慢性胰腺炎（CP）是一种胰腺持续性炎症性疾病，临床表现为腹痛、结石、脂肪泻、糖尿病等。我国大部分CP患者病因不明，发病机制不清，已知遗传因素起重要作用，东西方遗传背景差异大。为寻找我国CP特有的致病基因，我们前期对青少年三口之家进行全外显子测序，发现一例携带Sec16A基因移码突变，进一步在散发CP患者中进行验证，发现非同义突变在病例中高发（43.6%，OR=2.3）。基于前期研究基础，我们推测Sec16A基因突变可能间接调控CFTR等因子影响腺泡细胞功能，促进CP发生。本课题拟采用体外CRISPR-Cas9技术构建Sec16A突变位点细胞株，共转染腺泡分泌蛋白表达质粒，结合突变携带者的成纤维细胞和胰腺组织实验结果，评估突变对胰腺功能的影响，并进一步探讨该基因调控CP发生的可能机制。通过基因型与临床表型的关联分析，明确突变对疾病进程和临床疗效的影响，以期为CP早期检测和治疗提供新的靶点。

Chronic pancreatitis (CP) is a persistent inflammatory disease of the pancreas, characterized by abdominal pain, pancreatic stones, steatorrhea, and diabetes. The pathogenesis of CP remains unclear currently. Most Chinese patients with CP are idiopathic, accounting for over 70% of the total. Genetic susceptibility has emerged during the last two decades as a strong determinant of disease risk. However, Chinese Han population has a distinct genetic background from the Caucasian. To identify Chinese-specific CP susceptibility genes, we performed whole exome sequencing in 16 trios of teenager CP and found one patient carrying a frameshift mutation in Sec16A gene. Further targeted sequencing were validated in idiopathic CP patients and controls, showing high frequency of non-synonymous mutations in cases (43.6%, OR=2.3). Based on the preliminary studies, we speculated that Sec16A gene mutations may indirectly regulate the function of CFTR and other molecular factors to affect the function of acinar cells, thus promoting the occurrence of CP. To evaluate the effects of Sec16A mutations on pancreatic functions and further explore the possible mechanisms of gene regulation, we prepared to construct in vitro cell lines carrying selected Sec16A mutations using CRISPR-Cas9, co-transfected with expression plasmids of pancreatic secretory proteins. Then we perform similar protein tests in fibroblasts and pancreatic tissues of mutation-carrying patients. Finally, we would perform the association analysis of genotype and clinical phenotype, to evaluate the effects of mutations on the disease course, thus providing novel targets for the early detection and treatment of CP.