SCCOR in Cardiac Dysfunction and Disease

SCCOR 在心脏功能障碍和疾病中的应用

基本信息

批准号：
7184295
负责人：
DANIEL PATRICK KELLY
金额：
$ 262.46万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-22 至 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7184295
关键词：
Accounting Acids Acute Acute myocardial infarction Address Adolescent Adrenergic beta-Antagonists Adult Affect African American Age Alabama Americas Angiography Angiotensin-Converting Enzyme Inhibitors Animal Model Animals Appointment Area Atherosclerosis Award Basic Science Biochemical Biochemical Genetics Bioinformatics Biology Biomedical Engineering Biostatistics Core Black race Blood Vessels Blood flow Boston Candidate Disease Gene Cardiac Cardiology Cardiomyopathies Cardiovascular Diseases Cardiovascular Models Cardiovascular system Caring Catabolism Catheterization Cause of Death Cessation of life Chemistry Chest Chest Pain Childhood Chromosome Mapping Chronic Cities Clinical Clinical Research Collaborations Color Colorado Communities Complex Condition Coronary Coronary Arteriosclerosis Coronary Artery Bypass Country DNA DNA Sequence Analysis Data Data Collection Decision Making Development Diabetes Mellitus Diet Dietary Fats Dietary Intervention Discipline Disease Doctor of Philosophy Early Diagnosis Echocardiography Economics Educational Activities Electrospray Ionization Endocrinologist Energy Metabolism Enrollment Environment Epidemic Esterification Evaluation Event Exhibits Faculty Family FarGo Fatty Acids Fellowship Fingerprint Fostering Foundations Frequencies Functional disorder Funding Future Gene Frequency Gene Targeting Genes Genetic Genetic Determinism Genetic Polymorphism Genetically Engineered Mouse Genomics Genotype Glucose Glycosylated Hemoglobin Goals Grant Growth Half-Life Head Health Health Status Healthcare Heart Heart Diseases Heart Hypertrophy Heart failure Hospitals Human Human Genetics Human Genome Project Hyperlipidemia Hypertension Ice Image Imaging Device Impact evaluation In Vitro Inborn Genetic Diseases Incidence Individual Infarction Injury Institutes Institution Insulin Insulin Resistance Interest Group International Intracellular Accumulation of Lipids Invasive Investigation Ischemia Joints Kansas Knock-out Laboratories Lead Leadership Lesion Life Link Lipid Biochemistry Lipids Lipoproteins Love Measurement Measures Medicine Mentorship Metabolic Metabolic Diseases Metabolic Marker Metabolic Pathway Metabolic syndrome Metabolism Methodology Minority Mission Missouri Mitochondria Modeling Molecular Biology Molecular Genetics Monitor Morbidity - disease rate Mus Muscle Cells Myocardial Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Names Nature Non-Insulin-Dependent Diabetes Mellitus Non-Invasive Cancer Detection Nuclear Receptors Numbers Obesity Operative Surgical Procedures Outcome Outcome Study Outcomes Research Oxygen Consumption PPAR Pathway PPAR alpha Participant Pathogenesis Pathologic Pathology Pathway interactions Patient Care Patients Performance Peroxisome Proliferator-Activated Receptors Peroxisome Proliferators Pharmacogenetics Pharmacogenomics Pharmacology Phase Phenotype Philosophy Physiological reperfusion Physiology Plasma Population Population Study Positron-Emission Tomography Predictive Value Predisposition Preparation Prevalence Primary Care Physician Principal Investigator Procedures Process Production Program Research Project Grants Prospective Studies Protein Overexpression Province Publications Publishing Quality of life Race Radiochemistry Radiology Specialty Range Rate Registries Regulation Regulator Genes Regulatory Pathway Reperfusion Injury Reperfusion Therapy Research Research Personnel Research Project Grants Research Proposals Research Training Resources Risk Risk Factors Role Saints Sampling Science Scientist Secondary Prevention Seminal Serum Services Signal Transduction Single Nucleotide Polymorphism Site Specialized Center Staging Standards of Weights and Measures Stratification Symptoms Techniques Technology Testing Text Therapeutic Time Tissue Sample Tissues Tracer Training Training Programs Transcriptional Regulation Transgenic Mice Transgenic Model Transgenic Organisms Translations United States United States National Institutes of Health Universities University Hospitals Upper arm Ursidae Family Utah Variant Ventricular Dysfunction Ventricular Remodeling Viola Washington Work abstracting acute coronary syndrome base cancer therapy cardiovascular imaging career clinically significant cohort design diabetes mellitus genetics diabetic diabetic cardiomyopathy disability experience fatty acid metabolism fatty acid oxidation fatty acid transport genetic variant genome sequencing heart disease risk heart metabolism human disease human study human subject improved in vivo innovation insight interdisciplinary approach interest lipid metabolism lipoprotein lipase medical schools member metabolic abnormality assessment mortality mouse model non-diabetic novel novel diagnostics oxidation patient oriented research patient registry pediatric pharmacology pressure prevent professor prognostic programs protein function racial difference radioligand receptor response skills socioeconomics sperm cell symposium tandem mass spectrometry technology development tool transcription factor trend uptake validation studies

项目摘要

DESCRIPTION (provided by applicant): To decrease the morbidity and mortality of cardiovascular disease in patients with diabetes, we propose to establish a Specialized Center for Clinically-Oriented Research (SCCOR) in Cardiac Function and Disease at Washington University. The central unifying theme of the proposed SCCOR is to eliminate the excess burden of myocardial disease in people with diabetes. The program is designed to test the hypothesis that derangements in myocardial fatty acid metabolism leads to cardiac dysfunction and increased susceptibility to ischemic insult. We propose that metabolic (diabetes), genetic, racial, and clinical determinants influence the outcome of patients at risk for an acute coronary ischemic event. This SCCOR proposal envisions a multidisciplinary approach involving five Research Projects and four Core Units. The focus of this highly interactive proposal will span from fundamental studies of mouse models of the diabetic heart to outcomes studies in humans. Our approach will combine molecular genetics, development and characterization of genetically modified mice, mechanism-based cardiovascular phenotyping in humans, and population outcomes research. We will examine the role of alterations in myocardial metabolism related to the PPARalpha gene regulatory pathway in response to ischemic insult in mouse models of the diabetic heart (Project 1); define the role of myocardial lipotoxicity in the development of diabetic cardiac dysfunction in mice and humans (Project 2); delineate the contribution of increased myocardial fatty acid metabolism to pathologic ventricular remodeling in patients with diabetes mellitus following coronary ischemia/reperfusion or myocardial infarction using innovative metabolic imaging approaches (Project 3); investigate the basis of racial disparities, lipid metabolic derangements, and genetic factors in outcomes following myocardial infarction (Project 4); and define pharmacogenetic predictors of outcome in diabetic and non-diabetic patients following acute coronary syndrome (Project 5). The long-term objective of this SCCOR is to develop a rigorously defined risk-stratifying panel of imaging, biochemical, genetic, and clinical determinants comprising a phenotypic profile of the patient with diabetes at risk for a cardiovascular event. INDIVIDUAL PROJECTS AND CORE UNITS: PROJECT 1: Altered PPARa Signaling in the Ischemic Diabetic Heart (Kelly, D.) DESCRIPTION (provided by applicant): This SCCOR project will focus on abnormalities of myocardial lipid metabolism in the diabetic patient. Chronically increased rates of fatty acid utilization in the diabetic heart predispose to cardiotoxic effects related to increased oxygen consumption and accumulation of intracellular lipids ("lipotoxicity"). In the setting of myocardial ischemia, high rates of mitochondrial fatty acid oxidation (FAO) may lead to increased myocyte injury and death. Recently, we have found that the nuclear receptor, peroxisome proliferators activated receptor a or PPARa drives increased fatty utilization in the diabetic heart. This project will test the hypothesis that metabolic derangements due to chronic activation of the cardiac PPARa pathway are a major determinant of heart failure and death in diabetics following acute coronary isehemic insult. We have developed mouse models to reproduce the lipid metabolic derangements of the diabetic heart. Transgenic mice with cardiac-specific overexpression of PPARa (MHC-PPAR) exhibits a metabolic phenotype remarkedly similar to the diabetic heart. A second model involves cardiac-specific overexpression of lipoprotein lipase to increase delivery of fatty acids to the heart. We will study the response of the mouse models to ischemic insult. First, the mouse models will be used to evaluate the metabolic and functional response to myocardial infarction and ischemia/reperfusion. Second, we will evaluate the contributory role of cardiac lipotoxicity in the diabetic cardiomyopathic phenotype by evaluating the influence of dietary fat content and the effects of increased or decreased delivery of lipoprotein-derived fatty acid using LPL transgenics and "knockouts", respectively. Third, we will evaluate the influence of pharmacologic agents targeted at the PPAR pathway and its target genes. Lastly, we will perform functional studies of the effects of common single nucleotide polymorphisms (SNPs) within genes of the PPARa complex to compliment the results of population studies planned in Projects 4 and 5. The long-term goal of this project, in collaboration with Projects 2-5, is to identify novel lipid biochemical, metabolic imaging, and genetic determinants predictive of outcome in an individual diabetic patient at risk for acute cornary ischemic insult. (End of Abstract)

描述（由申请人提供）：为了降低糖尿病患者心血管疾病的发病率和死亡率，我们建议在华盛顿大学建立心脏功能和疾病临床导向研究专业中心 (SCCOR)。拟议的 SCCOR 的中心统一主题是消除糖尿病患者心肌疾病的过度负担。该计划旨在检验心肌脂肪酸代谢紊乱导致心脏功能障碍和缺血性损伤易感性增加的假设。我们认为代谢（糖尿病）、遗传、种族和临床决定因素影响有急性冠状动脉缺血事件风险的患者的结果。该 SCCOR 提案设想了一种多学科方法，涉及五个研究项目和四个核心单元。这项高度互动的提案的重点将从糖尿病心脏小鼠模型的基础研究到人类的结果研究。我们的方法将结合分子遗传学、转基因小鼠的发育和表征、基于机制的人类心血管表型分析以及群体结果研究。我们将研究与 PPARα 基因调控通路相关的心肌代谢改变在糖尿病心脏小鼠模型中对缺血性损伤的反应中的作用（项目 1）；确定心肌脂毒性在小鼠和人类糖尿病性心功能不全发展中的作用（项目 2）；使用创新的代谢成像方法描述心肌脂肪酸代谢增加对冠状动脉缺血/再灌注或心肌梗死后糖尿病患者病理性心室重构的影响（项目3）；调查心肌梗死后结局中种族差异、脂质代谢紊乱和遗传因素的基础（项目 4）；并定义急性冠状动脉综合征后糖尿病和非糖尿病患者结局的药物遗传学预测因子（项目 5）。该 SCCOR 的长期目标是开发一个严格定义的影像学、生化、遗传和临床决定因素的风险分层小组，其中包括有心血管事件风险的糖尿病患者的表型特征。个别项目和核心单元：项目 1：缺血性糖尿病心脏中 PPARa 信号传导的改变（凯利，D.）描述（由申请人提供）：该 SCCOR 项目将重点关注糖尿病患者心肌脂质代谢异常。糖尿病心脏中脂肪酸利用率的长期增加容易产生与耗氧量增加和细胞内脂质积累相关的心脏毒性作用（“脂毒性”）。在心肌缺血的情况下，线粒体脂肪酸氧化（FAO）率高可能导致心肌细胞损伤和死亡增加。最近，我们发现核受体、过氧化物酶体增殖物激活受体 a 或 PPARa 会增加糖尿病心脏中的脂肪利用率。该项目将检验以下假设：心脏 PPARa 通路慢性激活导致的代谢紊乱是糖尿病患者急性冠状动脉缺血性损伤后心力衰竭和死亡的主要决定因素。我们开发了小鼠模型来重现糖尿病心脏的脂质代谢紊乱。心脏特异性过度表达 PPARa (MHC-PPAR) 的转基因小鼠表现出与糖尿病心脏非常相似的代谢表型。第二种模型涉及脂蛋白脂肪酶的心脏特异性过度表达，以增加脂肪酸向心脏的输送。我们将研究小鼠模型对缺血性损伤的反应。首先，小鼠模型将用于评估对心肌梗塞和缺血/再灌注的代谢和功能反应。其次，我们将通过分别评估膳食脂肪含量的影响以及使用LPL转基因和“敲除”增加或减少脂蛋白衍生脂肪酸的输送的影响，来评估心脏脂肪毒性在糖尿病心肌病表型中的贡献作用。第三，我们将评估针对 PPAR 途径及其靶基因的药物的影响。最后，我们将对 PPARa 复合体基因内常见单核苷酸多态性 (SNP) 的影响进行功能研究，以补充项目 4 和 5 中计划的群体研究结果。该项目的长期目标是与项目 2-5 旨在确定新的脂质生化、代谢成像和遗传决定因素，以预测有急性角膜缺血损伤风险的个体糖尿病患者的结果。（摘要完）