Gene Transfer to Prevent Intimal Hyperplasia in CABG

描述（由申请人提供）：隐静脉移植物仍然是外科冠状动脉血运重建的重要管道。然而，这些导管具有有限的耐久性。静脉移植失败的机制包括炎症和内膜损伤，随后是平滑肌细胞增殖和内膜增厚。最近，静脉移植物的离体遗传修饰已经实现了在这个复杂机制中的一些步骤的中断。在这个项目中，我们建议用两种不同的基因来检测静脉移植物，以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）是一种肽，可结合G蛋白β-γ亚基，从而阻止参与平滑肌细胞增殖的Ras/MAP激酶途径的激活。一氧化氮（NO）是内皮功能的重要介质，其已被证明在血管移植过程中被破坏。成功转染内皮型一氧化氮合酶（eNOS）基因的隐静脉移植物中保留NO的生产。在手术时用这两种基因（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.