血浆激肽释放酶-激肽系统对内皮祖细胞的调控在血管稳态失衡中的作用与机制

项目名称： 血浆激肽释放酶-激肽系统对内皮祖细胞的调控在血管稳态失衡中的作用与机制

项目编号： No.91539122

项目类型： 重大研究计划

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 武艺

作者单位： 苏州大学

项目金额： 75万元

中文摘要： 类风湿性关节炎（RA）等自身免疫性疾病患者普遍并发动脉粥样硬化，心脑血管性疾病占其死亡原因的首位。目前RA患者血管稳态失衡和血管重构的机制不清楚，是亟待解决的临床难题。我们近来发现，血浆激肽释放酶-激肽系统 (KKS)不但在关节炎发病中起重要作用，而且抑制内皮祖细胞（EPC）的功能。EPC在维持血管稳态中非常关键。本项目的假说是，KKS调控EPC功能，介导血管稳态失衡和血管重构，是RA动脉粥样硬化形成的重要因素。我们将应用KKS缺陷小鼠，结合KKS抑制剂，通过关节炎并发动脉粥样硬化模型，研究在关节炎发病中KKS通过调控EPC功能，介导血管损伤修复障碍和动脉粥样硬化形成的作用，并剖析其作用机制。本项目将首次揭示炎症环境下KKS介导的活化网络在血管稳态失衡与血管重构中的重要作用，将为阐明炎症诱发动脉粥样硬化的演变过程和发病机制提供创新性认识，为心脑血管性疾病的转归揭示新的分子标志及干预靶点。

中文关键词： 血管稳态；血管重构；内皮祖细胞；动脉粥样硬化；激肽释放酶-激肽系统

英文摘要： Rheumatoid arthritis (RA) is a major autoimmune disease which is characterized by development of atherosclerosis. Cardio-cerebrovascular diseases are major cause of mortality and morbidity in these patients. However, the mechanisms underlying the desruption of vascular homeostasis and vascular remodeling in RA remain poorly understood. Recently, we found that plasma kallikrein-kinin System (KKS) not only plays an important role in the pathogenesis of RA. but also inhibits the function of endothelial progenitor cell (EPC). It has been well known that EPC is critical for vascular repair and thus the maintenance of vascular homeostasis. In this proposal, we hypothesize that the KKS regulation of EPC function contributes to vascular homeostasis desruption and vascular remodeling, leading to development of atherosclerosis in the setting of arthritis. To test our hypothesis, we will observe the phenotype of KKS deficient mice in combination with KKS inhibitors in the model of arthritis with atherosclerosis. We will investigate the in vivo activities of the KKS in regulation of EPC, and will determine the role of the KKS in vascular repair impairment and atherosclerosis pathogenesis, as well as the underlying mechanisms. Our study will for the first time reveal the importance of the KKS in vascular homeostasis desruption and vascular remodeling, and will offer novel insight into the pathogenesis of inflammation-induced atherosclerosis. Additionally, this project will provide new molecular marker and therapeutic target for diagnosis and prognosis of cardio-cerebrovascular diseases.

英文关键词： vascular homeostasis;vascular remodeling;endothelial progenitor cells;atherosclerosis;kallikrein-kinin system