E3泛素连接酶FBXW11降解RASSF1A阻碍自噬流促进急性胰腺炎损伤的机制研究

急性胰腺炎（acute pancreatitis, AP）是消化系统最常见的一种急性炎症性疾病，胰蛋白酶原激活与炎症反应是其早期启动的核心事件。胰腺腺泡细胞的异常自噬主要特征为自噬流受阻，其可引起胰蛋白酶原异常激活及炎症反应，是AP发病的关键因素之一。E3泛素连接酶作为泛素-蛋白酶体系统的重要成分，其介导的泛素化修饰可参与人类多种疾病的发生发展，但其在AP中的功能尚缺乏系统的研究。通过前期研究挖掘到一个在AP中显著上调表达的E3泛素连接酶FBXW11，发现其可抑制腺泡细胞自噬流，并可促进RASSF1A泛素化降解。本项目拟综合利用分子生物学、细胞生物学及动物模型等手段，在分子-细胞-动物水平探讨以下问题：①FBXW11是否通过阻碍腺泡细胞自噬流促进AP胰腺损伤？②RASSF1A是否参与了FBXW11对腺泡细胞自噬流的调控作用？这些研究将揭示AP发病的新机制，为寻找AP治疗新靶点提供实验依据。

Acute pancreatitis (AP) is the most common acute inflammatory disease of the digestive system. Trypsinogen activation and inflammation are critical early events in the initial development of AP. Abnormal autophagy of pancreatic acinar cells is characterized by a disrupted autophagic flux. The abnormal trypsinogen activation and inflammation caused by dysfunctional autophagy is one key factor in AP pathogenesis. As an important component of the ubiquitin-proteasome system, E3 ubiquitin ligase-mediated ubiquitination can participate in the occurrence and development of many human diseases, but its function in AP has yet to be systematically studied. Through previous research, we discovered an E3 ubiquitin ligase FBXW11 that was significantly up-regulated in AP. Meanwhile, we found that FBXW11 could inhibit the autophagic flux of pancreatic acinar cells and promote RASSF1A degradation by ubiquitination. This study intends to comprehensively use molecular biology, cell biology and animal models to explore the following issues at the molecular-cell-animal level: ① Does FBXW11 promote AP pancreatic injury by obstructing the autophagic flux of acinar cells? ② Does RASSF1A participate in the regulation of FBXW11 on autophagic flux in acinar cells? These studies will reveal the new mechanism of AP pathogenesis and provide experimental basis for finding new targets for AP treatment.