Orai1通过NFAT/c-Myc信号轴调控糖酵解参与肥大细胞活化及在慢性自发性荨麻疹发病机制中的作用研究

肥大细胞活化是荨麻疹发病的中心环节，最新的研究表明降低糖酵解水平能够显著性抑制肥大细胞活化。Orai1是钙离子通道重要组成部分，其基因多态性与慢性自发性荨麻疹发病密切相关，而CaN-NFAT是钙离子活化的主要信号通路。我们的前期结果显示：敲降Orai1能够抑制糖酵解水平，下调包括c-Myc在内的糖酵解途径关键分子的表达，并抑制肥大细胞活化。而糖酵解途径关键分子的表达（如：c-Myc,Glut1等）在慢性自发性荨麻疹患者外周血来源肥大细胞中表达显著升高，且c-Myc启动子区域内存在NFAT的结合位点，因此我们认为Orai1能够通过Ca2+-CaN-NFAT通路，调控c-Myc的表达，影响糖酵解，参与肥大细胞活化。本项目将通过膜片钳、CHIP、Seahorse等方法研究Orai1调控糖酵解及肥大细胞活化的作用机制，阐明Orai1在慢性荨麻疹中的意义和地位，为该病的防诊治提供新的思路和策略。

The mast cell activation plays a central role in urticaria pathogenesis. Recent evidence showed that inhibition of glycolysis significantly attenuates mast cells activation. Orai1 is an important part of calcium channel, and its gene polymorphism is closely related to chronic spontaneous urticaria. The CaN-NFAT is a pivotal pathway in calcium dependent activated signaling pathway. Our previous results showed that knock down of Orai1 could inhibit glycolysis, down-regulate the expression of key molecules of glycolysis, such as c-Myc, and block the activation of mast cells, meanwhile, the expression of key molecules of glycolysis including c-Myc, Glut1 were significantly raised in mast cells isolated from chronic spontaneous urticaria patients. Furthermore, there are NFAT recognized sites in c-Myc promoter. Based on these results, we propose that Orai1 could regulate c-Myc expression through Ca2+-CaN-NFAT pathway, which affects on glycolysis and IgE-mediated mast cell activation. In this study, patch clamp, CHIP and Seahorse were performed to investigate the role of Orai1 in glycolysis and mast cell activation, which provide novel insights for the prevention and treatment of urticaria.