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. ? ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
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Lundberg, Martha
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Beth Israel Deaconess Medical Center
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Bodewes, Thomas C F; Johnson, Joel M; Auster, Michael et al. (2016) Intraluminal delivery of thrombospondin-2 small interfering RNA inhibits the vascular response to injury in a rat carotid balloon angioplasty model. FASEB J :
Raof, Nurazhani A; Rajamani, Deepa; Chu, Hsun-Chieh et al. (2016) The effects of transfection reagent polyethyleneimine (PEI) and non-targeting control siRNAs on global gene expression in human aortic smooth muscle cells. BMC Genomics 17:20
Nabzdyk, Christoph S; Chun, Maggie C; Oliver-Allen, Hunter S et al. (2014) Gene silencing in human aortic smooth muscle cells induced by PEI-siRNA complexes released from dip-coated electrospun poly(ethylene terephthalate) grafts. Biomaterials 35:3071-9
Pradhan-Nabzdyk, Leena; Huang, Chenyu; LoGerfo, Frank W et al. (2014) Current siRNA targets in the prevention and treatment of intimal hyperplasia. Discov Med 18:125-32
Pradhan-Nabzdyk, Leena; Huang, Chenyu; LoGerfo, Frank W et al. (2014) Current siRNA targets in atherosclerosis and aortic aneurysm. Discov Med 17:233-46
Nabzdyk, Christoph S; Chun, Maggie; Pradhan Nabzdyk, Leena et al. (2012) Differential susceptibility of human primary aortic and coronary artery vascular cells to RNA interference. Biochem Biophys Res Commun 425:261-5
Bhasin, Manoj; Huang, Zhen; Pradhan-Nabzdyk, Leena et al. (2012) Temporal network based analysis of cell specific vein graft transcriptome defines key pathways and hub genes in implantation injury. PLoS One 7:e39123
Yoshida, Shunsuke; Nabzdyk, Christoph S; Pradhan, Leena et al. (2011) Thrombospondin-2 gene silencing in human aortic smooth muscle cells improves cell attachment. J Am Coll Surg 213:668-76
Nabzdyk, Christoph S; Chun, Maggie; Pradhan, Leena et al. (2011) High throughput RNAi assay optimization using adherent cell cytometry. J Transl Med 9:48
Andersen, Nicholas D; Chopra, Atish; Monahan, Thomas S et al. (2010) Endothelial cells are susceptible to rapid siRNA transfection and gene silencing ex vivo. J Vasc Surg 52:1608-15

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