Myosin IIa信号轴介导内皮与免疫细胞互作调控血管保护的作用与机制

在血管损伤初期，炎症反应失控、内皮功能失调是疾病发生的关键机制。近几年来，申请人团队首次报道粘附斑分子Zyxin与Myosin IIa同属一个信号蛋白复合体（简称Myosin IIa信号轴），是一组内皮胞吐介导的全新血管损伤保护分子。有意思的是，最近发现它们对内皮细胞增殖或存活无直接影响，而能调控早期炎症反应，涉及固有免疫细胞及其活性因子（如HMBG2；S100A9；MIF等），并与细胞极性分泌有关。本课题将1）研究Myosin IIa信号轴在血管损伤早期保护性炎症反应中的作用；2）明确Myosin IIa信号轴调控极性分泌并介导内皮与固有免疫细胞互作的关键分子；3）应用高解析度成像等技术，揭示细胞胞吐介导内皮与固有免疫细胞互作及其极性规律；4）通过与合作，探讨Myosin IIa信号轴血管保护作用新机制的临床意义。该项目将为血管损伤保护机制提供全新视角。

In the early stage, de-regulated inflammatory response and endothelial dysfunction belong to critical mechanisms for the pathogenesis of vascular injury. In the past years, our group demonstrated for the first time that focal adhesion molecules Zyxin and Myosin IIa, which belong to the same signaling complex, are new vessel protectors against injury mediated via endothelial exocytosis. Interestingly, our recent studies have shown that they have no direct effects on endothelial proliferation or survival but exert exocytosis-mediated vaso-protection through modulating early vascular inflammation against multiple injuries, involving innate immune cells and several related multiple bioactive mediators (such as HMBG2, S100A9, MIF, and etc.). In this application, we propose 1) to study the role of Myosin IIa signaling axis in innate immune response-mediated protective inflammation under vascular injury, 2) to determine molecular mechanism underlying Myosin IIa axis-mediated cellular polarity in regulating endothelium/leukocyte interactions and secretion, 3) to visualize exocytosis-associated endothelium/leukocyte interactions by using superresolution microscopy, and 4) to elucidate the pathological significance of Myosin IIa axis-mediated protective effects in related vascular diseases under clinical settings in collaboration with physician scientists. This proposal is based on our original findings and will not only provide new insights into the cellular and molecular mechanisms of vasoprotective inflammatory responses against vascular injury, but may also reveal potentially new targets for treating related diseases.