支气管哮喘发病中MUC1缺失通过NEDD4-2促进Occludin泛素化导致气道上皮屏障功能紊乱的机制研究

气道上皮屏障功能紊乱是支气管哮喘(BA)发病的重要原因之一。外界刺激通过破坏紧密连接(TJ)蛋白导致气道上皮屏障功能紊乱，促进BA的发生发展，然而其中的机制尚不清楚。我们发现：粘蛋白1(MUC1)在BA大鼠肺组织中表达降低；MUC1缺失可诱导气道上皮屏障功能紊乱，并加重BA大鼠肺部炎症；且MUC1缺失可增加Occludin的ser490磷酸化，并增强其与NEDD4-2结合，促进其泛素化降解。有研究表明，c-Src的活化可导致Occludin的降解，且MUC1可与c-Src形成复合物抑制其活化。由此提出科学假说：MUC1缺失诱导c-Src活化，促进Occludin磷酸化，使NEDD4-2介导Occludin泛素化降解，导致气道上皮屏障功能紊乱，加重BA炎症水平。本项目拟从临床、动物及分子细胞水平，探讨MUC1在BA发病中的作用及其调控气道上皮屏障功能的分子机制，有望为BA的防治提供新的策略。

The dysfunction of airway epithelial barrier is one of the important pathogeny of asthma (BA). External stimulation leads to dysfunction of airway epithelial barrier and promotes the pathogenesis of BA by destroying TJ protein. However, the mechanism is not clear. We found that the expression of MUC1 decreased in the lung tissue of BA rats; the absence of MUC1 could lead to the dysfunction of airway epithelial barrier and aggravate the lung inflammation of BA rats; moreover, the absence of MUC1 could increase the ser490 phosphorylation level of occludin, enhance the combination of occludin and NEDD4-2, and promote its ubiquitin degradation. Studies have shown that activation of c-Src can lead to the degradation of occludin, and MUC1 can inhibit c-Src activation by forming complex with c-Src. Therefore, the hypothesis is put forward: the absence of MUC1 induces the activation of c-Src, promotes the phosphorylation of occludin, and then promotes the ubiquitin degradation mediated by NEDD4-2, leading to the dysfunction of airway epithelial barrier, and further aggravates the level of BA inflammation. This project aims to explore the role of MUC1 in the pathogenesis of BA and its molecular mechanism of regulating the function of airway epithelial barrier from the clinical, animal and molecular cell levels, which is expected to provide a new strategy for the prevention and treatment of BA.