GENOMICS OF CARDIOVASCULAR DEVELOPMENT, ADAPTION

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The goal of this PGA is to begin linking genes to function, dysfunction and structural abnormalities of the cardiovascular system caused by clinically relevant, genetic and environmental stimuli. The principal biological theme to be pursued is how the transcriptional network of the cardiovascular system responds to genetic and environmental stresses to maintain normal function and structure, and how this network is altered in disease. In Specific Aim 1, the investigators will take a multidisciplinary approach combining well-defined mouse models of cardiomyopathy and vasculopathy with an integrated analysis of physiology, pathology, and RNA expression profiling to search for prototypical patterns of gene expression in response to various genetic and non-genetic perturbations. In Specific Aim 2, the investigators will perform transcriptional profiling using human myocardium and vascular tissues obtained at the time of cardiac transplant or biopsy, and compare the transcriptional profile data with those of various mouse models. In Specific Aim 3, the investigators will screen for mutations that cause cardiovascular malformations with particular emphasis on hypertrophic cardiomyopathy, dilated cardiomyopathy, and selected sets of patients with congenital heart disease. In Specific Aim 4, the investigators will examine 200 candidate genes, identified by the mouse and human expression studies, in 2093 individuals drawn from the Framingham Heart Study. In these studies, a single nucleotide DNA polymorphism analysis (SNP) will be correlated with echocardiographic evidence of left ventricle mass, ventricular function, cardiac chamber size and aortic root size. The data generated by all of the above studies will be analyzed by state-of-the-art informatics to search for logics for common as well as disease specific pathways. The data will be extensively annotated and made freely available to the scientific community through the interactive website. In summary, this PGA will generate a high quality, comprehensive data set for the functional genomics of structural and functional adaptation of the cardiovascular system by integrating expression data from animal models and human tissue samples, mutation screening of candidate genes in patients, and DNA polymorphisms in a well characterized general population. Such a data set will serve as a benchmark for future basic, clinical and pharmacogenomic studies.