Survivin: a novel regulator of intimal hyperplasia and vein graft remodeling

描述（由申请人提供）：血管干预的失败，包括血管成形术、支架植入和搭桥手术，通常是由于血管壁的过度愈合反应，导致狭窄和闭塞。这一过程的特点是内膜增生（IH）的形成，这是一种主要由平滑肌细胞（SMC）组成的病变，具有增殖、合成和去分化的表型。最近的证据表明，survivin （SW）是一种调节细胞凋亡和增殖的新蛋白，可能是癌症和IH等以生长不受调节为特征的疾病的重要治疗靶点。在这个转化研究计划中，我们试图验证SW作为IH的分子靶点，特别是在静脉移植失败的背景下。首先，我们将研究体外和体内直接抑制SW基因表达的方法。SW敲低对SMC表型和静脉移植增生的影响将被确定。在第二个特定目标中，我们将探索SW和热休克蛋白90 (HspQO)（一种分子伴侣）之间相互作用的治疗相关性，使用基于肽的方法来破坏这种关键的蛋白质-蛋白质相互作用。最后，在第三个目标中，我们将研究抗sw分子策略是否可能使血管SMC对他汀类药物的促凋亡作用敏感，从而有可能扩大这些动脉粥样硬化保护药物的治疗用途，从而扩大血管干预的益处。静脉搭桥手术目前在美国每年约有50万例，对于许多患有心血管疾病的患者来说，这是一种至关重要的挽救生命或肢体的干预措施。虽然静脉旁路移植通常是有效的，但随着时间的推移，其失败率很高（5年内30- 50%），直接导致死亡、截肢和生活质量下降。本研究旨在拓宽对静脉移植失败因素的理解，并将研究一种新的方法来重新设计可能抵抗闭塞的旁路移植物。这些研究还通过提供新的分子方法来控制血管损伤反应，与改善其他心血管干预措施（如经皮血管成形术和支架置入术）的长期结果直接相关。

DESCRIPTION (provided by applicant): Failure of vascular interventions, including angioplasty, stenting, and bypass surgery, frequently results from an exaggerated healing response in the vessel wall, leading to narrowing and occlusion. This process is characterized by the formation of intimal hyperplasia (IH), a lesion consisting primarily of smooth muscle cells (SMC) bearing a proliferative, synthetic, and de-differentiated phenotype. Recent evidence suggests that survivin (SW), a novel protein which regulates both apoptosis and proliferation, may be an important therapeutic target in disorders characterized by deregulated growth, such as cancer and IH. In this translational research proposal we seek to validate SW as a molecular target in IH, most particularly in the context of vein graft failure. First we will investigate approaches to directly inhibit SW gene expression, in- vitro and in-vivo. The effects of SW knockdown on SMC phenotype and vein graft hyperplasia will be determined. In the second specific aim, we will explore the therapeutic relevance of the interaction between SW and heat shock protein 90 (HspQO), a molecular chaperone, using a peptide-based approach to disrupt this critical protein-protein interaction. Finally in the third aim we will investigate whether anti-SW molecular strategies may sensitize vascular SMC to the pro-apoptotic effects of statin drugs, potentially expanding the therapeutic utility of these atheroprotective drugs to extend the benefits of vascular interventions. Vein bypass surgery, currently employed in some 500,000 cases annually in the United States, is a critical life- or limb-sparing intervention for many patients afflicted with cardiovascular disease. Although often effective, vein bypass grafts are subject to a significant rate of failure over time (30- 50% within five years), leading directly to mortality, limb amputation and diminished quality of life. This proposal seeks to broaden the understanding of factors which are involved in vein graft failure, and will examine a novel approach to re- engineer bypass grafts that may be resistant to occlusion. These studies also have direct relevance for improving the long term results of other cardiovascular interventions such as percutaneous angioplasty and stenting, by providing new molecular approaches to control the vascular injury response.