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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086741-02
Application #
7340551
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Lundberg, Martha
Project Start
2007-02-01
Project End
2010-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
2
Fiscal Year
2008
Total Cost
$509,665
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Nabzdyk, Christoph S; Pradhan-Nabzdyk, Leena; LoGerfo, Frank W (2017) RNAi therapy to the wall of arteries and veins: anatomical, physiologic, and pharmacological considerations. J Transl Med 15:164
Bodewes, Thomas C F; Johnson, Joel M; Auster, Michael et al. (2017) Intraluminal delivery of thrombospondin-2 small interfering RNA inhibits the vascular response to injury in a rat carotid balloon angioplasty model. FASEB J 31:109-119
Moll, Herwig P; Lee, Andy; Peterson, Clayton R et al. (2016) A20 Haploinsufficiency Aggravates Transplant Arteriosclerosis in Mouse Vascular Allografts: Implications for Clinical Transplantation. Transplantation 100:e106-e116
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
Enesa, Karine; Moll, Herwig P; Luong, Le et al. (2015) A20 suppresses vascular inflammation by recruiting proinflammatory signaling molecules to intracellular aggresomes. FASEB J 29:1869-78
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 atherosclerosis and aortic aneurysm. Discov Med 17:233-46
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
Guedes, Renata P; Rocha, Eduardo; Mahiou, Jerome et al. (2013) The C-terminal domain of A1/Bfl-1 regulates its anti-inflammatory function in human endothelial cells. Biochim Biophys Acta 1833:1553-61
Siracuse, Jeffrey J; Fisher, Mark D; da Silva, Cleide G et al. (2012) A20-mediated modulation of inflammatory and immune responses in aortic allografts and development of transplant arteriosclerosis. Transplantation 93:373-82

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