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

描述（由申请人提供）：血管介入治疗（包括血管成形术、支架植入术和旁路手术）的失败通常是由于血管壁愈合反应过度导致狭窄和闭塞。该过程的特征在于内膜增生（IH）的形成，这是一种主要由具有增殖、合成和去分化表型的平滑肌细胞（SMC）组成的病变。最近的证据表明，生存素（SW），一个新的蛋白质，调节细胞凋亡和增殖，可能是一个重要的治疗目标，以失调的增长为特征的疾病，如癌症和IH。在这项转化研究提案中，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，我们将研究在体外和体内直接抑制SW基因表达的方法。将确定SW敲减对SMC表型和静脉移植物增生的影响。在第二个具体目标，我们将探讨SW和热休克蛋白90（HspQO），分子伴侣之间的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分子策略是否可以使血管SMC对他汀类药物的促凋亡作用敏感，从而潜在地扩展这些动脉粥样硬化保护药物的治疗效用以扩展血管干预的益处。静脉旁路手术，目前在美国每年约50万例，是一个关键的生命或肢体保留干预许多患者患有心血管疾病。虽然静脉旁路移植术通常有效，但随着时间的推移，失败率很高（5年内为30- 50%），直接导致死亡、截肢和生活质量下降。这项提案旨在扩大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控制血管损伤反应的新分子方法，与改善其他心血管干预（如经皮血管成形术和支架植入术）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.