哺乳动物Ste20样激酶1（MST1）负向调控肥大细胞介导的过敏反应及其分子机制研究

Mast cells are widely involved in a variety of allergic responses. The pathogenesis and mechanisms study of mast cell-mediated allergic responses are of great significance for the protection of human health. Mammalian sterile 20-like kinase 1 (MST1) plays the important roles in cellular differentiation, prompting cellular migration and adhesion, inhibiting autophagy and prompting apoptosis, but the function of MST1 in allergic responses mediated by FcεRI signaling pathway in mast cells has not been reported. Here, we found that the gene expression of MST1 in peripheral blood from asthma patients was significantly increased, and the expression of MST1 in mouse primary mast cells was inhibited by the FcεRI signaling activation. MST1 knockdown promoted the activation of mast cells induced by FcεRI. Furthermore, MST1 deficient mice showed enhanced allergic responses mediated by mast cells. These results suggested that MST1 negatively regulated the activation of mast cells and its mediated allergic reaction. In this study, we intend to further study the role of MST1 in mast cell-mediated allergic diseases (including asthma) and its underlying molecular mechanisms. The completion of this project will further enrich the pathophysiology of MST1 function, and provide new strategies and targets for the clinical treatment of mast cell-mediated allergic responses and asthma.

肥大细胞活化广泛参与多种过敏反应。研究肥大细胞介导的过敏反应的发病过程及机制对于保护人类身体健康具有重要意义。哺乳动物Ste20样激酶1（MST1）在细胞分化、凋亡，细胞黏附和迁移等多种生理活动中发挥重要作用，但其在肥大细胞FcεRI信号通路活化介导的过敏反应未见报道。我们发现MST1基因在哮喘患者外周血中表达显著降低，并且FcεRI活化抑制小鼠肥大细肥中MST1表达。而MST1敲除显著促进FcεRI诱导的肥大细胞活化。MST1在小鼠中敲除后，明显增强FcεRI诱导的肥大细胞介导的全身性过敏反应。以上结果提示MST1负向调控肥大细胞活化和其介导的过敏反应。本课题拟在此基础上深入研究MST1在肥大细胞介导的哮喘等过敏性疾病中的作用及具体分子机制，并明确MST1表达和临床哮喘病情的相关性。本项目的完成可进一步丰富MST1的病理生理功能，为肥大细胞介导的过敏反应调控及临床治疗提供新的思路和靶点。

肥大细胞是引发机体I型超敏反应极为关键的效应细胞。研究肥大细胞介导的过敏反应的发病过程及机制对于保护人类身体健康具有重要意义。哺乳动物Ste20样激酶1（MST1）在细胞分化、凋亡，细胞黏附和迁移等多种生理活动中发挥重要作用，但其在肥大细胞活化及过敏性疾病中的作用尚未有过报道。我们发现MST1基因在哮喘患者外周血中表达显著降低，并且在肺泡灌洗液中与疾病严重程度呈负相关。在小鼠肥大细肥FcεRI活化后，MST1表达同样下降。MST1在小鼠中敲除后，明显增强肥大细胞依赖性哮喘，以及肥大细胞介导的全身性和局部性过敏反应。而MST1敲除能显著促进肥大细胞FcεRI活化后诱导炎性细胞因子的产生和细胞脱颗粒。信号通路实验发现MST1靶向Lyn/Fyn磷酸化从而负向调控FcεRI介导的肥大细胞活化。综上所述，本研究结果提示MST1负向调控肥大细胞活化和其介导的过敏反应，进一步丰富了MST1的病理生理功能，为肥大细胞介导的过敏反应调控及临床治疗提供新的思路和靶点。