Gene expression in cardiovascular disease

第一部分的目标是发展鉴定导致心血管疾病的基因的方法和途径。我们建议使用各种基因表达测量，采用DNA微阵列，SAGE和蛋白质分析，开发实验方法来表征主动脉动脉粥样硬化的分子特征。具体来说，我们将采取多种方法来确定血管组织中动脉粥样硬化进展特征的基因表达变化。总体目标是利用基因表达的大规模分析来识别反映血管疾病进展阶段的模式。我们的工作将侧重于分析来自移植供体的主动脉，这些主动脉根据年龄分为三组：组织样本将在移除存在血管疾病的组织时进行分析。我们建议利用SAGE和DNA微阵列分析来鉴定反映疾病表型的表达模式，然后利用这些信息来鉴定可能导致心血管疾病过程的基因。我们还将使用蛋白质组学来鉴定在这些组织中特异性修饰的蛋白质。这将作为鉴定导致疾病过程的基因和其中多态性变异可能导致疾病过程的基因的基础。在此组件中生成的基因表达数据，通过组件4中详细的统计方法进行分析，将产生优先的基因列表，该列表将提供给组件2的活动，以发现多态基因变异。

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.