SPINK1/Spink1蛋白缺失在慢性胰腺炎纤维化发生发展中的作用及机制研究

慢性胰腺炎（CP）是一种以胰腺组织进行性纤维化为特征的疾病，发生机制不明，治疗困难。我们针对中国人特征性的、致病基因突变SPINK1 c.194+2T＞C在世界上首次构建了该位点转基因小鼠，发现：该小鼠可自发出现胰腺纤维化这一CP最为典型的病理改变。因此，本研究将通过转基因鼠模型，明确该突变所造成的SPINK1/Spink1蛋白缺失是造成CP胰腺纤维化的始动因素；利用表达谱芯片筛选并鉴定介导该蛋白缺失促纤维化的关键分子；通过体内外实验，多角度验证SPINK1/Spink1蛋白缺失可直接激活腺泡细胞内NF-κB/TGF-β信号通路，活化PSCs，调控纤维化；和/或通过激活AP-1/IL-33信号通路，进而活化PSCs胞内NF-κB信号通路，调控胰腺纤维化进程这一假说；最后拟通过干预NF-κB通路的激活，探索其潜在治疗价值；为阐明胰腺纤维化分子机制和治疗CP提供新的思路和靶点。

Chronic pancreatitis (CP) is a disease characterized by progressive fibrosis of pancreatic tissue. The pathogenesis is unknown and the treatment is difficult. We first constructed the transgenic mice with SPINK1 c.194+2T>C mutation，and then we found that the mice could spontaneously develop to the pancreatic fibrosis which is the most typical pathological change of CP. Therefore, the study will confirm that the deletion of SPINK1/Spink1 protein caused by the mutation is the initiating factor of CP fibrosis through transgenic mice; and then screen and identify the differentially expressed downstream genes caused by the deletion of SPINK1/Spink1 protein using expression microarray; We will verify that the deletion of SPINK1/Spink1 protein can directly activate NF-κB/TGF-β signaling pathway in acinar cells and regulates fibrosis，and/or activates AP-1/IL-33 signaling pathway in acinar cells and then activate NF-κB signaling pathway in PSCs to regulate the process of pancreatic fibrosis through in vivo and in vitro experiments. Finally, we intend to explore its potential therapeutic value by interfering with the activation of NF-κB signaling pathway; and provide new ideas and targets for elucidating the molecular mechanism of pancreatic fibrosis and treatment of CP.