Thrombospondin-1, VSMC Migration and Intimal Hyperplasia - a role for statins

Thrombospondin-1、VSMC 迁移和内膜增生 - 他汀类药物的作用

• 批准号: 8698267
• 负责人: Vivian Gahtan
• 金额: --
• 依托单位: STRATTON VETERANS ADMIN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698267
• 关键词: Acute; Acute-Phase Proteins; Address; Aging; Angioplasty; Animal Model; Attenuated; Balloon Angioplasty; Biological Assay; Blood Vessels; Caring; Carotid Arteries; Cell Culture Techniques; Cessation of life; Chemotaxis; Chemotaxis Inhibition; Cholesterol; Common carotid artery; Coronary artery; Data; Development; Disease; Drug Delivery Systems; Drug usage; Dyslipidemias; Effectiveness; Enzyme-Linked Immunosorbent Assay; FOS gene; Failure; Functional disorder; Gel; Gene Expression; Genes; Glycoproteins; Goals; Health; High Density Lipoproteins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperplasia; In Situ Hybridization; Injury; Intervention; Knockout Mice; Knowledge; Lesion; Life; Ligation; Limb structure; Lipids; Longevity; Low-Density Lipoproteins; Methodology; Methods; Micelles; Mission; Modality; Oral; Outcome; Pathogenesis; Pathway interactions; Patients; Peripheral arterial disease; Pluronics; Polymerase Chain Reaction; Population; Positioning Attribute; Procedures; Process; Proteins; Publications; Quality of life; Rattus; Research; Role; Secondary to; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Specimen; Staining method; Stains; Stents; Testing; Therapeutic; Thrombospondin 1; Time; Up-Regulation; Veterans; Western Blotting; base; clinically relevant; disability; improved; in vivo; inhibitor/antagonist; innovation; mevalonate; migration; novel; novel therapeutics; prevent; response to injury; restenosis; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): Peripheral arterial disease and restenosis after balloon angioplasty to treat arterial blockages is a significant cause of disability and death in the veteran population. Endovascular interventions are among the fastest growing treatments for peripheral arterial disease; however, restenosis secondary to intimal hyperplasia (IH) remains a major cause of failure from these procedures. Thrombospondin-1 (TSP-1) clearly contributes to IH by regulating the arterial response to injury. However, the mechanisms by which dyslipidemia enhances TSP- 1's actions, how TSP-1 induces IH, and optimal therapies to prevent IH after angioplasty in patients with peripheral arterial disease represent important gaps in our knowledge and is addressed by this application. Our long-term goal is to understand how TSP-1 signaling pathways can be manipulated therapeutically to prevent IH in vivo. The objective of this proposal is to investigate the mechanisms by which TSP-1, dyslipidemia and enhanced statin delivery regulate IH development. Our central hypothesis is that dyslipidemia enhances and that statin therapy will effectively inhibit the pro-stenotic effects of TSP-1. This hypothesis has been formulated on the basis of our strong preliminary data. The rationale for the proposed project is that understanding the underlying mechanisms of TSP-1 and dyslipidemia on IH and establishing optimal statin delivery to inhibit IH, will result in novel and innovative approaches to prevent restenosis after angioplasty. Our hypothesis will be tested by pursuing the following Specific Aims: 1) investigate how dyslipidemia modifies TSP-1-induced chemotaxis and signaling; 2) elucidate the mechanisms of acute statin inhibition on TSP-1-induced signaling; 3) determine the magnitude of TSP-1's role in statin efficacy; and 4) ascertain the optimal modality of statin delivery to reduce IH. The methodologies utilized to investigate these Specific Aims include: 1) modified Boyden chamber to assess vascular smooth muscle cell chemotaxis; 2) western blot and ELISA for cell signaling; 3) quantitative real time polymerase chain reaction for gene expression; 4) two animal models of IH - carotid artery ligation in the TSP-1 knockout mouse and balloon injury of the common carotid artery in normal and dyslipidemic rats; 5) different statin delivery methods in vivo - oral, intraluminal (using targeted micelles) and topical (using pluronic gel); and 6) morphometric analysis, immunohistochemical staining and in situ hybridization for analysis of the arterial specimens. The significance of the proposed research is that the findings will provide a major advance which is expected to result in the development of new treatment strategies to prevent restenosis after angioplasty for peripheral arterial disease lesions. The proposed research in this application is innovative, in our opinion, because the proposed development and testing of a targeted drug delivery system using statins for the treatment of these lesions would be a new treatment modality. The findings from this application will advance efforts to improve the quality of life and longevity by providing safer and more effective therapeutic options for veterans with peripheral arterial disease.

描述（由申请人提供）： 周围动脉疾病和球囊血管成形术治疗动脉阻塞后的再狭窄是退伍军人群体残疾和死亡的重要原因。血管内介入治疗是外周动脉疾病发展最快的治疗方法之一。然而，继发于内膜增生（IH）的再狭窄仍然是这些手术失败的主要原因。血小板反应蛋白-1 (TSP-1) 通过调节动脉对损伤的反应，显然有助于 IH。然而，血脂异常增强TSP-1作用的机制、TSP-1如何诱导IH以及外周动脉疾病患者血管成形术后预防IH的最佳疗法代表了我们知识中的重要空白，并且通过本申请解决。我们的长期目标是了解如何通过治疗手段操纵 TSP-1 信号通路来预防体内 IH。本提案的目的是研究 TSP-1、血脂异常和增强他汀类药物递送调节 IH 发展的机制。我们的中心假设是血脂异常会增强，而他汀类药物治疗将有效抑制 TSP-1 的促狭窄作用。这一假设是根据我们强有力的初步数据提出的。该项目的基本原理是了解 IH 中 TSP-1 和血脂异常的潜在机制并建立抑制 IH 的最佳他汀类药物递送，将产生预防血管成形术后再狭窄的新颖和创新方法。我们的假设将通过追求以下具体目标进行检验：1）研究血脂异常如何改变 TSP-1 诱导的趋化性和信号传导； 2) 阐明他汀类药物对TSP-1诱导信号传导的急性抑制机制； 3) 确定 TSP-1 在他汀类药物疗效中的作用程度； 4) 确定他汀类药物给药的最佳方式以减少 IH。用于研究这些具体目标的方法包括：1) 改良博伊登室以评估血管平滑肌细胞趋化性； 2) 用于细胞信号转导的蛋白质印迹和ELISA； 3) 基因表达定量实时聚合酶链式反应； 4）两个 IH动物模型——TSP-1基因敲除小鼠的颈动脉结扎以及正常和血脂异常大鼠的颈总动脉球囊损伤； 5)不同的他汀类药物体内递送方法——口服、腔内（使用靶向胶束）和局部（使用普朗尼克凝胶）； 6) 用于分析动脉标本的形态测量分析、免疫组织化学染色和原位杂交。拟议研究的意义在于，这些发现将提供重大进展，预计将导致开发新的治疗策略，以预防外周动脉疾病病变血管成形术后的再狭窄。我们认为，本申请中拟议的研究具有创新性，因为拟议开发和测试使用他汀类药物治疗这些病变的靶向药物输送系统将是一种新的治疗方式。该应用的研究结果将通过为患有外周动脉疾病的退伍军人提供更安全、更有效的治疗选择，推动改善生活质量和延长寿命的努力。