慢性胃炎恶性转化的基因调控网络及其关键节点的研究

项目名称： 慢性胃炎恶性转化的基因调控网络及其关键节点的研究

项目编号： No.91529302

项目类型： 重大研究计划

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 刘炳亚

作者单位： 上海交通大学

项目金额： 250万元

中文摘要： 非可治愈性慢性炎症是导致胃癌发生的重要因素之一。因此，了解慢性炎症致癌的机制，从中筛选调控关键基因是临床控制或者干预炎症致癌的实验基础。本项目从临床标本、动物模型和细胞模型三个层面出发，获得慢性胃炎恶性转化各个阶段样本，以激光显微切割获得高纯度细胞样品，以深度测序获得DNA变异、DNA甲基化、mRNA和miRNA表达谱数据，通过数据整构建动态复合基因调控网络，从而识别参与炎癌转化相关的甲基化调控子、转录因子、原因性变异及其信号转导通路等，以前期研究结果为先验知识对网络进行验证，并以这些关键因子对网络进行干预，观察网络的转归，同时以这些关键因子对细胞模型进行干预，观察细胞表型转变；然后，再以临床标本进行检验其临床病理学意义，以期揭示胃炎致胃癌发生发展的分子机制，为胃癌的防治提供新策略和新靶标。

中文关键词： 胃肿瘤；慢性胃炎；基因调控网络；炎症相关肿瘤

英文摘要： The incurable chronic gastritis is one of the major initiators inducing gastric cancer. Hence, revealing mechanisms of chronic gastritis-inducing gastric cancer provides the experimental basis of identification and application of key factors in clinical control and intervention. The goal of this project is to disclose the molecular mechanisms of gastric cancer develop from chronic gastritis. We will get the clinical samples (normal gastric mucosea, intestinal metaplasia, dysplasia, and gastric cancer) animal models (induced by H.felis) and cell model specimens (retro-differentiate and trans-differentiate) and get high purity cells from these samples by laser capture microdissection. The datasets of DNA mutation, DNA methylation, mRNA and miRNA expression profiles will be developed by DNA sequencing and RNA sequencing. Identify the the methylation of regulator and transcription factors, driver variation and its signal transduction pathways which associated with chronic gastritis transformed into gastric cancer by integrating data analysis and building gene regulatory network. The validation experiments will be performed by perturbation the network in animal models and cell models. The significance will be verified by clinical samples..This project will contribute to the comprehensive understanding in mechanisms of the transformation from chronic gastritis to gastric cancer, and will provide new strategies and therapeutic targets for gastric cancer prevention and treatment.

英文关键词： gastric cancer;chronic gastritis;gene regulatory network;inflammation associated cancer