Role of Tie-1 in Vascular Inflammation and Atherosclerosis

描述（由申请人提供）： 这项研究的长期目标是研究Tie-1在血管炎症和动脉粥样硬化中的作用。Tie-1在易发生动脉粥样硬化的动脉分支点和动脉粥样硬化病变中上调。我们推测Tie-1在这些位点的激活是引发动脉粥样硬化发展的沉淀分子事件之一。事实上，我们有证据表明Tie-1活性在体外诱导内皮炎症。该研究计划旨在探索Tie-1与动脉粥样硬化之间的联系，并在分子水平上获得对该疾病的机制理解。具体而言，我们建议：1）通过单细胞培养实验和人工动脉壁重建模型研究Tie-1在体外内皮细胞中的促炎特性，通过检测ICAM-1、VCAM-1、E-选择素、IL-6和IP-10的作用来研究Tie-1在内皮细胞中的促炎特性; 2）为了剖析负责Tie-1的信号通路，通过阐明p38 MAP激酶的激活机制和通过功能蛋白质组学鉴定酪氨酸磷酸化蛋白质诱导炎症反应; 3）通过使用胶原-纤连蛋白凝胶植入小鼠模型和以内皮特异性方式条件性表达Tie-1的转基因小鼠系，研究Tie-1在体内炎症和动脉粥样硬化发展中的作用。这些实验的结果可能会阐明为什么动脉粥样硬化病变往往发生在特定的血管部位。这一提议与NIDDK的使命高度相关，因为动脉粥样硬化影响肾功能。动脉粥样硬化是肾动脉狭窄的主要原因，约占90%。RAS引起肾动脉狭窄和肾灌注减少，导致高血压。最终，可能发生缺血性肾病，导致终末期肾衰竭。RAS中的动脉粥样硬化斑块通常发生在肾动脉口。引人注目的是，Tie-1在腹主动脉-肾动脉交界处显著上调。因此，了解Tie-1在动脉粥样硬化中的作用可能对预防RAS有直接影响。 动脉粥样硬化是西方国家的主要健康问题之一。对血管炎症导致动脉粥样硬化的机制的进一步了解将产生诊断和/或治疗目的所需的宝贵信息。

DESCRIPTION (provided by applicant): The long-term goal of this study is to examine the role of Tie-1 in vascular inflammation and atherosclerosis. Tie-1 is upregulated at atherosclerosis-prone arterial branch points and in atherosclerotic lesions. We postulate that Tie-1 activation at these sites is one of the precipitating molecular events that initiates the development of atherosclerosis. Indeed, we have evidence to show that Tie-1 activity in vitro induces endothelial inflammation. The experiments proposed in this grant are designed to probe the connection between Tie-1 and atherosclerosis and to gain mechanistic understanding of the disease at the molecular level. Specifically, we propose: 1) To study the proinflammatory property of Tie-1 in endothelial cells in vitro by examining the roles of ICAM-1, VCAM-1, E-selectin, IL-6, and IP-10 using both mono-cell-type culture experiments and an artificial arterial wall reconstruction model; 2) To dissect signaling pathways responsible for Tie-1-induced inflammatory response by elucidating the mechanism of activation of p38 MAP kinase and by identifying tyrosine-phosphorylated proteins via functional proteomics and ; 3) To study the role of Tie-1 in inflammation and atherosclerosis development in vivo by using a collagen-fibronectin gel implantation mouse model and a transgenic mouse line that conditionally expresses Tie-1 in an endothelial specific manner. Results from these experiments may shed light on the question why atherosclerotic lesions tend to develop at particular vascular sites. This proposal is highly relevant to the mission of NIDDK, because atherosclerosis affects kidney function. Atherosclerosis is the main cause of renal artery stenosis (RAS), accounting for 90% of the cases. RAS causes narrowing of the renal artery and reduction in renal perfusion, resulting in hypertension. Ultimately, ischemic nephropathy can occur, leading to end stage renal failure. Atherosclerotic plaques in RAS usually develop at the ostium of the renal artery. Strikingly, Tie-1 is dramatically upregulated at the aorta-renal artery junction. Therefore, understanding the role of Tie-1 in atherosclerosis may have a direct impact on the prevention of RAS. Atherosclerosis is one of the major health problems in western countries. An improved mechanistic understanding of vascular inflammation leading to atherosclerosis will yield invaluable information necessary for diagnostic and/or therapeutic purposes.