幽门螺杆菌致长爪沙鼠胃癌模型高发群体的选育及发病机制研究

幽门螺杆菌（Hp）是人类胃癌Ⅰ类致癌物，长爪沙鼠是与人胃癌病理进程最接近的Hp感染胃癌模型，但其胃癌发生率却较低。研究显示人感染Hp胃癌与遗传组成相关。我们前期证明通过定向培育可以将沙鼠的某一性状固定下来。据此提出假说：长爪沙鼠Hp感染易发胃癌是由遗传因素决定的，通过定向培育可提高或降低胃癌成模率，并有相关差异基因存在。本课题拟利用自行培育的2个封闭群和2个近交系长爪沙鼠感染Hp，模型鉴定后分别繁殖敏感和抵抗后代，经多代选育获得长爪沙鼠Hp感染胃癌高发和低发2个模型群体。以此为材料，采用基因组重测序和转录组测序等技术发现胃癌相关基因，分析胃癌发生过程中各病理阶段基因突变和表达差异，通过生物信息学和分子生物学方法筛选验证这些基因在各病理阶段的作用，初步揭示Hp感染致胃癌的发生机制。本研究将率先在国际上建立长爪沙鼠Hp感染致胃癌高发和低发群体，为Hp诱发胃癌发生机制研究和药物试验提供支撑。

Helicobacter pylori (Hp) is a carcinogen of human gastric cancer classified Group I by International Agency for Research on Cancer (IARC). The Mongolian gerbil harbors the most similar animal model of Hp-induced gastric cancer in humans. However, the incidence of this model is a bit low (about 40%). Scientific researches indicated that genetic factors played a vital role in Hp-induced gastric cancer. Our previous studies have confirmed that a biological characteristic of gerbil could be fixed by selectively breeding. Thus, we hypothesized that the prone of Hp-induced gastric cancer in gerbil was mainly affected by genetic factor. Selective breeding could increase or decrease the successful modeling ratio; and the gastric cancer related genes would exist in such gerbil groups. In this project, we will infect 2 outbred populations and 2 inbred strains of gerbils using Hp and selectively breed the litters of sensitive and resistant gerbils separately by identifying and ascertaining the models. Therefore, we could get two different gerbil groups after several generations. Using the tissue samples from the sensitive and resistant groups of Hp-induced gastric cancer, the disease-related genes would be screened by whole genome re-sequencing and RNA sequencing. The mutations and different expression levels of these genes also would be analyzed in each pathological stages of gastric cancer. The function of the selected genes in pathological stages could be validated by biological information and molecular biological assays to primarily reveal the mechanism of every stage in Hp-induced gastric cancer. This research will newly establish the groups of sensitive and resistant Hp infected gastric cancer in gerbils and provide a new animal model for mechanism studies and drug trials in Hp-induced gastric cancer.