Gene Transfer to Prevent Intimal Hyperplasia in CABG

基因转移预防冠状动脉搭桥术中的内膜增生

• 批准号: 6836809
• 负责人: Brian Lima
• 金额: $ 4.73万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2006-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6836809
• 关键词: Adenoviridae; angiography; autologous transplantation; beta adrenergic receptor kinase; biological signal transduction; biotechnology; blood vessel transplantation; cell growth regulation; cell line; cell proliferation; coronary disorder; dogs; gene expression; gene therapy; growth inhibitors; hyperplasia; immunocytochemistry; nitric oxide synthase; postdoctoral investigator; postoperative complications; protein structure function; transfection /expression vector; transplant rejection; vascular endothelium; veins

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.

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，这些导管的耐用性有限。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。在这个项目中，我们建议用两种不同的基因转染静脉移植物，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，从而防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，已被证明在血管移植过程中会受到破坏。在隐静脉移植物中成功转染内皮一氧化氮合酶 (eNOS) 基因可保留一氧化氮的产生。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，保留内皮功能，从而防止静脉移植物失败。