特发性慢性胰腺炎SPINK1基因致病突变位点的筛查及其功能研究

Idiopathic pancreatitis is diagnosed with chronic pancreatitis by exclusion of other potential causes including rare ones. Because the aetiopathogenesis of idiopathic chronic pancreatitis frequently remains obscure, the early diagnosis and etiological therapy are difficult. To explore the pathogenesis is becoming an international hotspot. Recent data suggest that genetic mutations, including the serine protease inhibitor Kazal type-1 (SPINK1) gene is associated with ICP. The p.N34S variant was the most common mutation identified in patients in India and Western countries. However, the c.194+2T>C mutation in SPINK1 is the most common mutation in East Asians. But now the research about this is still weak in China. Therefore, we sought to determine the frequency of the SPINK1 c.194+2T>C mutation in a cohort of Chinese ICP patients. We also investigated the impact of this mutation on the clinical course of ICP, and then determine the role site of the mutation site action by in vivo and in vitro experiments. Finally, we screening the proteins which are regulated by SPINK1, to reveal the mechanism of these proteins in the pathogenesis of ICP. We hope that we could provide the new ideas and theoretical basis for the early diagnosis and treatment of ICP.

特发性慢性胰腺炎（ICP）病因不明，早期诊断困难，无法对因治疗，预后不佳。探索其发病机制成为国际热点。丝氨酸转肽酶抑制剂（SPINK1）涉及慢性胰腺炎发病机制的中心环节，其基因突变与ICP的发病密切相关。不同人种的突变位点存在差异，其导致ICP患者临床特征以及致病机制的不同。我国仍缺乏相应研究。因此我们开展针对我国汉族ICP患者易感基因的筛查及鉴定工作，寻找具有中国人群特点的致病位点，分析该致病位点与患者临床表现之间的相关性，通过体内及体外实验定位该突变的关键作用位点，最后拟通过在胰腺细胞中过表达野生型或突变型SPINK1，筛选受SPINK1调控的蛋白质，揭示这些蛋白在ICP发病中的作用机制。最终通过该研究为ICP的早期诊断及治疗提供新的理论基础和研究思路。

特发性慢性胰腺炎（ICP）病因不明，早期诊断困难，无法对因治疗，预后不佳。探索其发病机制成为国际热点。丝氨酸转肽酶抑制剂（SPINK1）涉及慢性胰腺炎发病机制的中心环节，其基因突变与ICP 的发病密切相关。不同人种的突变位点存在差异，其导致ICP患者临床特征以及致病机制的不同。我们的研究结果发现：（1）寻找到中国大陆汉族ICP人群SPINK1基因上特有的致病位点：c.194+2T＞C；（2）该突变位点与ICP患者临床表现以及内镜治疗效果密切相关；（3）SPINK1下调表达会造成胰腺腺泡细胞凋亡；（4）成功构建SPINK1转基因小鼠；（5）SPINK1 c.194+2T＞C转基因小鼠更易发生慢性胰腺炎。因此，本项目不仅找到了具有中国人群特点的致病位点，并深入的分析了该致病位点与患者临床表现及治疗效果之间的相关性，通过体内及体外实验揭示出该突变在ICP 发病中的作用机制，为ICP 的早期诊断及治疗提供新的理论基础和研究思路。