Endothelial Barrier Regulation by Simvastatin

辛伐他汀对内皮屏障的调节

• 批准号: 6901259
• 负责人: JEFFREY R JACOBSON
• 金额: $ 12.5万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-05 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6901259
• 关键词: actin binding protein; antihypercholesterolemic agent; caldesmon; cardiovascular pharmacology; drug screening /evaluation; gene expression; integrins; laboratory mouse; lung; lung injury; microarray technology; nonhuman therapy evaluation; proteomics; respirators; respiratory disorder chemotherapy; respiratory pharmacology; simvastatin; stimulant /agonist; thrombin; tumor necrosis factor alpha; vascular endothelium; vascular endothelium permeability; actin binding protein; antihypercholesterolemic agent; caldesmon; cardiovascular pharmacology; drug screening /evaluation; gene expression; integrins; laboratory mouse; lung; lung injury; microarray technology; nonhuman therapy evaluation; proteomics; respirators; respiratory disorder chemotherapy; respiratory pharmacology; simvastatin; stimulant /agonist; thrombin; tumor necrosis factor alpha; vascular endothelium; vascular endothelium permeability

DESCRIPTION (provided by applicant): Derangements in lung vascular permeability, particularly in the context of acute lung injury (ALI), represent a common yet difficult clinical problem clearly associated with increased morbidity and mortality and effective therapies for the vascular leak associated with ALI are currently not available. The statins, a class of HMG CoA-reductase inhibitor, are used clinically for their ability to lower serum lipid levels and reduce the morbidity and mortality associated with coronary artery disease. However, not all of their beneficial effects can be attributed to cholesterol lowering. Accordingly, we have hypothesized that via complex effects on endothelial cells (EC), simvastatin induces barrier protection and offers a novel therapeutic strategy for acute lung injury (ALI) and ventilator-associated lung injury (VALI). In support of our hypothesis, we recently reported that simvastatin promotes endothelial cell (EC) barrier function in vitro in the presence of edemagenic agonists, a finding with dramatic significance with respect to clinical conditions characterized specifically by increased vascular permeability such as ALI/VALI. The underlying mechanism by which simvastatin augments EC barrier function, however, remains unclear and is the subject of this K08 application. We have identified a dual EC simvastatin response characterized by distinct early and delayed effects. We now propose to enlist a highly translational, mechanistic approach to further investigate simvastatin effects on EC. In Specific Aim 1, we will characterize simvastatin modulation of EC responses to thrombin and TNF-a, clinically relevant agonists, and to cyclic stretch, relevant to VALI. In Specific Aim 2, we will explore the temporal (early) EC simvastatin response with respect to the functional role of cortactin, an actin-binding protein which translocates peripherally within 2 h of simvastatin treatment. In Specific Aim 3, we will examine the temporal (delayed) effects of simvastatin on differential EC gene expression employing microarray analysis of human and mouse lung microvascular EC with specific focus on gene ontologies including cytoskeletal components and regulators. Finally, in Specific Aim 4, we will use a well-developed mouse model to investigate the potential therapeutic role of simvastatin in ALI/VALI. Our proposed studies will further the current understanding of statin effects on the endothelium and may have profound clinical relevance.

描述（由申请人提供）： 目前尚无肺血管通透性（特别是在急性肺损伤（ALI）的背景下）的危险，这是一个常见但困难的临床问题，与目前尚无与ALI相关的血管泄漏的发病率和有效疗法有关的常见但困难的临床问题。 他汀类药物是一类HMG CoA还原酶抑制剂，在临床上用于降低血清脂质水平并降低与冠状动脉疾病相关的发病率和死亡率的能力。 但是，并非所有的有益作用都可以归因于降低胆固醇。 因此，我们假设通过对内皮细胞（EC）的复杂作用，辛伐他汀，诱导屏障保护，并为急性肺损伤（ALI）和与呼吸机相关的肺损伤（VALI）提供了新的治疗策略。 为了支持我们的假设，我们最近报道说，辛伐他汀在存在递增性激动剂的情况下在体外促进内皮细胞（EC）屏障功能，这一发现相对于临床条件具有显着意义的发现，其特异性特征在于增加的血管通透性，例如Ali/Vali等血管通透性。 然而，辛伐他汀增强EC屏障功能的基本机制尚不清楚，并且是该K08应用的主题。 我们已经确定了一个双重EC辛伐他汀的反应，其特征是不同的早期和延迟作用。 现在，我们建议采用一种高度转化的机械方法，以进一步研究辛伐他汀对EC的影响。 在特定的目标1中，我们将表征辛伐他汀对EC对凝血酶和TNF-A的反应，临床相关的激动剂以及与Vali相关的循环拉伸的反应。 在特定的目标2中，我们将探索与肌动蛋白结合蛋白Cortactin的功能作用有关的时间（早期）EC辛伐他汀的反应，该蛋白质是肌动蛋白结合蛋白，在辛伐他汀治疗后2小时内易位。 在特定目标3中，我们将检查辛伐他汀对差异EC基因表达的时间（延迟）作用，采用对人和小鼠肺微血管EC的微阵列分析，并特别关注包括细胞骨架成分和调节剂在内的基因本体论。 最后，在特定的目标4中，我们将使用一个发达的小鼠模型来研究辛伐他汀在ALI/Vali中的潜在治疗作用。 我们提出的研究将进一步了解他汀类药物对内皮的影响，并可能具有深远的临床意义。