Gene Transfer to Prevent Intimal Hyperplasia in CABG

描述(申请人提供)：大隐静脉移植仍然是外科冠状动脉血运重建的重要管道。然而，这些管道的耐用性有限。静脉移植失败的机制包括炎症和内膜损伤，其次是平滑肌细胞增殖和内膜增厚。最近，静脉移植物的体外基因修饰已经实现了这一复杂机制中的一些步骤的中断。在本项目中，我们建议将两个不同的基因导入静脉移植物，以努力影响静脉移植物失败过程中的不同步骤。β-肾上腺素能受体激酶羧基末端(BARKct)是一种与G蛋白β-伽马亚基结合的多肽，从而阻止参与平滑肌细胞增殖的RAS/MAP激酶通路的激活。一氧化氮(NO)是血管内皮细胞功能的重要介质，在血管移植过程中受到干扰。成功地将内皮型一氧化氮合酶(ENOS)基因导入大隐静脉移植物，可保留一氧化氮的产生。在手术时将这两种基因(BARKct和eNOS)共转染静脉移植物，可以减少内膜增生，保护内皮功能，从而防止静脉移植物失败。

DESCRIPTION (provided by applicant): Saphenous vein grafts remain an important conduit for surgical coronary revascularization. These conduits, however, have limited durability. The mechanisms for vein graft failure include inflammation and intimal injury followed by smooth muscle cell proliferation and intimal thickening. Recently, ex vivo genetic modification of vein grafts has achieved interruption of some of the steps in this complex mechanism. In this project, we propose to transfect vein grafts with two different genes in an effort to affect different steps in the process of vein graft failure. The beta-adrenergic receptor kinase carboxyl terminus (BARKct) is a peptide, which binds G-protein beta gamma subunits and thereby prevents activation of Ras/MAP kinase pathways involved in smooth muscle cell proliferation. Nitric oxide (NO) is an important mediator for endothelial function, which has been shown to be disrupted during the process of vascular grafting. Successful transfection of the endothelial NO synthase (eNOS) gene in saphenous vein grafts preserves NO production. Cotransfection of vein grafts with both of these genes (BARKct and eNOS) at the time of surgery may reduce intimal hyperplasia, preserve endothelial function, and thereby prevent vein graft failure.