胰蛋白酶原基因及胰腺癌遗传异质性研究

Pancreatic cancer is a malignat tumor of digestive system with high mortality, which presents great genetic heterogeneity and clinical heterogeneity. however,the molecular biological mechanism of pancreatic cancer was not clarified. Previous studies showed that the trypsinase can participate in the invasion and metastasis of pancreatic cancer by degrading the extracellular matrix and promoting the proliferation and adhesion of cancer cells as the key signal molecule activating the PAR-2. The trypsinogen gene mutant could be detected in peripheral blood of pancreatic cancer patients and the rs10273639 C/T could act as a protective factor. Hence,the hypothesis is proposed that the abnormal quality and quantity of trypsinase probably play an important role in the development and prognosis of pancreatic cancer based on our previous findings.In our study, the mutant expression system and anti-PAR-2 excited peptide will be used to interfere the growth of pancreatic cancer cells in vitro,and evaluate the role of trypsinogen gene mutation/polymorphism effecting expression of trypsinase in the pathomechanism of pancreatic cancer. The relationship between the clinical phenotypes and trypsinogen genetypes will be discussed. And the molecular biological mechnism of hereditary predisposition will be enriched.

胰腺癌致死率极高，存在着遗传异质性和临床异质性，而且其分子机制也不明确。胰蛋白酶可通过降解细胞外基质参与胰腺癌的侵袭和转移过程，还可以作为信号分子激活PAR-2刺激胰腺癌细胞的增殖和黏附。本研究拟在前期发现胰腺癌患者的外周血中存在胰蛋白酶原基因（PRSS1）突变和rs10273639 C/T是胰腺癌的保护因子等遗传背景上，提出胰蛋白酶质和量的异常影响着胰腺癌的发生、发展和临床转归的设想。通过构建PRSS1基因突变体表达体系和反PAR-2激动肽体外干预胰腺癌细胞生长的实验，阐明胰蛋白酶原基因突变/多态影响胰蛋白酶的表达在胰腺癌病理过程中的作用，并在基因易感性筛查的基础上深入探讨胰腺癌临床表型与胰蛋白酶原基因型之间的关系，揭示胰腺癌遗传易感性的分子生物学基础。

胰腺癌致死率极高，存在着遗传异质性和临床异质性，而且其分子机制也不明确。胰蛋白酶可通过降解细胞外基质参与胰腺癌的侵袭和转移过程，还可以作为信号分子激活PAR-2刺激胰腺癌细胞的增殖和黏附。通过临床样本和构建PRSS1基因突变体表达体系阐明胰蛋白酶原基因突变/多态影响胰蛋白酶的表达在胰腺癌病理过程中的作用，并在基因易感性筛查的基础上深入探讨胰腺癌临床表型与胰蛋白酶原基因型之间的关系。项目组共发表15篇高质量的学术论文，10篇为SCI收录，其中影响因子3以上2篇，申请人作为第一作者或通讯作者发表SCI论文6篇。受邀在《Saudi Journal of Gastroenterology》发表胰腺疾病相关的综述。1.首次阐明由PRSS1_IVS 2 +56_60 del CCCAG基因突变，导致胰蛋白酶原激活肽缺失引发的自身免疫性胰腺炎。2.阐明高血清胰蛋白酶是新生儿败血症的新型标志物，并且和胰蛋白酶原基因启动子不同的基因型密切相关。3. 阐明由PRSS1_p.Leu81Met基因突变，导致胰蛋白酶原原位激引发的自身免疫性胰腺炎。4.研究发现2型自身免疫性胰腺炎存在PHKD1、线粒体和MEN1基因变异。5. 联合应用外周血细胞化学染色、等电共聚焦电泳等技术构建1型自身免疫性胰腺炎那无创监测技术。6. 阐述血清胰蛋白酶等与IgG4相关性疾病病情进展的关系。7.证明胰蛋白酶基因突变造成胰蛋白抗胰蛋白酶失衡的理论。