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

血管介入治疗的失败，包括血管成形术、支架植入和搭桥手术，通常是由于 血管壁上过度的愈合反应，导致狭窄和闭塞。这个过程是 以形成内膜增生(IH)为特征，这是一种主要由平滑肌组成的病变 具有增殖、合成和去分化表型的细胞(SMC)。最近的证据表明 Survivin(Sw)，一种同时调节细胞凋亡和增殖的新蛋白，可能是一个重要的 治疗以生长失调为特征的疾病，如癌症和高血压。在这 翻译研究建议我们试图验证Sw作为IH的分子靶点，尤其是在 静脉移植失败的背景。首先，我们将研究直接抑制SW基因表达的方法，在- 体外和体内。Sw基因敲除对SMC表型和静脉移植物增生的影响 下定决心。在第二个具体目标中，我们将探索相互作用的治疗相关性 Sw和热休克蛋白90(HspQO)，一种分子伴侣，使用基于多肽的方法破坏 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 策略可能使血管SMC对他汀类药物的促凋亡作用敏感，潜在地扩大 这些抗动脉粥样硬化药物的治疗效用，以延长血管干预的益处。 静脉搭桥手术目前在美国每年约有50万例患者使用，是一种关键的 为许多患有心血管疾病的患者提供保全生命或保肢的干预。尽管经常 随着时间的推移，有效的静脉搭桥术的失败率很高(五年内为30%-50%)， 直接导致死亡、截肢和生活质量下降。这项建议旨在扩大 了解参与静脉移植失败的因素，并将研究一种新的方法来重新治疗。 设计可能抵抗闭塞的搭桥术。这些研究也与 改善其他心血管干预措施的长期效果，如经皮血管成形术和 支架，通过提供控制血管损伤反应的新的分子方法。

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 dysregulated 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.