补体C5a受体信号在动脉粥样硬化早期过程中的作用及其机制研究

动脉粥样硬化是一种多细胞多因素参与的慢性炎症疾病，发病机制与病理过程尚未完全阐明，故仍缺乏有效的预防与根治方法。补体系统活化产生的小片段C5a是重要的促炎症介质,其主要受体C5aR广泛表达于炎症及实质细胞，C5a-C5aR信号在多种炎症及免疫相关疾病中起着重要病理作用。已有研究提示C5aR信号可能同样参与动脉粥样硬化过程并起着重要作用，但其作用机制不清。本研究里将使用C5aR及ApoE 双基因敲除小鼠（C5aR-/-ApoE-/-）以明确C5aR信号在高脂饮食诱导动脉粥样斑块形成过程的重要作用。拟采用骨髓重构建立"嵌合"小鼠以及主动脉移植、颈动脉内膜剥离、体外细胞共培养等实验技术靶向性探索C5aR信号对血管内皮细胞、平滑肌细胞以及单核/巨噬细胞的分别作用以及细胞间的相互影响，以阐明C5aR信号参与动脉粥样硬化早期过程的细胞分子机制，为今后动脉粥样硬化的早期干预提供可靠的理论与实验依据。

Atherosclerosis is a chronic inflammatory disease which involves multiple cellular and molecular events. The pathogenesis and pathological process of atherosclerosis (AS) remains unclear, and there still lack of effective therapies for prevention and treatment of AS. C5a generated by complement activation is a potent proinflammatory mediator. The major receptor for C5a (C5aR) is widely expressed in inflammatory and parenchymal cells. Recent researches have demonstrated that C5a-C5aR signaling is an important pathogenic factor in a wide range of inflammatory and immune diseases. The pathogenic role for C5aR has also been suggested in the process of AS, though the mechanism is unclear. In the proposed research, we will employ several improved approaches (i.e. cross-breeding of C5aR-/- and ApoE-/- mice, and combining with bone morrow chimeras, aortic transplantation and wire-induced endothelial denudation of the carotid artery, as well as primary cell cultures) to determine the role of C5aR in atherosclerotic plaque formation and explore the mechanisms through which C5a-C5aR signaling through acting on monocytes/macrophages, endothelial cells and smooth muscle cells contributes to the pathogenesis of AS. Results from these studies will provide new insight into mechanisms underlying AS and potential novel therapies for prevention and treatment of this disease.