一种在体激活EGFR用于研究神经干细胞增殖与肿瘤转化的新方法

胶质母细胞瘤（glioblastoma）是一种最常见的脑癌，它通常起源于神经干细胞，但神经干细胞转化为胶质母细胞瘤的分子机制仍有待阐明。胶质母细胞瘤中通常能检测到表皮生长因子受体（EGFR）水平或活性上调。申请人前期开发了基于SNAP蛋白标签的选择性二聚化技术，成功诱导激活了EGFR信号通路。本项目拟利用此技术建立可在体诱导斑马鱼神经干细胞EGFR二聚化并激活其下游信号通路的动物模型，并在此模型中在体观测激活EGFR对神经干细胞分裂增殖的影响，特别是细胞不对称分裂模式向对称分裂模式的转变。申请人将进一步在此斑马鱼模型中研究激活EGFR对其它肿瘤相关因子例如细胞极性蛋白Par3胞内定位和功能的影响，以及敲除par3并激活神经干细胞上的EGFR是否导致神经干细胞转化为肿瘤细胞，从而建立通过小分子诱导神经干细胞向胶质母细胞瘤转化的斑马鱼模型，该模型可用于肿瘤分子机制研究及抗癌药物筛选。

Glioblastoma is the most common form of brain cancer, it is usually derived from neural stem cells (NSCs), but the molecular mechanisms that transforming NSCs to glioblastoma remain to be elucidated. Increased levels or activities of epidermal growth factor receptor (EGFR) are often detected in glioblastoma cells. Previously, the applicant has developed a protein dimerization technique based on SNAP-tag technology, and induced EGFR dimerization and activation successfully. In this project, the applicant will use this technique to activate EGFR signaling pathway in NSCs in a zebrafish model, and then examine the division and proliferation of NSCs in vivo, focusing on the switching of cell division modes from asymmetric to symmetric. The applicant will further study the effect of activating EGFR on the intracellular localization and function of other tumor-related factors, such as the cell polarity protein Par3, and examine whether knocking out par3 in combination with activating EGFR will lead to the transforming of NSCs to glioblastoma cells. These findings will lay groundwork for elucidating glioblastoma tumorigenesis and facilitate phenotype-based drug screening.