Mechanisms and Functions of MBP mRNA Transport in Oligodendrocytes

少突胶质细胞中 MBP mRNA 转运的机制和功能

• 批准号: 8833702
• 负责人: Meng-Meng Fu
• 金额: $ 2.12万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833702
• 关键词: 3' Untranslated Regions; Animal Model; Axon; Binding; Biology; Cell physiology; Cells; Cellular biology; Cerebral Palsy; Cultured Cells; Cytoplasmic Granules; Data; Detection; Disease; Distal; Engineering; Imaging Device; Immunoprecipitation; Label; Life; Link; Mass Spectrum Analysis; Messenger RNA; Modification; Molecular; Molecular Motors; Motor; Multiple Sclerosis; Myelin; Myelin Basic Proteins; Neuraxis; Neuroglia; Neurons; Nuclear Export; Oligodendroglia; Organism; Post-Translational Protein Processing; Process; Property; Proteins; Proteomics; RNA; RNA Binding; RNA Splicing; RNA-Binding Proteins; Regulation; Reporter; Scaffolding Protein; Signal Transduction; Site; Small Interfering RNA; System; Time; Translating; Translations; Travel; cell motility; cellular imaging; in vivo; mouse model; mutant; myelination; neuronal cell body; new therapeutic target; novel; protein expression; public health relevance; research study; therapeutic target

DESCRIPTION (provided by applicant): In the central nervous system, oligodendrocytes ensheath and wrap axons in many concentric layers of myelin, a process that is essential for efficient electrical signaling in axons. In diseases such as multiple sclerosis and cerebral palsy, oligodendrocytes fail to form compact myelin and proper distal localization of myelin basic protein (MBP) is absent. MBP is the most highly expressed mRNA in oligodendrocytes by over 10-fold. It is also a special protein who's mRNA must be transported to distal processes of oligodendrocytes before it can be translated. The mechanism and in vivo function of MBP mRNA transport, however, has remained elusive. This project aims to determine whether regulation of MBP mRNA transport at the cargo level is necessary for myelination. In order to visualize MBP mRNA transport in living primary oligodendrocytes, modern imaging tools, such as the RNA-binding reporter protein MS2, will be developed for the detection and analysis of MBP mRNA motility. Furthermore, two independent mass spectrometry approaches will be used to identify proteins in the MBP mRNA granule that are involved in its transport. Regulators of transport are often scaffolding proteins that have the ability to bind to multiple motor proteins. Thus, candidate regulators of MBP mRNA transport will be confirmed via their ability to associate with motor proteins as well as with siRNA knockdown strategies. Finally, two different mouse models will be made to determine whether MBP mRNA transport is necessary for myelination in vivo. The proposed project will elucidate how motor proteins associate with mRNA cargos and identify the molecular mechanism underlying a pivotal process in oligodendrocyte maturation and myelination and will have important implications for the fields of glial cell biology, molecular motors, RNA protein biology, and myelin diseases. Importantly, since distal MBP protein expression and compact myelin formation fail in myelinating diseases, these findings may reveal novel therapeutic targets for stimulating myelination in disease.

描述（由申请人提供）：在中枢神经系统中，少突胶质细胞以许多同心髓鞘层包裹并包裹轴突，这一过程对于轴突中有效的电信号传导至关重要。在多发性硬化症和脑瘫等疾病中，