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.
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