基于NLRP3/Caspase-1/GSDMD经典细胞焦亡途径探讨M3受体诱导小鼠急性胰腺炎的作用及机制研究

急性胰腺炎（acute pancreatitis，AP）的主要特征为胰腺细胞死亡造成大量炎症，进而发展为全身急性炎症反应综合征引起重症急性胰腺炎。目前针对AP的发病机制与胰腺细胞死亡机制过程仍未完全阐明。许多证据表明胆碱能神经可能参与AP的发生，我们前期发现胰腺细胞中M3受体的激活可诱导AP小鼠模型，同时观察到胰腺组织中NLRP3炎症小体激活、大量的炎症细胞以及细胞焦亡的形成。细胞焦亡是近期提出的细胞死亡方式之一，以诱导大量炎症为主要特征。本项目拟通过体内外干预NLRP3、焦亡关键蛋白GSDMD靶点，减少AP过程中胰腺腺泡细胞焦亡从而降低炎症反应过程，探讨NLRP3/Caspase-1/GSDMD经典细胞焦亡途径在M3受体诱导AP发生过程中的机制，为临床上AP的靶向治疗以及减少AP患者重症化的发生奠定理论基础。

The main features of acute pancreatitis (AP) are pancreatic acinar cells death and inflammatory response, inducing systemic acute inflammatory response syndrome and subsequent progression to severe acute pancreatitis. However, the pathogenesis of AP and the mechanism of pancreatic acinar cells death have not been fully clarified at present. A lot of clinical evidence has found that cholinergic nerves may be involved in the occurrence of AP. We previously found that the activation of M3 receptor in pancreatic acinar cells can induce the mouse model of AP. Meanwhile, we observed the activation of NLRP3 inflammasome, a large number of inflammatory cells and the formation of pyroptosis in pancreatic tissues. Pyroptosis is one of the methods of cell death recently proposed, which is mainly characterized by the induction of large amounts of inflammation. This project intends to intervene the target of NLRP3 and the key protein of pyrolysis, GSDMD in vivo and in vitro, to reduce pyrolysis of pancreatic acinar cell during AP process, thereby reducing the inflammatory process. To explore the mechanism of NLRP3/Caspase-1/GSDMD classical pyroptosis pathway in the occurrence of M3 receptor induced AP, so as to lay a theoretical foundation for the targeted therapy of AP in clinical practice and the reduction of the occurrence of severe disease in AP patients.