorhabditis elegans;Caloric Restriction;Cerebrovascular Circulation;Cerebrum;Cognition;Cognitive;Discipline;Disease;Disease Progression;Dopamine D2 Receptor;Energy-Generating Resources;Exhibits;Functional disorder;Glucose;Glutamates;Goals;Health;Hippocampus (Brain);Human;Image;Imaging Techniques;Impaired cognition;Intervention;Investigation;K-Series Research Career Programs;Learning;Life;Longevity;Magnetic Resonance Imaging;Measurement;Measures;Memory;Metabolic;Metabolism;Methods;Mitochondria;Monitor;Monkeys;Mus;Neurodegenerative Disorders;Neurons;Organ;Outcome;Oxidative Phosphorylation;Oxygen;Performance;Physiological;Physiology;Positron-Emission Tomography;Production;Prosencephalon;Published Comment;Research;Resolution;Rest;Rodent;Rodent Model;Saccharomyces cerevisiae;Structure;Synapses;System;Technology;Testing;Time;Training;Training Programs;Translating;Treatment Efficacy;age related;aged;aging brain;anti aging;behavior test;brain metabolism;brain volume;career;cognitive function;cognitive testing;functional loss;gray matter;healthy aging;hemodynamics;imaging modality;in vivo;indexing;information processing;innovation;interest;metabolic rate;morris water maze;mouse model;neuroimaging;neuromuscular;non-invasive imaging;nonhuman primate;normal aging;protective effect;quantitative imaging;skills;spatial memory;spectroscopic imaging;white matter

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The purpose of the study is to use multimodal neuroimaging methods (PET MRI and MRS) to investigate the brain integrity of aging mice and identify possible protective effects of caloric restriction (CR). The findings from the study will advance our understanding on the interplay between brain metabolic structural and cognitive functions in aging. In addition brain metabolism observed in long-lived animal models (e.g. with CR) might predict positive cognitive outcomes in humans. The findings are thus expected to be applicable to the health of human beings especially for aging and age-related neurodegenerative disorders.


application_id: 9111184
project_number: 3T32ES011564-10S2
project_title: UofL Environmental Health Sciences Training Program
project_terms: Environmental Health;Training Programs
administering_ic: NIEHS
award_notice_date: 2015-08-07
opportunity_number: PA-06-468
application_type: 3
activity_code: T32
ic: ES
serial_number: 011564
suffix: S2
program_official: SHREFFLER, CAROL A
project_start_date: 2004-07-01
project_end_date: 2016-06-30
study_section: Environmental Health Sciences Review Committee[EHS(T2)]
contact_pi_person_id: 1924912
contact_pi: HEIN, DAVID W
other_pis: Not Applicable
congressional_district: 03
department: PHARMACOLOGY
primary_duns: 057588857
primary_uei: E1KJM4T54MK6
duns_number: 057588857
uei: E1KJM4T54MK6
fips: US
organization_id: 4679701
organization_name: UNIVERSITY OF LOUISVILLE
organization_city: LOUISVILLE
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 402920001
project_abstract:
We have made strategic changes in our environmental health sciences training program in response to theannounced restructuring and redirection of NIEHS training programs. Participating Centers Institutes andSchools and the 43 members of the training faculty provide critical resources for cutting edge basic scienceclinical research computational sciences and public health. Environmental health science partnerships haveresulted in a very successful NIEHS training program in environmental health sciences and recently in thefunding of a NIEHS P30 Center for Environmental Genomics and Integrative Biology (CEGIB). Our renewalproposal incorporates and integrates several new Schools Centers and Institutes including CEGIB theClinical and Translational Sciences Institute and the School of Public Health and Information Sciences. Wepropose a substantially improved predoctoral and postdoctoral training program that serves as an umbrellafor interdisciplinary and integrated approaches to environmental health sciences. The training program willsupport six predoctoral and three postdoctoral trainees. Initial student recruitment and funding forpredoctoral trainees is provided by the University of Louisville Integrated Programs in the BiomedicalSciences recruitment gateway. As in the first cycle predoctoral trainees will not be recruited directly into theenvironmental health sciences training program. All faculty mentors are asked to nominate trainees whohave completed an approved dissertation proposal with a defined focus in environmental health sciencesresearch. Faculty mentors will be asked to nominate either existing postdoctoral fellows (for example thosealready matriculated into the Clinical Chemistry and Toxicology Translational Sciences Program) or fromtrainees to be recruited. Teams of mentors (basic and clinical scientists or basic and population-basedscientists) will be particularly encouraged to emphasize the importance of multidisciplinary training andtranslation of basic science findings to the patient and/or community. Our training program facilitates multi-disciplinary approaches for effective intervention and interfaces exceptionally well with the NIH Roadmap aswell as with the strategic plans of NIEHS and the University of Louisville.RELEVANCE (Seeinstructions):The environmental health problems faced by the nation are multi-factorial in nature and therefore requiremulti-disciplinary approaches for effective intervention. Our training program emphasizes the importance ofmultidisciplinary training and translation of basic science findings to benefit the patient and/or community.This multi-disciplinary translational program interfaces with the NIH Roadmap and the NIEHS strategic plan.


application_id: 9110959
project_number: 5R01DK048498-21
project_title: Mechanistic Impact of PI3K/mTOR Signaling on Intestinal Homeostasis
administering_ic: NIDDK
award_notice_date: 2016-06-21
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: DK
serial_number: 048498
program_official: SERRANO, JOSE
project_start_date: 1996-03-15
project_end_date: 2020-05-31
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_terms:
3-hydroxy-3-methylglutaryl-coenzyme A;Atrophic;Biochemistry;Biometry;Cell Differentiation process;Cell Proliferation;Cell model;Cells;Colorectal Cancer;Complex;Deacetylase;Development;Enterocytes;Enteroendocrine Cell;Enzymes;Event;Excision;FRAP1 gene;Glycolysis;Goals;Goblet Cells;Grant;Growth;Health;Histones;Human;Hydroxybutyrates;In Vitro;Inflammatory Bowel Diseases;Intestinal Mucosa;Intestines;Ketone Bodies;Lead;Maintenance;Mediating;Metabolic;Metabolism;Molecular;Morbidity - disease rate;Mus;Operative Surgical Procedures;Organoids;Paneth Cells;Pathology;Pathway interactions;Phenotype;Play;Process;Protein Isoforms;Proteins;Publishing;Regulation;Role;Signal Pathway;Signal Transduction;Sirtuins;Stem cells;Stress;System;Testing;Time;Transgenic Mice;Tuberous sclerosis protein complex;Villus;base;beta-Hydroxybutyrate;cell type;clinically relevant;design;in vivo;inhibitor/antagonist;insight;intestinal homeostasis;ketogenesis;ketogentic;mTOR Signaling Pathway;mTOR inhibition;metabolomics;migration;mortality;mouse model;multidisciplinary;novel;novel therapeutic intervention;nuclear factors of activated T-cells;research study;stable isotope


application_id: 9110476
project_number: 1R21AI119557-01A1
project_title: Elucidating the Biogenesis of the Yersinia pestis Containing Vacuole
administering_ic: NIAID
award_notice_date: 2016-02-29
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: AI
serial_number: 119557
suffix: A1
program_official: MUKHOPADHYAY, SUMAN
project_start_date: 2016-03-01
project_end_date: 2018-02-28
study_section: Special Emphasis Panel[ZRG1 IDM-B (80)]
contact_pi_person_id: 8061232
contact_pi: LAWRENZ, MATTHEW B
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
project_abstract:
DESCRIPTION (provided by applicant): Yersinia pestis is a facultative intracellular pathogen that causes the disease known as plague. Growing evidence indicates that intracellular growth in macrophages is important for Y. pestis virulence. Upon phagocytosis Y. pestis alters the maturation of the phagosome to generate a protective compartment within the cell known as the Yersinia containing vacuole (YCV). Key steps in the generation of the YCV include inhibition of YCV acidification expansion into a spacious vacuole and acquisition of the autophagic markers. However the mechanisms used by the bacterium to subvert the normal phagosome maturation process and generate the YCV have not been defined. Recently we have identified a subset of host Rab GTPases that are required for Y. pestis to survive within macrophages. Because Rab proteins are key mediators of vesicular trafficking phagosome maturation and autophagy we hypothesize that these GTPases are required by Y. pestis to subvert phagosome maturation and generate the YCV thus protecting the bacterium from macrophage clearance. As Rab proteins mediate many aspects of vesicular trafficking through direct interactions with specific organelles and recruitment of effector proteins in Aim 1 we will determine if Rab GTPase required for Y. pestis intracellular survival are specifically recruited to the YCV. In Aim 2 we will determine the contribution of individual Rab proteins on the biogenesis of the YCV. These studies will be the first to define the contribution of host Rab GTPases to the formation of the YCV. Ultimately understanding the YCV biogenesis process will enable us to identify Y. pestis pathogenicity factors that contribute to intracellular survival.

project_terms:
Acute;Autophagocytosis;Autophagosome;Bacteria;Biogenesis;Bubonic Plague;Cells;Comprehension;Confocal Microscopy;Data;Development;Disease;Electron Microscopy;Exclusion;Generations;Goals;Growth;Guanosine Triphosphate Phosphohydrolases;Immune;Individual;Infection;Integration Host Factors;Killings;Life;Lysosomes;Mediating;Mediator of activation protein;Membrane;Molecular;Organelles;Pathogenesis;Phagocytosis;Phagolysosome;Phagosomes;Plague;Play;Process;Proteins;RNA Interference;Recombinant Proteins;Recruitment Activity;Role;Staging;Testing;Time;Transmission Electron Microscopy;Vacuole;Virulence;Virulence Factors;Work;Yersinia;Yersinia pestis;base;combat;defined contribution;design;human disease;improved;knock-down;macrophage;novel therapeutic intervention;novel vaccines;pathogen;public health relevance;rab GTP-Binding Proteins;trafficking

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Yersinia pestis is the causative agent of plague an acute human disease and potential bioweapon. The work proposed here will define the role of host Rab GTPases in biogenesis of an intracellular niche which protects Y. pestis from macrophage killing. Understanding the interactions between Y. pestis and macrophages will provide a broader understanding of Y. pestis pathogenesis which may impact the design of new vaccine and therapeutic approaches to combat plague infections.


application_id: 9110452
project_number: 1R21DE025345-01A1
project_title: Nanoparticle delivery vehicles targeting P. gingivalis
administering_ic: NIDCR
award_notice_date: 2016-08-31
opportunity_number: PA-13-303
application_type: 1
activity_code: R21
ic: DE
serial_number: 025345
suffix: A1
program_official: LUNSFORD, DWAYNE
project_start_date: 2016-09-01
project_end_date: 2018-08-31
study_section: Oral, Dental and Craniofacial Sciences Study Section[ODCS]
contact_pi_person_id: 1859425
contact_pi: DEMUTH, DONALD R
other_pis: STEINBACH-RANKINS, JILL
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
project_abstract:
DESCRIPTION (provided by applicant):  Porphyromonas gingivalis is strongly associated with adult periodontitis a widespread and costly disease that is primarily manifest in the oral cavity but also associated with systemic diseases such as atherosclerosis and rheumatoid arthritis. The adherence of P. gingivalis to commensal organisms such as Streptococcus gordonii facilitates the initial colonization of the oral cavity by P. gingivalis and our prior work identifed a peptide that potently inhibits this interaction. The main goal of this application is to develop ne nanoparticle (NP) delivery vehicles that will deliver high localized concentrations of the peptide for prolonged periods of time to sites in the oral cavity that are colonized by P. gingivalis. Two approaches will be used. Aim 1 will generate NPs that are surfacemodified with the peptide in order increase effectiveness of the peptide by facilitating multivalent interactions with P. gingivalis. The potency of the modified NPs will be compared to soluble peptide using established in vitro biofilm models and an in vivo animal model of periodontitis. In Aim 2 we will
initially synthesize sustained release NPs that encapsulate the peptide. The load and release properties of the NPs will be optimized such that NPs will release an inhibitory concentration of the peptide for at least 24 hrs. Once NPs with the desired release properties are obtained they will be surface modified with the CafA protein which mediates coaggregation of Actinomyces with S. gordonii. The efficiency of NP adherence to streptococci will be determined and the function of sustained release NPs will be assessed using both in vitro biofilm models and a mouse model of periodontitis. It is anticipated that by targeting sustained release NPs to streptococci the peptide will be delivered and released into a niche in the oral biofilm that is normally occupied by P. gingivalis thus increasing the effectiveness of the peptide inhibitor.

project_terms:
Actinomyces;Adherence;Adult;Animal Model;Antigens;Atherosclerosis;Bolus Infusion;Development;Disease;Drug Delivery Systems;Effectiveness;Encapsulated;Environment;Event;Glycolates;Goals;Heart Diseases;Homeostasis;Human;I-antigen;In Vitro;Infection;Inflammation;Mediating;Methods;Microbe;Microbial Biofilms;Minor;Modeling;Mouth Diseases;Nanotechnology;Oral;Oral cavity;Organism;Peptides;Periodontitis;Physiological;Population;Porphyromonas gingivalis;Property;Prophylactic treatment;Proteins;Reagent;Rheumatoid Arthritis;Site;Streptococcus;Streptococcus gordonii;Surface;System;Systemic disease;Therapeutic;Therapeutic Agents;Therapeutic Intervention;Time;Tissues;Virulence;Work;compare effectiveness;density;improved;in vivo;in vivo Model;inhibitor/antagonist;mouse model;nanoparticle;novel;novel therapeutics;oral biofilm;oral microbiome;oral streptococci;pathogen;prevent;public health relevance;research clinical testing;subgingival biofilm;targeted treatment

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  Porphyromonas gingivalis is strongly associated with adult periodontitis a common oral disease that is present in up to 40% of the adult population and with systemic illnesses such as heart disease and rheumatoid arthritis. We have discovered a peptide that inhibits the colonization of the oral cavity by P. gingivalis. This study will use nanotechnology to develop new drug delivery vehicles that will deliver higher amounts of this peptide to sites in the oral cavity that are commonly occupied by P. gingivalis. It is anticipated that the effectiveness of the peptide to reduce periodontitis and limit P. gingivalis colonization will be improved if it can be delivered in greater amounts and for longer periods of time.


application_id: 9110328
project_number: 5R01HL127682-02
project_title: Specific Lysis for Large-Volume High-Purity Endothelial Progenitor Cell Isolates
administering_ic: NHLBI
award_notice_date: 2016-04-25
opportunity_number: PAR-13-137
application_type: 5
activity_code: R01
ic: HL
serial_number: 127682
program_official: LEE, ALBERT
project_start_date: 2015-07-15
project_end_date: 2019-04-30
study_section: Instrumentation and Systems Development Study Section[ISD]
contact_pi_person_id: 10218003
contact_pi: BERRON, BRADLEY JOSEPH
other_pis: Not Applicable
congressional_district: 06
department: ENGINEERING (ALL TYPES)
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: BIOMED ENGR/COL ENGR/ENGR STA
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION:  Ischemic heart disease is the primary cause of death in both men and women globally. Ischemic heart conditions including angina and myocardial infarction are characterized by loss of blood flow to the heart tissue and reduced cardiac function both reducing quality of life and increasing mortality. Improved recovery of cardiac function following a myocardial infarction has been observed in several studies upon the injection of high concentrations of endothelial progenitor cells (EPCs) to the ischemic area. Multiple types of EPCs have been shown to play pivotal roles in the formation of new blood vessels and are promising candidates for accelerated and increased repair of ischemic tissues. Follow up studies indicate both high purity and quantity of EPCs are critical to recovery of function yet current technologies for sorting of EPCs are incapable of isolating these cells in the purity and speed required for widespread clinical use. This research grant will develop a novel technique for the isolation of EPCs which yields a high-purity isolate at high throughput. The developed technology Antigen Specific Lysis (ASL) is capable of being performed in a typical research lab setting where batches exceeding 200 mL (>1010 cells) are completed in under an hour. The proposed work will develop high speed selection modalities for the isolation of high purity functional EPCs. ASL uses targeted coatings to selectively protect EPCs while all other cells are lysed. Preliminary results demonstrate 1) antibody- initiator conjugates are capable of selectively forming a ~100 nm polymer coating on the exterior of only antigen expressing cells 2) these coatings stabilize cells in harsh environments (5% SDS) and 3) viable cells are released at high purity (>99% purity for antigen positive cells spiked into blood). This research grant drives new advances in wavelength specific polymerization and degradation for the selective protection of targeted cells and the subsequent release of cells with increased viabilityand proliferative capacity. Sequential selection for CD133+ and CD34+ cells is expected yielding a >99% pure population of EPCs. This system will also have the capability to process multiple smaller batches at one time using only standard disposable labware for cell- contacting materials. Finally the functional properties of clinically-relevant EPC populations isolated fluorescently or by ASL will be evaluated through in vitro and in vivo assays. ASL shows considerable promise as a powerful isolation technique that can be applied both clinically for the treatment of acute myocardial infarctions and in individual research settings for the analysis of rare cellular species in blood. This project is significant because in-lab isolation of large volums of cells will enable the widespread use of EPC therapy for improved cardiac function following acute myocardial infarctions. Future directions of this work include the use of ASL in the isolation of other rare cell populations (other progenitor cells circulating tumor cells) emergingin clinical research diagnostics prognostics and treatment.

project_terms:
Acute myocardial infarction;Antibodies;Antigens;Area;Automobile Driving;Biological;Biological Assay;Biological Preservation;Blood;Blood Vessels;Blood flow;CD34 gene;Capital;Cardiac;Cause of Death;Cell Separation;Cell Therapy;Cells;Clinical;Clinical Research;Cytolysis;Data;Deterioration;Diagnostic;Environment;Follow-Up Studies;Future;Goals;Growth;Health;Heart;Home environment;Hour;In Vitro;Individual;Injection of therapeutic agent;Leukocytes;Life;Light;Magnetism;Medical;Methodology;Methods;Modality;Morbidity - disease rate;Mus;Myocardial Infarction;Myocardial Ischemia;Neoplasm Circulating Cells;Patients;Perfusion;Play;Polymers;Polystyrenes;Population;Procedures;Process;Property;Quality of life;Recovery;Recovery of Function;Research;Research Project Grants;Risk;Role;Sampling;Science;Site;Sorting - Cell Movement;Source;Speed;Stem cells;Sterilization;System;T-Lymphocyte;Technical Expertise;Techniques;Technology;Time;Tissues;Training;Translations;Tube;Umbilical Cord Blood;Woman;Work;base;cell type;clinical application;clinically relevant;cost;hospital laboratories;improved;in vivo;irradiation;magnetic beads;matrigel;men;migration;mortality;new technology;novel;novel strategies;peripheral blood;polymerization;prognostic;prototype;repaired;scale up;subcutaneous;time use

public_health_relevance:
PUBLIC HEALTH RELEVANCE:  This project develops a new approach to isolating a rare type of cell capable of repairing heart damage. This approach promises to deliver cells with fewer contaminants faster and at a lower cost than is possible today. This technology is also expected to both accelerate and reduce the cost of research across a broad spectrum of biological and medical sciences.


application_id: 9110311
project_number: 5R01GM105977-03
project_title: Exploring Post-Type II PKS Frame Modifications
administering_ic: NIGMS
award_notice_date: 2016-07-20
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: GM
serial_number: 105977
program_official: FABIAN, MILES
project_start_date: 2014-09-10
project_end_date: 2018-07-31
study_section: Synthetic and Biological Chemistry B Study Section[SBCB]
contact_pi_person_id: 2257319
contact_pi: ROHR, JURGEN T
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 have a major impact on drug discovery. They have contributed to approximately 50% of new chemical entities between 1940 and 2006 because they offer a unique richness in structural skeletons combined with a high degree of chirality that has the potential to selectively match bio-receptors. Natural products have been particularly useful for the treatment of cancer and infectious diseases nonetheless new drugs are urgently needed because current drug regimens inevitably lose their effectiveness due to resistance mechanisms. Many important natural product drugs are generated by polyketide synthases (PKS multiple enzyme complexes) and various frame-modifying reactions called post-PKS tailoring steps. Type II PKSs assembling multicyclic aromatic intermediates together with the respective tailoring enzymes are responsible for the generation of important drugs such as the clinically used tetracycline antibiotics or anthracycline and aureolic acid anticancer drugs. While type II PKSs are well studied the post-PKS steps are much less understood although the frame modifying enzymes typically render an inert scaffold into a bioactive drug. The primary goal of this proposal is to functionally and mechanistically characterize uniquely reacting and organized frame modifying post-PKS enzymes involved in the biosynthesis of anticancer polyketide drugs of the angucycline and aureolic acid groups. It is our expectation that uncovering the molecular details of catalysis willhelp to evolve these critical enzymes so that they can be exploited to modify type II PKS scaffolds. This could lead to novel second-generation 'unnatural' natural products and/or derivatives of natural products via combinatorial biosynthesis mutasynthesis or chemo-enzymatic synthetic strategies. The studies also will help to generate new mithramycin and gilvocarcin analogues that will be useful to further study and steer the interactions of these drugs with their recently discovered specific targets.

project_terms:
Address;Anabolism;Anthracyclines;Antibiotics;Antineoplastic Agents;Biochemical;Biological;Catalysis;Characteristics;Chemicals;Chemotherapy-Oncologic Procedure;Clinical;Collaborations;Communicable Diseases;Complex;Development;Drug Interactions;Effectiveness;Engineering;Enzyme Interaction;Enzymes;Epirubicin;Event;Evolution;Future;Generations;Goals;Health;In Vitro;Investigation;Kentucky;Laboratories;Lead;Malignant Neoplasms;Methods;Methylation;Michigan;Modeling;Modification;Molecular;Multienzyme Complexes;National Institute of Diabetes and Digestive and Kidney Diseases;Natural Product Drug;Natural Products;Nature;Oxidoreductase;Oxygenases;Parents;Pathway interactions;Pharmaceutical Preparations;Pharmacotherapy;Pharmacy facility;Plicamycin;Proteins;Reaction;Recombinant Proteins;Regimen;Resistance;Side;Skeleton;System;Tetracyclines;United States National Institutes of Health;Universities;Vertebral column;Work;analog;antineoplastic antibiotics;base;cancer therapy;catalyst;chemotherapy;college;combinatorial;cost;drug discovery;drug synthesis;expectation;glycosylation;glycosyltransferase;improved;interest;member;novel;novel therapeutics;overexpression;polyketide synthase;protein structure;receptor;resistance mechanism;scaffold;screening;tigecycline;tool;transamination

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed work aims to study key enzymes and enzyme complexes of the type II post-polyketide synthase (PKS) machinery found in the biosynthesis of natural product anticancer drugs which are essential to turn primary polyketide scaffolds into bioactive drugs. Uncovering the molecular details of catalysis will help to evolve these critical enzymes so that they can be exploited to modify primary PKS scaffolds. This could lead to novel second-generation 'unnatural' natural products and/or derivatives of natural products via combinatorial biosynthesis mutasynthesis or chemo-enzymatic synthetic strategies. The studies also will help to generate new mithramycin and gilvocarcin analogues that will be useful to further study and steer the interactions of these drugs with their recently discovered specific targets.


application_id: 9109680
project_number: 5R01HL123358-02
project_title: A novel mechanism for ART-associated dyslipidemia and atherosclerosis
administering_ic: NHLBI
award_notice_date: 2016-05-13
opportunity_number: PA-13-302
application_type: 5
activity_code: R01
ic: HL
serial_number: 123358
program_official: FLEG, JEROME L
project_start_date: 2015-08-01
project_end_date: 2019-05-31
study_section: AIDS Discovery and Development of Therapeutics Study Section[ADDT]
contact_pi_person_id: 8880095
contact_pi: ZHOU, CHANGCHENG
other_pis: Not Applicable
congressional_district: 06
department: NUTRITION
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF MEDICINE
organization_zip: 405260001
organization_country: UNITED STATES
arra_indicator: N
project_abstract:
DESCRIPTION (provided by applicant): The rise in long-term HIV survivorship as a result of the introduction of effective antiretroviral therapy (ART) over the past decades has generated new awareness of the sequelae of both HIV infection and of the therapeutics used to treat HIV patients. Accumulating evidence of comorbidities associated with HIV infection and treatment with antiretroviral (ARV) drugs includes significant dyslipidemia and elevated risk of developing atherosclerotic cardiovascular disease (CVD). The goal of this project is to investigate a novel mechanism of ART-associated dyslipidemia and cardiovascular disease (CVD). Several ARV drugs have been identified as potent agonists for the pregnane X receptor (PXR) a nuclear receptor activated by numerous drugs xenobiotic and dietary chemicals. PXR functions as a xenobiotic sensor that induces expression of genes required for xenobiotic metabolism in the liver and intestine. In the past decade the function of PXR in the regulation of drug and xenobiotic metabolism has been extensively studied by many laboratories and the role of PXR as a xenobiotic sensor has been well established. We have recently revealed the pro-atherogenic effects of PXR in animal models and demonstrated that chronic PXR activation induces hyperlipidemia in wild-type mice and increases atherosclerosis in atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice. Preliminary studies demonstrated that HIV protease inhibitor amprenavir activates PXR and induces hyperlipidemia in wild- type mice but not in PXR-deficient mice; furthermore follow-up study of currently used first-line ARV drugs subsequently found that these drugs activated PXR and induced PXR-mediated gene expression. The goal of this project is to generate novel mechanistic insights into ART-associated dyslipidemia and risk of CVD. Our central hypothesis is that long-term treatment with ARV drugs that activate PXR will lead to aberrant lipid homeostasis and accelerated atherosclerosis. We propose the following specific aims to test this hypothesis: 1) Determine the contribution of PXR towards the adverse effects of currently recommended ARV drugs on lipid homeostasis; 2) Define the molecular mechanisms through which PXR agonistic ARV drugs induce hyperlipidemia; and 3) Determine the impact of ARV drug-mediated PXR activation on macrophage functions and atherosclerosis development. These studies will provide critical mechanistic insights and new understandings of ART-associated dyslipidemia and CVD risk and will have direct clinical consequences for patients undergoing long-term treatment with PXR agonistic drugs.

project_terms:
Adverse effects;Agonist;Amprenavir;Animal Model;Anti-Retroviral Agents;Apolipoprotein E;Arterial Fatty Streak;Atherosclerosis;Awareness;CD36 gene;Cardiovascular Diseases;Cells;Chemicals;Cholesterol;Chronic;Clinical;Comorbidity;Development;Diet;Disease;Dose;Dyslipidemias;Foam Cells;Gene Expression;Generations;Goals;HIV;HIV Infections;HIV Protease Inhibitors;HIV therapy;Health;Heart;Homeostasis;Hyperlipidemia;In Vitro;Individual;Infection;Inflammation;Intestines;Knockout Mice;Laboratories;Lead;Lipids;Liver;Long-Term Survivors;Longevity;Lopinavir;Mediating;Modeling;Molecular;Morbidity - disease rate;Mus;Nuclear Receptors;Pathway interactions;Patients;Pharmaceutical Preparations;Pilot Projects;Protease Inhibitor;Receptor Activation;Regulation;Risk;Ritonavir;Role;SXR receptor;Signal Pathway;Testing;Therapeutic Uses;Wild Type Mouse;Xenobiotic Metabolism;Xenobiotics;absorption;antiretroviral therapy;atherogenesis;base;cardiovascular disorder risk;cholesterol transporters;defined contribution;drug metabolism;efavirenz;follow-up;in vivo;insight;macrophage;mortality;mouse model;non-nucleoside reverse transcriptase inhibitors;novel;pregnane X receptor;receptor function;research study;scavenger receptor;sensor;survivorship;uptake

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Infection with HIV is known to elevate the risk for serious heart and arterial disease. With the advent of new generations of drugs for HIV infection the number of long-term HIV-infected patients has brought new recognitions of drug-related side effects including altered lipid profiles and even more greatly increased risk for heart and arteril disease. This study will provide important new information about the impact of HIV therapy on cardiovascular disease in patients undergoing long-term treatment with these drugs.


application_id: 9109168
project_number: 3R03DK101705-02S1
project_title: Reducing Diabetes Risk for Rural Appalachian Grandparent Headed Households
administering_ic: NIDDK
award_notice_date: 2015-08-03
opportunity_number: PAR-13-074
application_type: 3
activity_code: R03
ic: DK
serial_number: 101705
suffix: S1
program_official: AGODOA, LAWRENCE Y
project_start_date: 2014-07-01
project_end_date: 2017-11-30
study_section: ZDK1-GRB-9(J1)S
contact_pi_person_id: 8003903
contact_pi: HATCHER, JENNIFER
other_pis: Not Applicable
congressional_district: 06
department: NONE
primary_duns: 939017877
primary_uei: H1HYA8Z1NTM5
duns_number: 939017877
uei: H1HYA8Z1NTM5
fips: US
organization_id: 2793601
organization_name: UNIVERSITY OF KENTUCKY
organization_city: LEXINGTON
organization_state: KY
organization_type: SCHOOLS OF NURSING
organization_zip: 405260001
organization_country: UNITED STATES
project_abstract:
DESCRIPTION (provided by applicant): Residents of rural Appalachian Kentucky suffer rates of type II diabetes mellitus (DM) that are among the highest and most rapidly increasing in the country. Members of grandparent headed households (GHH) one of the fastest growing family constellations in rural Appalachian Kentucky and the US may be particularly vulnerable to health threats elevating their risk for DM. While the literature provides a starting point for the examination of this health disparity little is known about the socioecological factors that influence the risk for DM among GHH. Given the increasing prevalence of GHH their vulnerability to health threats and the current lack of information about their DM risk factors w propose to holistically examine the socio-ecological context of the health of GHH in rural Appalachian Kentucky in order to implement a culturally and contextually appropriate family intervention to reduce diabetes risk. We will conduct a two phase mixed methods study that culminates in a feasibility trial of such an intervention in rural Appalachian Kentucky. Phase I ofthe proposed study will utilize a simultaneous mixed methods design to assess socioecologic and biological risk of diabetes for GHH family members via surveys biological measures in-depth interviews with family members key informants interviews and a community assessment. Seventy families that are headed by a grandparent have one or more family members at risk for diabetes and include at least one grandchild ages 10 to 14 will be included in this phase of the study with 20 of those families participating in the in-depth qualitative interviews. Phase II of he study will include selection and refinement of an appropriate intervention to reduce diabetes risk for the families. Based on phase I findings and existing literature we will select an evidence based intervention and refine it to be culturally and contextually appropriate for the rural Appalachian families that are the focus of this project in collaboration with our strong network o community partners. Finally we will test he feasibility and acceptability of the refined intervention with 10 GHH. The proposed study will serve as the foundation for interventions for families in other rural areas with notable diabetes disparities.

project_terms:
Address;Adult;Advocacy;Affect;Age;American;Appalachian Region;Area;Asthma;Belief;Biological;Caregivers;Caring;Censuses;Centers for Disease Control and Prevention (U.S.);Child;Chronic Disease;Collaborations;Communities;Coronary heart disease;Country;Data;Development;Diabetes Mellitus;Emotional;Employment;Evidence based intervention;Family;Family health status;Family member;Food;Foundations;Goals;Head;Health;Health Services Accessibility;Health behavior;Health behavior outcomes;Household;Household Heads;Household and Family;Hypertension;Intervention;Interview;Kentucky;Life;Literature;Measures;Medical;Mental Depression;Methods;Minority;Non-Insulin-Dependent Diabetes Mellitus;Phase;Physical activity;Physical environment;Physically Handicapped;Population;Poverty;Predisposing Factor;Prevalence;Preventive;Research;Risk;Risk Factors;Risk Reduction;Rural;Social Environment;Social Health Services;Socioeconomic Status;Stress;Substance abuse problem;Surveys;System;Testing;Vulnerable Populations;Work;base;design;diabetes control;diabetes risk;experience;grandchild;grandparent;health disparity;informant;innovation;member;nutrition;peer;phase 2 study;prevent;public health medicine (field);rural area;sedentary lifestyle;therapy design

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Rapidly increasing rates of type 2 diabetes mellitus are a pressing public health concern. Residents of rural Appalachian Kentucky suffer disproportionately from this chronic disease. Members of grandparent headed households may be especially vulnerable to this threat for a number of reasons. The proposed project will allow us to holistically examine the socio-ecological context of this condition in this vulnerable group.We will also develop and pilot a culturally and contextually appropriate family intervention to reduce diabetes risk in grandparent headed households.


application_id: 9109039
project_number: 4R01HL118474-04
project_title: Hyperamylinemia in Diabetic Heart Disease: Mechanisms Responses and Prevention
administering_ic: NHLBI
award_notice_date: 2016-07-07
opportunity_number: PA-11-260
application_type: 4
activity_code: R01
ic: HL
serial_number: 118474
program_official: BUXTON, DENIS B
project_start_date: 2013-08-23
project_end_date: 2018-07-31
study_section: Myocardial Ischemia and Metabolism Study Section[MIM]
contact_pi_person_id: 9696701
contact_pi: DESPA, FLORIN
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): Increased secretion of amylin by pancreatic beta-cells (hyperamylinemia) is common in obese and insulin resistant patients coincides with hyperinsulinemia and promotes formation of toxic amylin oligomers. Oligomeric amylin induces beta-cell apoptosis contributing to the development of type-2 diabetes. Recent studies demonstrate that amylin oligomers also affect the vascular system kidneys and heart. Our data show large deposits of oligomerized amylin in failing hearts from obese and T2D patients but not in hearts from controls. Oligomeric amylin was found in myocyte injury areas suggesting a role in the mechanism of injury. Indeed our pilot study on a "humanized" rat model of hyperamylinemia (the HIP rat) indicates that amylin oligomers attach to cardiac myocytes and induce oxidative stress and Ca2+ dysregulation leading to diastolic dysfunction and hypertrophy. The pilot study also suggests that endogenous molecules with anti-aggregation properties such as plasmin and epoxyeicosanoids limit cardiac accumulation of amylin and its myopathic response. Based on these preliminary results our research proposal will test the hypotheses that 1) cardiac accumulation of oligomerized amylin accelerates diabetic heart injury by inducing sarcolemmal damage and oxidative stress and 2) limiting amylin deposition in the heart may reduce/ delay the onset of diabetic heart failure. These hypotheses will mechanistically be assessed by using transgenic rat models overexpressing either the amyloido- genic human amylin (HIP rats) or the non-amyloidogenic rat amylin isoform (UCD rats). Specifically planned studies will determine how accumulation of oligomerized amylin in the HIP rat heart a) disrupts sarcolemmal processes b) induces oxidative stress and myocyte Ca2+ dysregulation and c) activates Ca2+-mediated CaMKII-HDAC and calcineurin-NFAT hypertrophy signaling pathways. Based on the results of our pilot study cardiac dysfunction in HIP rats is expected to develop even in pre-diabetes as often observed in humans. In contrast our pilot study predicts that UCD rats matched for age and glucose but lacking cardiac amylin deposition may show signs of cardiac dysfunction after the onset of diabetes. Our research will also determine if disrupting deposition of oligomeric amylin in the heart and recovering sarcolemmal integrity improve cardiac function in the HIP rat model. This innovative concept will be explored in longitudinal studies using membrane sealants and scavengers of circulating amylin oligomers. Hence our research project proposes that amylin buildup is a key contributor to the multifactorial pathogenesis of diabetic heart injury and that mitigating amylin oligomer accumulation could delay the onset of diabetic heart failure. If our hypothesis of cardiotoxic amylin oligomer is proven then circulating amylin oligomers are a feasible therapeutic target to reduce diabetic heart injury.

project_terms:
Adjuvant;Affect;Age;Apoptosis;Area;Beta Cell;Binding;Blood;Calcineurin;Cardiac;Cardiac Myocytes;Cardiotoxicity;Cell membrane;Cells;Data;Deposition;Development;Diabetes Mellitus;Diagnosis;Epidemic;Excretory function;Figs - dietary;Functional disorder;Glucose;Health;Heart;Heart Diseases;Heart Hypertrophy;Heart Injuries;Heart failure;Histone Deacetylase;Hormones;Human;Hyperinsulinism;Hypertrophy;Injury;Insulin;Insulin Resistance;Ion Channel;Ions;Kidney;Left;Lipid Peroxidation;Longitudinal Studies;Mediating;Membrane;Membrane Potentials;Metabolic syndrome;Mitochondria;Modeling;Muscle Cells;Myocardial;Myocardial dysfunction;Non-Insulin-Dependent Diabetes Mellitus;Obesity;Oligonucleotides;Onset of illness;Oxidative Stress;Pancreas;Pathogenesis;Pathway interactions;Patients;Pilot Projects;Plasmin;Poloxamers;Prediabetes syndrome;Prevention;Process;Production;Property;Protein Isoforms;Rattus;Research;Research Project Grants;Research Proposals;Risk;Role;Sarcolemma;Signal Pathway;Solubility;Structure;Structure of beta Cell of islet;System;Testing;Therapeutic;Tissues;Transgenic Organisms;Vascular System;Ventricular;base;calmodulin-dependent protein kinase II;catalyst;diabetic;high risk;improved;in vivo;inhibitor/antagonist;innovation;islet amyloid polypeptide;overexpression;response;therapeutic target;tool

public_health_relevance:
PUBLIC HEALTH RELEVANCE: Obesity and type-2 diabetes have reached epidemic proportions in the US1 and are associated with a high risk of heart failure. The pathogenesis of heart dysfunction in obesity and T2D is multifactorial and not fully elucidated which makes diagnosis and treatment of diabetic heart disease challenging. Our study aims at understanding how hyperamylinemia a common condition in obese and insulin resistant patients promotes toxic accumulation of oligomerized amylin in the heart and how the buildup of amylin affects cardiac function. Planned studies also attempt to find therapeutic tools that can mitigate cardiac accumulation of oligomerized amylin and its deleterious effects. The focus is on modulating the endogenous system of scavenging the amylin oligomers circulating in the blood as a possible mean to reduce cardiotoxicity of hyperamylinemia. If our hypothesis of cardiotoxic amylin oligomer is proven then hyperamylinemia and the oligomerized amylin circulating in the blood will be feasible therapeutic targets to limit the risk of diabetic heart injury.


application_id: 9108795
project_number: 5R01AA021434-04
project_title: Role of microRNAs in Ethanol-induced Apoptosis and Teratogenesis
administering_ic: NIAAA
award_notice_date: 2016-06-22
opportunity_number: PA-11-260
application_type: 5
activity_code: R01
ic: AA
serial_number: 021434
program_official: HERELD, DALE
project_start_date: 2013-07-20
project_end_date: 2018-06-30
study_section: Neurotoxicology and Alcohol Study Section[NAL]
contact_pi_person_id: 7035096
contact_pi: CHEN, SHAO-YU
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): Prenatal ethanol exposure is the leading known cause of mental retardation. Growing evidence suggests that excessive cell death is a major component of the pathogenesis of ethanol-induced birth defects. However there is a fundamental gap in understanding how ethanol leads to apoptotic cell death in embryos. MicroRNAs (miRNAs) are a recently discovered class of small 18-23 nucleotide non-coding RNA that have been implicated in the regulation of genes involved in apoptosis. We have recently discovered that miR-34a a pro-apoptotic miRNA and miR-125b an anti-apoptotic miRNA are involved in ethanol-induced apoptosis in neural crest cells (NCCs). Our long-term goal is directed toward the development of effective strategies against ethanol's teratogenesis; strategies based on prevention of ethanol-induced apoptosis through targeting specific pathways involved in apoptosis. The overall objective of this particular proposal is to establish miRNA as a feasible target for the prevention of ethanol-induced apoptosis and teratogenesis. The central hypothesis to be tested is that miR-34a and miR-125b modulate ethanol-induced apoptosis in NCCs by the regulation of p53 and Bcl2 signaling pathways and that the inhibition of miR-34a or overexpression of miR-125b can prevent ethanol-induced teratogenesis. Our hypothesis has been formulated on the basis of strong preliminary data produced in our laboratory. To test our hypothesis the following specific aims will be addressed: Aim1: To characterize the role of miR-34a and miR-125b in ethanol-induced apoptosis in NCCs. We will determine the effects of ethanol on miR-34a and miR-125b expression in NCCs and in mouse embryos and the involvement of miR-34a and miR-125b in ethanol-induced apoptosis. Aim2: To test the hypothesis that miR-34a and miR- 125b modulate ethanol-induced apoptosis in NCCs by the regulation of p53 and Bcl2 pathways. This will be accomplished by determining the role of miR-34a in ethanol-induced activation of p53 and suppression of Bcl2 signaling and the effects of down-regulation of miR-125b by ethanol on p53 and Bcl2 signaling in ethanol- exposed NCCs. Aim3: To test the hypothesis that modulation of miR-34a and miR-125b represents a novel therapeutic strategy for preventing ethanol-induced teratogenesis. We will determine whether knockdown of miR-34a or overexpression of miR-125b diminishes ethanol-induced malformations in mouse embryos. The proposed work is innovative because it focuses on a novel approach targeting miRNAs involved in apoptosis to preventing ethanol-induced teratogenesis. The theoretical concept described in this application is also highly innovative because this is the first study attempting to prevent ethanol-induced apoptosis and teratogenesis specifically through the newly recognized actions of miR-34a and miR-125b in apoptosis. The results from this study will be significant because the insights gained by the accomplishment of these aims will help in elucidating the role of miRNAs in modulating ethanol-induced teratogenesis. They are also expected to yield strategies for preventing ethanol's teratogenesis and to fundamentally advance the field of FASD research.

project_terms:
Address;Alcohol consumption;Alcohols;Antioxidants;Apoptosis;Apoptotic;Brain;Brain region;Cell Death;Cell Line;Cells;Cessation of life;Congenital Abnormality;Data;Development;Down-Regulation;Embryo;Ethanol;Fetal Alcohol Exposure;Fetal Alcohol Spectrum Disorder;Gene Expression Regulation;Genes;Goals;Health;Human;Knockout Mice;Knowledge;Laboratories;Life;Mental Retardation;MicroRNAs;Mission;Molecular;Molecular Target;Mus;Neural Crest Cell;Neurons;Nucleotides;Pathogenesis;Pathway interactions;Population;Prevention;Prevention strategy;Preventive Intervention;Public Health;Regulation;Research;Role;Signal Pathway;Signal Transduction;Site;Staging;TP53 gene;Testing;Therapeutic;Therapeutic Intervention;Third Pregnancy Trimester;Time;Untranslated RNA;Up-Regulation;Work;alcohol effect;alcohol exposure;base;effective intervention;embryo culture;fetal;in vivo;innovation;insight;knock-down;malformation;mouse model;non-genetic;novel strategies;novel therapeutics;overexpression;prevent

public_health_relevance:
PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because the insights gained by the accomplishments of the proposed studies will help in elucidating the mechanisms underlying ethanol-induced cell death and validating possible molecular targets for the development of novel therapeutics for the prevention of human Fetal Alcohol Spectrum Disorders (FASD). Thus the proposed research is relevant to the NIAAA's mission that pertains to using knowledge gained in uncovering target sites for alcohol's action on the embryonic and fetal stages of life to begin developing potential therapeutic or preventative interventions.


