Abdominal sortie aneurysms (AAA) are a significant disease in the aging population, with approximately 10% of the population over the age of 65 harboring an aneurysm. The mortality from AAA is approximately 15,000 deaths per year, ranking it as the 13th leading cause of death in the United States. AAA is a complex disorder resulting from several environmental and genetic influences;known risk factors include smoking, family history, old age and male gender. However, not enough is known about the specific molecular mechanisms involved in AAA. This application proposes to combine genetics and immunology to better understand these mechanisms. We have already identified two regions on chromosomes 4 and 19 containing several functional candidate genes related to immune function. We have also found upregulation of signaling pathways involved in the activation of cytotoxic lymphocytes using global gene expression profiling. By screening immune-related genes for risk alleles and evaluating the expression of cytotoxic lymphocyte activation pathways in AAA tissue, this proposal will test the hypothesis that genes that confer immunity play an important role in the development of AAA. Specifically, we propose the following aims: 1) Determine whether polymorphisms in HCST, TYROBP, IL15 and other immune-related genes in the linked intervals on chromosomes 19q13 and 4q31 are associated with AAA and 2) Characterize cytotoxic lymphocyte activation pathway expression in AAA by a) performing a quantitative analysis of mRNA expression found by microarray analysis using real-time PCR, b) studying protein expression of upregulated cytotoxicity pathway genes in aneurismal tissue to correlate mRNA expression with protein levels and determine their localization in tissue, c) identifying the cell type(s) expressing the specific cytotoxicity genes of interest and d) testing for evidence of cytotoxic pathway activation and induction of apoptosis in smooth muscle cells in close proximity to the identified cell type responsible for the cytotoxicity.
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