CEL-HYB2杂合基因变异在早发型慢性胰腺炎中的遗传致病机制研究

慢性胰腺炎（chronic pancreatitis, CP）是一种与遗传因素密切相关的胰腺炎症性疾病，其机制不清，病因复杂，临床表现为腹痛、糖尿病和脂肪泻等。CEL基因编码一种胰腺外分泌酶-羧基酯脂肪酶，可与其下游假基因同源重组成CEL-HYB变异。欧洲人群主要为CEL-HYB1型，体外实验证实该变异可诱导细胞自噬发生；申请者前期发现亚洲CP主要携带CEL-HYB2型，且在早发型CP中高发，提示中西方差异。本课题拟通过扩大样本量，采用自主设计检测方法和生信分析，进一步明确CEL-HYB2在我国早发型CP中的作用、分子分型及其影响因素。基于前期体外功能实验，发现CEL-HYB2可发生无义介导mRNA降解，本研究拟进一步阐明该变异导致的蛋白水平变化、体外效应及具体致病机制；结合外源因素刺激，分别构建两种携带CEL-HYB的人源化基因小鼠，为CP基因和药物治疗提供新的依据和新的临床前动物模型。

Chronic pancreatitis (CP) is a genetic-related inflammatory disease of the pancreas with complex etiology and unclear mechanism. The clinical features of CP are characterized by abdominal pain, diabetes mellitus and steatorrhea. The CEL-HYB, a hybrid allele generated by homologous recombination between CEL (encoding carboxyl ester lipase) and its downstream pseudogene, including CEL-HYB1 and CEL-HYB2. The CEL-HYB1 was mainly found in European populations, which was previously confirmed to be induced autophagy in cell experiments. However, we found the CEL-HYB2 was predominated in the Asia cohort and highly carried in early-onset CP patients, which indicated the genetic differences between the West and East. We aim to screen for CEL-HYB2 in an extended cohort of Chinese early-onset CP patients by self-designed detection methods and bioinformatic analysis, in order to determine the exact role of CEL-HYB2 in CP and evaluate the molecular sub-types and its associated factors. Our previous in vitro functional studies suggested CEL-HYB2 was subject to nonsense-mediated mRNA decay. Based on previous findings, this study aims to further explore the protein level, enzyme activity, cellular clearance and pathogenic mechanisms of CEL-HYB2. We have been establishing the humanized CEL-HYB1 and CEL-HYB2 mice combining environmental stimulus (caerulein, alcohol and high-fat diet), in order to provide novel animal models and theoretical references for the preclinical drug development and gene therapy of CP.