胰腺炎恶性转化基因调控网络中转录因子Sp1作为关键节点的调控机制

项目名称： 胰腺炎恶性转化基因调控网络中转录因子Sp1作为关键节点的调控机制

项目编号： No.91229117

项目类型： 重大研究计划

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 王理伟

作者单位： 上海交通大学

项目金额： 90万元

中文摘要： 胰腺炎恶性转化在胰腺癌的发生发展中发挥重要作用，但其确切机制不明，特别是缺乏胰腺炎恶性转化基因调控网络和关键节点的研究。课题组前期研究提示转录因子Sp1为胰腺癌发生潜在关键节点。本课题拟在前期工作的基础上，运用高通量染色体免疫共沉淀芯片（CHIP-chip）和基因芯片技术相结合的手段，辅之以生物信息学及分子生物学方法，分析胰腺正常组织、炎症组织、癌旁组织和癌组织不同阶段的动态分子事件，深入研究转录因子Sp1在胰腺炎恶性转化中相关炎性因子基因启动子区域招募情况，基因启动子区域组蛋白乙酰化及甲基化水平变化，阐明转录因子Sp1介导的相关炎症因子激活在胰腺炎恶性转化基因调控网络中的作用机制；同时在已建立的胰腺炎和胰腺癌模式动物以及临床样本库中验证，从整体层面对转录因子Sp1作为关键节点在胰腺炎恶性转化过程中的作用进行解析，揭示胰腺炎恶性转化的分子机制及多维调控规律。

中文关键词： 胰腺炎；恶性转化；基因调控网络；Sp1；关键节点

英文摘要： The malignant transformation of pancreatitis plays a critical role in the tumorigenesis of pancreatic cancer; however, the molecular mechanism of genome regulatory networks and critical node of pancreatitis malignant transformation is unknown. Our preliminary studies suggest that the transcription factor Sp1 act as potential critical node in pancreatic cancer. Under our previous studies, the high-throughput chip of chromatin immunoprecipitation (CHIP-chip) and gene chip assays were carried out to investigate the epigenetic modifications during the malignant transformation of pancreatitis. The recruitment of transcription factor Sp1 in inflammatory factor gene promoters and the level of histone acetylation or methylation of these gene promoters were deeply studied. Furthermore,the results were validated in animal model and the clinical sample. The aim of this study was to clarify the mechanism of the transcription factor Sp1-mediated inflammatory factor transcriptional activation and multi-dimensional regulation law of pancreatitis malignant transformation. The study will provide novel clues for the intervention and targeted therapy for pancreatitis malignant transformation.

英文关键词： pancreatitis；malignant transformation；gene regulation network；Sp1；critical node