内质网整合应激对其加工能力的强化在气道黏液高分泌形成过程中的基础意义

气道黏液高分泌是慢性气道炎症性疾病的基本病理特点，尤其在急性加重期患者中，常表现为持续性“速发相”分泌状态。目前对粘蛋白（MUC）5AC转录水平的调控及后期糖化、硫化修饰研究已较明确，但相关影响因素纷乱交集，难于有效干预。慢性炎症刺激下，粘蛋白分泌细胞可通过内质网整合应激反应（ISR）提升其蛋白加工负荷量，该效应可能系通过IRE1/XBP1信号通路影响内质网信号识别颗粒受体（SRPR）及亲水性移位通道Sec61复合体这两个介导雏形肽向内质网移位的关键因子实现。本研究拟用免疫电镜技术观察炎症刺激通过内质网SRPR/Sec61门控复合体提升内质网对MUC5AC的受纳量。进一步籍CRISPR/Cas9基因敲除技术、RNA干扰及节点抑制剂的方法，验证IRE1/XBP1信号链的介导作用。研究结果将进一步完善气道黏液高分泌的形成机制，同时由于研究节点的门控特征，可能为其防治提供有效的干预靶点。

Airway mucus hypersecretion is one of the major pathologic features of aiway chronic inflammatory diseases. Especially in the duration of acute exacerbation of COPD, airway mucin, with large quantities and viscous properties, exhibits a ‘sparked’ manner of exocytosis. Till now, the specific mechanisms of the MUC5AC transcription, galactosylated modification and sulfated modification have been relatively explicit demonstrated. However, due to the intricate affecting factors, the effectively therapy hasn’t been concluded based on the specific target. Under the stimulation of chronic inflammation, airway goblet cell might expand its capacity of MUC5AC processing through an integrated stress response (ISR) of endoplasmic reticulum dependent signaling which might be activated by the signal recognition particle receptor (SRPR) and a hydrophilic channel consisted of a Sec61 heterotrimer with a IRE1/XBP1 signaling cascade. In this project, with electron microscope techniques in vitro, we intend to investigate an elevated MUC5AC loading capacity of endoplasmic reticulum (ER) induced by chronic inflammation via the SRPR/Sec61 gating channels. Based on the CRISPR/Cas9 technology, RNA interference and signaling inhibitors, we aim to demonstrate the critical role of IRE1/XBP1 signaling cascade in chronic inflammation promoted- ER loading tolerance of MUC5AC.The results of this project might improve the mechanisms of the formation of MUC5AC hypersecretion and provide a new target based therapy for airway mucus hypersecretion.