Arp2/3复合物对血管壁细胞微丝骨架与分泌通路的调控在主动脉夹层中的作用及机制

Aortic dissection is a catastrophic cardiovascular disease, but its pathogenesis remains unclear. Aortic wall remodeling caused by various factors and secretion pathway changes become the currently main research directions of aortic dissection. Biomechanics of vascular wall cells （vascular smooth muscle cell and endothelia cell）play a crucial role in the dissected aorta remodeling, and cell mechanical response closely relates to microfilament cytoskeleton. Arp2/3 complex is a protein complex, which can regulate behaviors of microfilament cytoskeleton, and its function in biomechanics becomes the hot research topic in recent years. We firstly confirmed the decisive role of Arp2/3 in formation of branched actin cytoskeleton and reported its significant mechanisms on secretion pathway. Based on our previous studies, we found the obvious change of Arp2/3 complex expression in aortic dissection, which would open up a new field for the biomechanical study of aortic dissection. Thus, We come to this research proposal, from different levels (cell, tissue and animal model levels), using advanced techniques like the next generation sequencing, proteomics, micro fluid, live cell microscopy and hemodynamics simulation system, to confirm the function of Arp2/3 complex in the regulation of aortic wall cell microfilament cytoskeleton and secretion pathway in aortic dissection, and reveal biomechanical mechanisms of aortic dissection for providing a new strategy for its early prevention, early intervention and prognostic evaluation.

主动脉夹层是一种极其凶险的心血管疾病，但发病机制尚不清楚。各种因素导致的主动脉重构与分泌通路的改变是目前其发病机制研究的主要方向。血管壁细胞生物力学在夹层血管重构中起着至关重要的作用，而细胞力学应答与细胞微丝骨架密切相关。Arp2/3复合体是一种极重要的调控微丝骨架的复合蛋白，其细胞生物力学相关性成为近年来的研究热点。我们在国际上首次证实Arp2/3对分支状微丝骨架形成起决定性作用，并报道了其影响细胞分泌通路的重要机制。在前期研究中，我们发现主动脉夹层中Arp2/3表达的改变，这为主动脉夹层发病的生物力学研究开辟了新领域。我们计划在细胞、组织和模式动物水平，利用下一代测序、蛋白质组学、微流体、活细胞显微和血流动力学模拟系统等先进技术，证实Arp2/3在夹层发生过程中对细胞微丝骨架与分泌通路的调控，揭示夹层中细胞生物力学作用及调控机制，为主动脉夹层的早期预防、早期干预及预后评价提供新策略。

主动脉夹层是一种极其凶险的心血管疾病，但发病机制尚不清楚。Arp2/3复合体是一种极重要的调控微丝骨架的复合蛋白，其细胞生物力学相关性成为近年来的研究热点。我们在国际上首次证实Arp2/3对分支状微丝骨架形成起决定性作用，并报道了其影响细胞分泌通路的重要机制。我们在细胞、组织和模式动物水平，利用下一代测序、蛋白质组学、微流体、活细胞显微和血流动力学模拟系统等先进技术，发现亲水组结果显示病人和对照组存在明显差异；病人与对照组中IL-6存在明显差异，病人组升高；小动物模型构建成功，提示免疫遗传背景夹层有影响，卵磷脂代谢通路在夹层发生发展中发挥了作用，从主动脉夹层的小动物模型构建、代谢组研究、血清免疫因子检测几方面证实Arp2/3在夹层发生过程中对细胞微丝骨架与分泌通路的调控，揭示夹层中细胞生物力学作用及调控机制，为主动脉夹层的早期预防、早期干预及预后评价提供新策略。