SCCOR in Cardiac Dysfunction and Disease

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一个专门的心脏功能和疾病临床导向研究中心(SCCOR)。拟议的SCCOR的中心统一主题是消除糖尿病患者的过度心肌疾病负担。该程序旨在检验这样一个假设，即心肌脂肪酸代谢紊乱会导致心脏功能障碍，并增加对缺血性损伤的敏感性。我们认为代谢(糖尿病)、遗传、种族和临床决定因素会影响有急性冠状动脉缺血事件风险的患者的预后。这项SCCOR建议设想了一种涉及五个研究项目和四个核心单位的多学科方法。这一高度互动的提案的重点将从糖尿病心脏的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、转基因小鼠的发展和特征、基于机制的人类心血管表型和种群结果研究。我们将研究与PPARpha基因调控通路相关的心肌代谢改变在糖尿病心脏模型中的作用(项目1)；确定心肌脂毒性在小鼠和人类糖尿病心功能障碍发展中的作用(项目2)；利用创新的代谢成像方法描绘糖尿病患者冠状动脉缺血/再灌注或心肌梗死后心肌脂肪酸代谢增加对病理性心室重构的贡献(项目3)；调查种族差异、脂代谢紊乱和遗传因素在心肌梗死后预后中的基础(项目4)；并确定急性冠脉综合征后糖尿病患者和非糖尿病患者预后的药物遗传学预测因子(项目5)。SCCOR的长期目标是开发一个严格定义的成像、生化、遗传和临床决定因素的风险分层小组，包括糖尿病患者心血管事件风险的表型特征。 个别项目和核心单位： 项目1：缺血性糖尿病心脏中PPARa信号的改变 (凯利，D.) 描述(由申请人提供)： 该SCCOR项目将重点研究糖尿病患者的心肌脂代谢异常。糖尿病心脏中脂肪酸利用率的长期增加易导致与氧气消耗增加和细胞内脂质积累相关的心脏毒性效应(“脂毒性”)。在心肌缺血的背景下，线粒体脂肪酸氧化(FAO)的高比率可能导致心肌细胞损伤和死亡的增加。最近，我们发现核受体，过氧化物酶体增殖物激活的受体a或PPARa推动糖尿病心脏脂肪利用率的增加。该项目将检验这样一种假设，即心脏PPARa途径的慢性激活引起的代谢紊乱是糖尿病患者急性冠脉缺血后心力衰竭和死亡的主要决定因素。我们已经开发了小鼠模型来复制糖尿病心脏的脂代谢紊乱。心脏特异过表达PPARa的转基因小鼠(MHC-PPAR)表现出与糖尿病心脏明显相似的代谢表型。第二种模型涉及心脏特有的脂蛋白脂肪酶的过度表达，以增加脂肪酸向心脏的输送。我们将研究小鼠模型对缺血侮辱的反应。首先，将使用小鼠模型来评估对心肌梗死和缺血/再灌注的代谢和功能反应。其次，我们将通过评估饮食脂肪含量的影响，以及利用LPL转基因和“基因敲除”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复合体基因中常见的单核苷酸多态(SNPs)的影响进行功能研究，以补充项目4和5中计划的人群研究的结果。该项目的长期目标是与项目2-5合作，识别新的脂类生化、代谢成像和遗传决定因素，预测有急性冠脉缺血性损伤风险的个体糖尿病患者的预后。(摘要结束)

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)