慢性胰腺炎（CP）是胰腺器官的慢性炎症性疾病，我国大多数CP患者的发病与遗传因素有关，编码羧肽酶A1的CPA1基因是CP易感基因之一。既往研究认为，某些CPA1错义突变通过诱发内质网应激导致羧肽酶A1蛋白被破坏而分泌减少，进而发生胰腺炎。申请者前期对CPA1非错义突变的初步研究表明：无义突变转录出的异常mRNA稳定性降低，诱导无义介导的mRNA降解而被大量清除，导致转录产物减少；外显子/内含子交界处序列突变导致异常剪接，无法转录出正常的mRNA。上述两者均为不同于内质网应激的新致病机制。考虑到基因突变具有种族特异性，本项目拟检测我国CP患者和对照人群携带的CPA1外显子和外显子/内含子交界处序列突变，由于不同突变类型以及同一突变类型不同突变位点的致病情况和致病机制不尽相同，拟通过功能学实验明确每个突变的具体情况，同时结合患者信息，阐明其临床意义，为相关靶点应用于临床转化医学奠定理论基础。

Chronic pancreatitis (CP) is a chronic inflammatory process of the pancreas. Most CP patients in China is related to genetic factors, and CPA1 gene encoding carboxypeptidase A1 is one of the susceptible genes of CP. Previous studies have suggested that certain CPA1 missense mutations reduce the secretion of carboxypeptidase A1 protein by inducing endoplasmic reticulum stress, resulting in pancreatitis. The applicant’s preliminary research on CPA1 non-missense mutations showed that the stability of abnormal mRNA transcribed by nonsense mutations is reduced, and the transcription is largely eliminated by nonsense-mediated RNA decay; mutations at the junction of the exon and intron lead to abnormal splicing and cannot produce normal mRNA. Both of the above are new pathogenic mechanisms different from endoplasmic reticulum stress. Considering that the gene mutation is ethnically specific, this project intends to detect CPA1 exon and exon / intron junction sequence mutations carried by CP patients and the control in China. Due to the different pathogenic conditions and pathogenic mechanisms of different mutation types and different mutation sites of the same mutation type, it is planned to clarify the specific condition of each mutation through functional experiments, and to clarify its clinical significance combined with the information of patients. This project will lay a theoretical foundation for the application of related targets in clinical translational medicine.