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

Survivin：内膜增生和静脉移植重塑的新型调节剂

• 批准号: 7885253
• 负责人: Michael S Conte
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7885253
• 关键词: Amputation; Angioplasty; Apoptosis; Apoptotic; Arterial Injury; Arteries; Atherosclerosis; Attenuated; Balloon Angioplasty; Binding; Blood Vessels; Bypass; Cardiovascular Diseases; Cardiovascular system; Cell Cycle; Cell Cycle Progression; Cell Survival; Cells; Client; Coronary; Data; Development; Disease; Embryonic Development; Engineering; Failure; Gene Expression; Genes; Genetic; Goals; Growth; Healed; Heat-Shock Proteins 90; Human; Hyperplasia; In Vitro; Injury; Intervention; Lesion; Life; Limb structure; Malignant Neoplasms; Mitosis; Modeling; Molecular; Molecular Chaperones; Molecular Target; Normal tissue morphology; Operative Surgical Procedures; Oryctolagus cuniculus; Oxidoreductase; Paracrine Communication; Pathway interactions; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Phenotype; Play; Prevention; Process; Proliferating; Proteins; Proteomics; Quality of life; RNA Interference; Regulation; Research Personnel; Research Proposals; Resistance; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Testing; Therapeutic; Time; Translational Research; United States; Vascular remodeling; Veins; artery occlusion; atheroprotective; base; cell growth; clinical efficacy; clinically relevant; comparative efficacy; design; effective therapy; graft failure; healing; improved; in vivo; inhibitor-of-apoptosis protein; inhibitor/antagonist; interest; mortality; neoplastic; neoplastic cell; novel; novel strategies; peptide analog; protein protein interaction; research study; response; response to injury; restenosis; survivin; therapeutic target

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.

描述（由申请人提供）：血管干预措施的失败，包括血管成形术，支架和旁路手术，经常是由于血管壁上夸张的愈合反应而导致的，从而导致变窄和闭塞。该过程的特征是形成内膜增生（IH），这是一种主要由平滑肌细胞（SMC）组成的病变（SMC），具有增殖，合成和脱节的表型。最近的证据表明，Survivin（SW）是一种调节细胞凋亡和增殖的新型蛋白质，可能是以失控生长（例如癌症和IH）为特征的疾病中的重要治疗靶标。在这项翻译研究建议中，我们试图将SW验证为IH的分子靶标，尤其是在静脉移植衰竭的情况下。首先，我们将研究直接抑制SW基因表达，体外和体内的方法。将确定SW敲低对SMC表型和静脉移植增生的影响。在第二个特定目的中，我们将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的方法，探索SW和热激蛋白90（HSPQO）之间相互作用（HSPQO）之间相互作用的治疗相关性。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，从而有可能扩大这些动脉保护药物的治疗效用，以扩大血管干预的益处。目前，在美国每年约有500,000例病例中使用的静脉旁路手术是对许多患有心血管疾病的患者的关键生命或肢体治疗干预措施。尽管通常有效，但静脉旁路移植物会随着时间的流逝（五年内30-50％）的显着故障率，直接导致死亡率，肢体截肢和生活质量降低。该提案旨在扩大对静脉移植失败涉及的因素的理解，并将检查一种新型方法，以绕过可能对遮挡具有抗药性。这些研究还具有直接相关性，可通过提供新的分子方法来控制血管损伤反应，从而改善其他心血管干预措施（例如经皮血管成形术和支架）的长期结果。