The goal of Component I is to develop the methodologies and approaches to identification of genes that contribute to cardiovascular disease. We propose to use various measures of gene expression, employing DNA microarrays, SAGE , and protein analysis, to develop experimental approaches to the molecular characterization of atherosclerosis in the aorta. Specifically, we will take a variety of approaches to the determination of gene expression changes that characterize the advance of atherosclerosis in vascular tissue. The overarching goal is to utilize large scale analysis of gene expression to identify patterns that reflect the stages of vascular disease progression. Our work will focus on the analysis of aorta derived from transplant donors that are separated into three groupings based on age: The tissue samples will be analyzed at the time of removal from the presence of vascular disease. We propose to utilize both SAGE and DNA microarray analysis to identify patterns of expression that reflect disease phenotype and then use this information to identify genes that may contribute to cardiovascular disease process. We will also employ proteomics to identify proteins that are specifically modified in these same tissues. This will serve as the basis for the identification of genes that contribute to the disease process and in which polymorphic variations may contribute to the disease process. The gene expression data generated in this component, analyzed by the statistical methodologies detailed in component 4, will yield prioritized gene lists that will feed into the activities of Component 2 for the discovery of polymorphic gene variants. To accomplish these goals we will focus our attention on the collection of vascular tissue from organ transplant donors, that have been characterized with respect to disease progression, to enable the gene expression and protein analyses. We will utilize a variety of complementary technologies for the generation of this data and to then allow a determination of the original approach to the identification of genes that contribute to the disease process.
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