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Mechanisms of mTOR-mediated myelin sheath growth

mTOR介导的髓鞘生长机制

基本信息

批准号：
9906666
负责人：
Karlie N Fedder
金额：
$ 3.2万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906666
关键词：
Action Potentials Animals Axon Brain Cellular Neurobiology Characteristics Cues Data Dendritic Spines Distal Event Exhibits Exocytosis FRAP1 gene Family member Fluorescence Resonance Energy Transfer Foundations Genetic Genetic Epistasis Genetic Models Goals Growth Image Individual Knowledge Larva Lead Length Long-Term Potentiation Mediating Membrane Messenger RNA Molecular Probes Mutation Myelin Myelin Basic Proteins Myelin Sheath Neuraxis Neurons Oligodendroglia Pathway interactions Phosphorylation Phosphotransferases Production Protein Biosynthesis Protein Family Proteins Proteolipids Ribosomal Protein S6 Kinase Series Signal Transduction Spinal Structure Synapses Synaptic Vesicles System Testing Therapeutic Intervention Translating Translational Regulation Translational Repression Translations Vertebral column Work Zebrafish base cognitive function experimental study extracellular genetic approach genetic manipulation in vivo live cell imaging loss of function mTOR Signaling Pathway mutant myelination neurotransmission novel postsynaptic presynaptic relating to nervous system response sensor sensory system translation assay

项目摘要

PROJECT SUMMARY In the central nervous system, individual oligodendrocytes produce variable amounts of myelin on different axons. The underlying mechanisms governing how specific amounts of myelin are made on certain axons remains a fundamental question in cellular neurobiology. Recent work has provided evidence that neural activity promotes myelin sheath growth in spinal circuits, yet the signaling mechanisms that function within oligodendrocytes to transduce activity-evoked signaling from axons into selective myelin membrane growth remain unknown. The PI3K-Akt-mTOR signaling pathway is a prime candidate to mediate these events, as it both promotes myelin sheath growth and can be activated in response to neural activity. Using a combination of genetic manipulations and in vivo live-cell imaging of zebrafish larvae, this project seeks to build on this knowledge to further elucidate the intracellular signaling events within oligodendrocytes that drive myelin sheath growth. The proposed work has two parts: Aim 1 will identify a novel regulator of myelin sheath growth and Aims 2 and 3 will test if this mediates mTOR and neural activity-regulated myelin sheath growth. Together, this work will define a signaling axis within oligodendrocytes that mediates myelin sheath growth in response to neural activity.

项目摘要在中枢神经系统中，单个少突胶质细胞在不同的神经元上产生不同数量的髓鞘。轴突决定特定数量的髓鞘如何在某些轴突上产生的潜在机制仍然是细胞神经生物学中的一个基本问题。最近的研究表明，促进脊髓回路中髓鞘的生长，然而，少突胶质细胞对从轴突到选择性髓鞘膜生长的神经活性诱发的信号传导仍然未知。PI 3 K-Akt-mTOR信号通路是介导这些事件的主要候选者，因为它两者都促进髓鞘生长，并可响应神经活动而被激活。结合使用基因操作和斑马鱼幼虫的体内活细胞成像，该项目旨在建立在此基础上，进一步阐明少突胶质细胞内驱动髓鞘的细胞内信号传导事件的知识增长本论文的工作分为两个部分：目的一是寻找一种新的髓鞘生长调节因子，图2和图3将测试这是否介导mTOR和神经活性调节的髓鞘生长。在一起，这项工作将在少突胶质细胞内定义一个信号传导轴，该轴介导髓鞘生长，以响应神经元的生长。活动