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

基本信息

批准号：
7318102
负责人：
Michael S Conte
金额：
$ 40.56万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7318102
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 Losses 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 Rate 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 design 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

项目摘要

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）：血管介入治疗（包括血管成形术、支架置入术和搭桥手术）的失败常常是由于血管壁过度愈合反应导致狭窄和闭塞。该过程的特征是内膜增生（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）是一种调节细胞凋亡和增殖的新型蛋白质，可能是癌症和 IH 等以生长失调为特征的疾病的重要治疗靶点。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，尤其是在静脉移植失败的情况下。首先，我们将研究体外和体内直接抑制 SW 基因表达的方法。将确定 SW 敲低对 SMC 表型和静脉移植物增生的影响。在第二个具体目标中，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粥样硬化药物的治疗效用，从而扩大血管干预的益处。目前，美国每年约有 50 万例患者采用静脉搭桥手术，对于许多患有心血管疾病的患者来说，这是一种重要的保命或保肢干预措施。尽管静脉旁路移植通常有效，但随着时间的推移，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。该提案旨在扩大对静脉移植失败因素的理解，并将研究一种重新设计可能抵抗闭塞的旁路移植物的新方法。这些研究还通过提供新的分子方法来控制血管损伤反应，从而改善经皮血管成形术和支架置入术等其他心血管干预措施的长期结果。