Ogt介导的O-GlcNAc糖基化修饰对成年小鼠神经干细胞和学习记忆的调控作用与机制研究

The self-renewal and multipotency of adult neural stem cells (aNSCs) are intensively modulated by environmental, genetic and epigenetic mechanisms at transcriptional, translational and post-translational levels. ANSCs-derived neurogenesis involves in learning and memory, also relates to multiple neurological disorders. O-GlcNAcylation, an important post-translational modification, is catalyzed by O-linked β-N-acetylglucosamine O-GlcNAc transferase (Ogt). O-GlcNAcylation not only plays critical roles in modulating protein function, also involves in regulating gene expression, cell signaling, apoptosis, the maintenance of embryonic stem cells, and other biological processes. The alteration of O-GlcNAcylation has been demonstrated in cancer, diabetes, and neurodegenerative diseases. However, it is largely unknown about the function of O-GlcNAcylation in aNSCs and adult neurogenesis. Utilizing multiple methods, this project aims to study the roles of Ogt-mediated O-GlcNAcylation in regulating aNSCs and adult neurogenesis，and learning and memory, reveal the mechanism, and thus provide novel idea and targets for treating some neurological disorders.

成体神经干细胞具有自我更新能力和多分化潜能，受到环境、遗传学和表观遗传学等多种机制在转录、翻译和翻译后水平的精细调控。成体神经干细胞驱动的神经发生在学习记忆和多种神经系统疾病中发挥重要作用。N-乙酰氨基葡萄糖转移酶(Ogt)催化的O-GlcNAc糖基化修饰(O-GlcNAcylation)是一种重要的翻译后修饰形式。O-GlcNAc糖基化修饰不仅对于蛋白质正常发挥功能具有重要作用，而且调控基因表达、信号转导、细胞凋亡和胚胎干细胞的干性维持等多种生物学过程，与癌症、糖尿病和神经退行性病变等疾病密切相关。但是O-GlcNAc糖基化修饰在成体神经干细胞和神经发生中的作用尚不清楚。本项目旨在利用多种实验手段在体内和体外研究O-GlcNAc糖基化修饰对成体神经干细胞生物学特性和神经发生以及学习记忆的调控作用，揭示其作用机制和靶向位点，为相关神经系统疾病的治疗提供新的思路和靶点。

既往研究证实Ogt和O-GlcNAcylation在神经发育、神经细胞代谢和神经系统疾病中可能发挥重要作用，但是关于Ogt和O-GlcNAcylation对神经干细胞的调控作用和机制尚不明确。本项目研究了Ogt和O-GlcNAcylation在成体神经干细胞增殖和分化的调控作用及其分子机制。研究发现ogt特异性敲除抑制神经发生，损伤小鼠的学习和记忆。RNA测序发现ogt特异性敲除而引起的表达改变的基因与细胞周期，神经发生和神经发育密切相关。分子机制研究发现ogt可以和Notch1相互作用并进行糖基化修饰。Notch1糖基化修饰的减少促进了泛素连接酶Itch与Notch1的结合并促进其降解。Notch信号激活和Itch敲定都可以拯救ogt敲除导致的神经发生异常。OGT同时还调节人类脑器官的发育。我们的研究揭示了Ogt和O-GlcNAcylation下成体神经发生和小鼠认知功能中的重要作用和分子机制。