c-MYC：神经干细胞静息激活稳态中微环境的整合器、细胞周期和代谢活性的大管家

Resident tissue stem cells can transit between quiescence and activation—two states of distinct material and energy metabolic status as well as cell cycle activity. However, it remains essentially unexplored that how stem cells could regulate and coordinate diverse biological processes including cell metabolic and cell cycle activities to amass such dramatic changes and transit between quiescence and activation. Equally poorly studied is how distinct niche factors such as BMP, WNT and nutrients could all manage the diverse biological processes and balance stem cell quiescence and activation. We now have data suggesting that MYC, a major oncogene and master transcription factor controlling cell cycle and metabolic activities, could potentially integrate and relay extracellular and niche signaling to regulate stem cell fates. Thus, in the present application, we propose to utilize BMP and glucose signaling as the paradigms and 1) analyze the expression dynamics and functions of MYC and its related target genes in the transition between quiescence and activation; 2) elucidate how MYC coordinate cell metabolism and cell cycle to balance neural stem cell quiescence and activation; 3) investigate whether and how MYC may function as an integrator of diverse niche signaling and coordinate to control stem cell fates, and whether and how MYC may feedback and regulate niche signaling to fine-tune the homeostasis of quiescence and activation. It is our hope that the present work could provide novel thinking and perhaps novel targets for future clinical purposes.

组织干细胞能够以静息和激活两种可以互相转换，但在物质、能量代谢和细胞周期活性等方面都迥然不同的状态存在。但在静息激活的转换中，干细胞如何协同细胞代谢和周期的剧变尚未有文献报道。作为关键的微环境因子，BMP、WNT和营养分子等迥然不同的信号和代谢通路如何协调细胞代谢和周期活性，调控静息激活的稳态也未有研究。我们初步研究提示MYC，一个在细胞周期和代谢中起关键作用的癌基因，能够感应整合微环境的变化，统筹协同细胞代谢和周期活性，调节神经的再生。在本项目中，我们将以BMP和葡萄糖等信号为代表，1）确定MYC及相关基因簇在神经干细胞静息激活转换中的表达动态及功能；2) 解析MYC协同调控细胞代谢和周期，维持静息激活平衡的详细机理；3) 确立MYC感应整合微环境信号通路调控静息激活的枢纽作用，解析其与关键信号通路的交互反馈作用机理。为解析发育、疾病包括肿瘤的机理和防治提供新的理念、思路和潜在的靶点。

在项目计划中，我们希望以BMP和葡萄糖等信号和代谢通路为代表，深入解析干细胞如何感应多样、动态的环境变化，统筹管理细胞代谢和周期，实现干细胞静息激活的转换与平衡。我们完成了A) 确定Myc及相关基因簇在神经干细胞静息激活转换中的表达动态及核心调控作用；B) 解析Myc协同调控细胞周期和代谢，维持神经干细胞静息激活动态平衡的详细机理；C) 确立Myc在细胞外信号通路调控静息和激活中的枢纽作用，并解析其关键信号通路交互反馈调控机理。与课题相关的部分数据已经发表5篇，一篇与量化调控相关的文章已投至Genome Research, 目前修稿中。Myc的部分功能和机制研究业已完成整理，正在撰稿，目标杂志是Nature Communication 。

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