具核梭杆菌外膜囊泡通过JNK/c-Jun/Claudin-4损伤口腔扁平苔藓上皮屏障的机制研究

口腔黏膜区域性免疫激活是口腔扁平苔藓（OLP）发病中的关键问题，树突状细胞（DCs）处于启动免疫反应的中心，但OLP中DCs活化的原因及机制不清。上皮屏障损伤是DCs活化的重要因素，闭合蛋白Claudin-4是上皮屏障的关键组成并直接影响其功能。申请人致力于菌群失调在OLP中的研究，率先验证具核梭杆菌（F.nucleatum）与OLP发病相关；并发现F.nucleatum外膜囊泡可抑制上皮细胞Claudin-4表达，Claudin-4表达受JNK/c-Jun转录因子调控。据此我们提出：F.nucleatum外膜囊泡通过JNK/c-Jun信号通路下调上皮细胞Claudin-4表达致口腔黏膜上皮屏障损伤进而参与DCs活化。本项目将从分子、细胞、体外和体内等多方面阐明F.nucleatum外膜囊泡损伤口腔黏膜上皮屏障的分子机制，将为OLP致病机理研究和基于黏膜屏障修复的新防治策略提供依据。

Focal immune activation is a key problem in the pathogenesis of oral lichen planus (OLP). Dendritic cells (DCs) are at the center of initiating the immune response, but the cause and mechanism of DCs activation in OLP are unclear. Epithelial barrier damage is an important factor in the activation of DCs. Claudin-4 is a key protein of the epithelial barrier and directly affects function of the epithelial barrier. The applicant is committed to the study of flora disorders in OLP, and is the first to verify that F.nucleatum is associated with the pathogenesis of OLP; and found that outer membrane vesicles of F.nucleatum can inhibit the expression of Claudin-4. The expression of Claudin-4 is regulated by the JNK/c-Jun transcription factor. Based on this, we propose that outer membrane vesicles from F.nucleatum down-regulate the expression of Claudin-4 in epithelial cells through the JNK/c-Jun signaling pathway damaging oral mucosal epithelial barrier damage and participating in the activation of DCs. This project will elucidate the molecular mechanism of outer membrane vesicles of F.nucleatum damaging the oral mucosal epithelial barrier from molecular, cellular, in vitro and in vivo, and will provide a basis for the study of the pathogenic mechanism of OLP and new prevention and treatment strategies based on mucosal barrier repair.