Intimal hyperplasia in arterialized vein bypass grafts is a significant cause of vein graft stenosis and delayed graft failure. Injury at the time of implantation or as a consequence of transplantation into the high pressure arterial system may contribute to these delayed events. Alterations in gene expression accompany implantation and arterialization injury. These alterations lead to intimal hyperplasia, including transformation of endothelial cells to an inflammatory state and initiating migration and transformation of smooth muscle cells from the contractile to secretory states thus creating the lesion of intimal hyperplasia. It is our hypothesis that silencing of genes upregulated by injury to the vein wall will diminish intimal hyperplasia. Furthermore, gene silencing can be accomplished within the constraints of operating room conditions. Our preliminary data demonstrates our ability to identify candidate genes associated with intimal hyperplasia and our ability to knockdown gene expression with siRNA. Using laser capture microscopy we have separated genetic events in the endothelium from those in smooth muscle. In the proposed study we will apply these technologies to (1) systematically identify silencing targets, (2) to silence target genes in vitro, (3) to silence target genes under surgical conditions, (4) to demonstrate inhibition of intimal hyperplasia in vein grafts in vivo. Both human tissue and canine models will be used as well as all cultures, microarrays, laser capture, RT-PCR, Western Blot, and related technology. This study will greatly strengthen the application of gene silencing to clinical problems in vascular surgery, and broaden our understanding of vascular wall biology. Public Lay Summary: Scar tissue formation due to surgical injury is a major cause for failure of heart bypass grafts and bypass grafts for peripheral vascular disease. The investigators propose to prevent formation of this scar tissue by controlling expression of the genes that cause it, using techniques that can be applied in the operating room.
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