蛋白运输调控因子Mgb抑制干细胞衍生脑肿瘤的机制研究

Correct establishment and maintenance of unidirectional Notch signaling is critical for the homeostasis of various stem cell lineages. Misregulation of Notch-mediated cell fate determination in stem cell lineages lead to various human diseases, including tissue dystrophy and cancer. Yet whether and how intracellular trafficking and processing of Notch receptor ensures asymmetric Notch activation and prevents ectopic Notch hyperactivation within stem cell lineages remains to be elucidated. In this project, we plan to use Drosophila type II neural stem cell lineages as an in vivo model system to reveal the molecular mechanisms by which the protein trafficking regulator Mega brain (Mgb) inhibits stem cell-derived brain tumor formation through ensuring asymmetric Notch activation in neural stem cells. We aim to understand 1) how Notch signaling is ectopically turned on in neural progenitors upon loss of Mgb, resulting in tumorigenesis; 2) how Mgb mediates Notch receptor intracellular trafficking; and 3) how the posttranslational modification of Notch receptor affects its endosomal sorting and processing in neural in neural stem cell lineages. Successful completion of this project promises to provide new mechanistic insights into the process of Notch-mediated stem cell fate decisions and ultimately help understand and treat stem cell-derived cancer and tissue dystrophy.

正确建立和维持单方向的Notch信号对多种干细胞系的稳态维持均至关重要。Notch信号介导的干细胞命运决定过程出现错误会引起包括组织器官萎缩和干细胞衍生癌症等在内的多种疾病的发生。然而，Notch受体的胞内运输和剪切加工何以确保Notch通路在干细胞-祖细胞间的不对称活化还尚不清楚。本项目将以果蝇幼虫中脑区II型神经干细胞作为模式，结合多种研究手段，探究蛋白运输调控因子Mgb通过调控Notch在神经干细胞-祖细胞间的不对称活化进而防止干细胞衍生脑肿瘤发生的分子机制。我们将阐明Notch信号在Mgb缺失时如何在神经祖细胞中被异位激活，并揭示Mgb如何调控Notch受体在神经干细胞系中的囊泡转运。这项研究的完成将有助于加深我们对干细胞谱系内Notch信号介导的细胞命运锁定过程的认识，为干细胞衍生癌症及器官萎缩等疾病的防治提供重要的理论依据。