NeuroD2调控人恶性神经胶质瘤细胞向神经元分化的作用研究

项目名称： NeuroD2调控人恶性神经胶质瘤细胞向神经元分化的作用研究

项目编号： No.81502683

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 周菂

作者单位： 中南大学

项目金额： 18.5万元

中文摘要： 神经胶质瘤（Glioma）是一种来源于神经上皮的肿瘤，恶性的占所有胶质瘤的77.5%。恶性神经胶质瘤的致命性表现在它的指数增长和侵润性上。如果能使肿瘤细胞分化成终末的神经元，维持在非增殖（或低增殖）状态，降低侵润性，这对于恶性神经胶质瘤的治疗也许是一种可行的辅助策略。申请人在前期的研究中首次发现敲除/敲减p53能促进NeuroD2的表达，使人成纤维细胞向功能性神经元转分化。本课题拟过表达NeuroD2来诱导人恶性神经胶质瘤细胞向终末神经元分化，并观察敲除p53是否能促进这个分化过程；对分化过程是否经历“干/祖细胞”阶段以及肿瘤细胞的自我更新能力和基因组稳定性的改变等进行分析；比较人胚胎干细胞，人成纤维细胞和恶性胶质瘤细胞向神经元分化中的基因表达差异，探索恶性胶质瘤分化的特点，期望寻找到几个关键的差异表达基因，从而进一步改善人恶性胶质瘤细胞向终末神经细胞分化的方法。

中文关键词： 神经胶质瘤；神经元；NeuroD2；转分化；p53

英文摘要： Gliomas are tumors that arise from neuroepithelium, malignant histological types consist 77.5% of all the gliomas. Malignant gliomas are the most common solid tumors in the central nervous system, are essentially incurable due to their rapid growth and very invasive nature. Despite therapeutic improvements through combined neurosurgery, chemotherapy and radiotherapy, current treatment modalities are still unable to significantly prolong patients’ survival. One potential approach is to induce them to become terminal differentiated cells, exciting cell cycle and staying the non-proliferating state. The applicant first reported that the depletion of p53 upregulates neurogenic transcription factors, which in turn boosts fibroblast-neuron conversion. p53 binds the promoter of the neurogenic transcription factor Neurod2 and regulates its expression during fibroblastneuron conversion. In this project we are going to investigate whether NeuroD2 could induce human malignant glioma cells into terminal neurons and whether knockout of p53 could boost this process, whether this conversion is direct or via a “stem/progenitor cell like” stage and what are the telomere length and telomerase change during this process, and what are the gene expression differences among hESC, fibroblast and glioma conversions, so that we can analysis the characterization of glimoas’ conversion and try to find some key genes to improve the induction method.

英文关键词： glioma;neuron;NeuroD2;coversion;p53