胶质瘤中IDH1突变诱导血管新生相关基因表达促进肿瘤微血管形成的研究

项目名称： 胶质瘤中IDH1突变诱导血管新生相关基因表达促进肿瘤微血管形成的研究

项目编号： No.81201979

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学2

项目作者： 崔大明

作者单位： 同济大学

项目金额： 23万元

中文摘要： 胶质瘤中IDH1突变的发现是近年来胶质瘤研究领域的重大进展。本课题基于当前胶质瘤中IDH1研究现状，结合前期工作中发现：同一病理级别的胶质瘤中IDH1突变与VEGF、MMP2、MMP9等血管新生相关基因表达增加及肿瘤微血管密度上调相关，提出假设即胶质瘤中IDH1突变可通过诱导血管新生相关基因表达上调，进而促进胶质瘤血管新生。本课题拟首先通过基因芯片，在同一病理级别的胶质瘤中，分析IDH1突变组与野生组差异表达的血管新生相关基因；其次采用RNA干扰技术模拟IDH1突变，在体外培养的胶质瘤细胞系U87中，分析IDH1活性下降对前述发现的差异表达的血管新生相关基因表达的影响；最后通过动物实验进一步验证上述实验过程所得到的结论。为阐明胶质瘤中IDH1突变在血管新生过程中的作用，在胶质瘤的治疗中寻找新的靶点提供理论依据及实验基础。

中文关键词： 异柠檬酸脱氢酶突变；Wnt/β-catenin通路；β-catenin蛋白；转录因子；胶质瘤

英文摘要： The finding of IDH1 mutations in gliomas is a significant advance in the field of glioma research.Based on the current situation of IDH1 research and our early results that IDH1 mutiations is correlated with high expressions of VEGF,MMP2,MMP9 and high levels of microvessel density in gliomas of the same pathological grade, we propose a hypothesis that glioma-derived IDH1 mutations could induce expressions of angiogenesis-related genes and further upregulate tumor's microvessel density. To confirm this hypothesis, we design the expriments. Firstly, we explore the different exprssions of angiogenesis-related genes with gene micro arrays between IDH1 mutation group and wild-type IDH1 group in the same pathological grade of gliomas. Secondly, we analyze the effect of IDH1 mutations on angiogenesis-related gene expressions in cultured U87(glioma cell line) cells in vitro by RNA interference,and observe the reversive effect of α-KG on angiogenesis-related gene expressions in cultured U87 cells transfected with IDH1 shRNA. Finally, we further verify the results of the experiments above in vivo. To clarify the possible mechanisms of IDH1 mutations contributing to angiogenesis of gliomas and explore new theropeutic targets in glioma treatment offer credible experimental and theoretical gist.

英文关键词： mutant IDH1-R132H；β-catenin；glioma；Wnt/β-catenin signal；