Mios介导的溶酶体信号通路在大脑髓鞘发育中的作用

批准号:
31970773
项目类别:
面上项目
资助金额:
60.0 万元
负责人:
肖波
依托单位:
学科分类:
组织器官发育及体外构建
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
肖波
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中文摘要
少突胶质细胞介导的髓鞘生成对出生后的脑发育过程至关重要,与整个脑功能以及神经发育相关疾病密切相关。少突胶质细胞的形成以及轴突的髓鞘生成受到了细胞内外相关机制的调控,近年来的研究发现细胞溶酶体信号可作为一个新的调控机制,通过协调细胞代谢和转录参与干细胞分化以及少突胶质细胞髓鞘生成的调控。Mios作为GATOR复合物的组成元件参与调节溶酶体氨基酸活化mTORC1信号通路,但其在高等生物中的功能尚未报道,本项目将主要利用转基因小鼠探讨Mios介导的溶酶体信号在脑髓鞘生成中的作用。首先我们将检测Mios在大脑髓鞘生成中的作用,验证Mios调控少突胶质前体细胞的增殖和分化。随后我们将研究Mios调节少突胶质细胞形成的分子机制,即Mios是否是通过溶酶体转录因子TFE3的细胞核易位来调控少突胶质细胞的发育。本研究将为溶酶体调控少突胶质细胞髓鞘形成提供新的见解。
英文摘要
Oligodendrocyte-mediated myelinogenesis is a major event in the postnatal brain development. It is intimately associated with all brain’s functions and neurodevelopmental disorders. The formation of oligodendrocytes and subsequent myelination of axons are regulated by cell-intrinsic and non-cell-intrinsic mechanisms. Recent studies identify oligodendrocyte-intrinsic lysosomal signaling as a novel mechanism to regulate stem cell differentiation and oligodendrocyte myelination, by coordinating cellular metabolism and transcriptional control. Mios is a component of GATOR complex that regulates amino acid signaling to mTORC1 at lysosomes. Its biological function in a complex organism such as mouse has not been reported. This proposal examines the role of Mios-mediated lysosomal signaling in brain myelination using genetically modified mouse. First, we will examine the role of Mios in developmental myelination. We test the hypothesis that Mios regulates the proliferation and differentiation of oligodendrocyte progenitors. Second, we will examine the molecular mechanisms by which Mios regulates oligodendrocyte formation. We assess if the lysosomal transcription factor TFE3 and its nuclear translocation that is regulated by mTORC1 plays a role in Mios-regulated myelination. This study provides novel insights into lysosome regulated oligodendrocyte myelinogenesis.
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
DOI:10.1073/pnas.2110917119
发表时间:2022-01-18
期刊:Proceedings of the National Academy of Sciences of the United States of America
影响因子:11.1
作者:Yu Z;Yang Z;Ren G;Wang Y;Luo X;Zhu F;Yu S;Jia L;Chen M;Worley PF;Xiao B
通讯作者:Xiao B
DOI:10.1016/j.celrep.2023.112801
发表时间:2023-07-17
期刊:CELL REPORTS
影响因子:8.8
作者:Huang,Haijiao;Jing,Bo;Xiao,Bo
通讯作者:Xiao,Bo
DOI:10.1007/s12264-022-00967-x
发表时间:2022-11
期刊:Neuroscience Bulletin
影响因子:5.6
作者:Zhiwen Yang;Zongyan Yu;Bo Xiao
通讯作者:Zhiwen Yang;Zongyan Yu;Bo Xiao
小G蛋白Rheb在小胶质细胞线粒体代谢调控溶酶体活性中的作用
- 批准号:32371011
- 项目类别:面上项目
- 资助金额:50万元
- 批准年份:2023
- 负责人:肖波
- 依托单位:
国内基金
海外基金
