The role of mTOR signaling in oligodendrocyte differentiation and CNS myelination

mTOR信号在少突胶质细胞分化和中枢神经系统髓鞘形成中的作用

• 批准号: 9751403
• 负责人: WENDY B MACKLIN
• 金额: $ 75.78万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751403
• 关键词: Actins; Adaptor Signaling Protein; Address; Adult; Automobile Driving; Axon; Biology; Brain; Collaborations; Complex; Corpus Callosum; Data; Demyelinations; Development; Disease; FRAP1 gene; Genetic Transcription; Goals; Human; Laboratories; MAP Kinase Gene; Mediator of activation protein; Modeling; Morphology; Multiple Sclerosis; Mus; Myelin; Neuraxis; Nuclear Accidents; Oligodendroglia; Pathology; Pathway interactions; Phase; Phosphorylation; Process; Proteins; Raptors; Regulation; Rodent; Role; Signal Pathway; Signal Transduction; Spinal Cord; Stem cells; Testing; Thick; Wood material; Zebrafish; base; bone; cellular targeting; dysmyelination; in vivo; inhibitor/antagonist; integrin-linked kinase; mouse model; myelination; nervous system development; oligodendrocyte progenitor; remyelination

To understand oligodendrocyte differentiation and myelin formation in the CNS, it is essential to define how intracellular signaling pathways regulate the cytoplasmic and nuclear events that drive myelination. A number of signaling pathways have been implicated in driving CNS myelination. The collaborative project between the Macklin and Wood laboratories was initiated to define the function specifically of mTOR signaling in oligodendrocyte and myelin biology. Over the past several years, our laboratories have contributed significant findings on the function of mTOR and its associated complexes through this successful collaboration. The current application addresses a fundamental gap in understanding the mechanisms by which mTOR regulates oligodendrocyte differentiation and myelination through regulating specific downstream targets. Our earlier studies demonstrated that oligodendrocyte loss of mTOR or raptor, the mTORC1-associated protein, results in deficits in oligodendrocyte differentiation and initiation of myelination in the spinal cord. Moreover, we found that these mice have reduced myelin thickness that was sustained in the adult spinal cord. A significant strength of the studies is that we have also begun to define distinct mTOR-dependent and –independent pathways that regulate developmental myelination in the brain versus spinal cord. The goal of the current studies is to address the fundamental questions of 1) what are the mTOR-dependent mechanisms that regulate the conversion of oligodendrocyte progenitors to differentiating oligodendrocytes through regulating transcriptional machinery, 2) how does mTOR regulate specific cytoskeletal changes necessary for initiation of myelination and myelin wrapping, and 3) how does the crosstalk between mTORC2 and integrin-linked kinase (ILK) pathways regulate myelination in the corpus callosum? We will address these questions in both rodent and zebrafish models by testing the following hypotheses: 1) mTOR promotes oligodendrocyte differentiation by suppressing bone morphogenetic pathway (BMP) signaling and down-regulating transcriptional inhibitors, 2) mTOR promotes initiation of myelination through regulating specific cytoskeletal targets during both process extension and axon wrapping, and 3) rictor regulates myelination in the corpus callosum through promoting Akt473 phosphorylation in coordination with both mTOR and ILK.

为了了解中枢神经系统中少突胶质细胞的分化和髓磷脂的形成，有必要定义如何 细胞内信号通路调节驱动髓鞘形成的细胞质和核事件。一个数字 信号通路与驱动中枢神经系统髓鞘形成有关。双方之间的合作项目 Macklin 和 Wood 实验室的成立是为了明确 mTOR 信号传导的功能 少突胶质细胞和髓磷脂生物学。在过去的几年里，我们的实验室做出了重大贡献 通过这次成功的合作，我们发现了 mTOR 及其相关复合物的功能。这 当前的应用解决了理解 mTOR 调节机制的根本差距 通过调节特定的下游靶点来实现少突胶质细胞的分化和髓鞘形成。我们早期的 研究表明，少突胶质细胞丢失 ​​mTOR 或 raptor（mTORC1 相关蛋白）会导致 脊髓中少突胶质细胞分化和髓鞘形成起始的缺陷。此外，我们发现 这些小鼠减少了成年脊髓中持续存在的髓磷脂厚度。一个重要的 研究的优势在于我们也开始定义不同的 mTOR 依赖性和独立性 调节大脑与脊髓发育髓鞘形成的途径。当前的目标 研究的目的是解决以下基本问题：1）mTOR 依赖机制是什么？ 通过调节少突胶质细胞祖细胞向分化少突胶质细胞的转化 转录机制，2) mTOR 如何调节启动转录所需的特定细胞骨架变化 髓鞘形成和髓鞘包裹，以及 3) mTORC2 和整合素连接激酶之间的串扰如何 （ILK）途径调节胼胝体中的髓鞘形成？我们将在两种啮齿动物中解决这些问题 和斑马鱼模型，通过测试以下假设：1）mTOR 促进少突胶质细胞分化 通过抑制骨形态发生通路 (BMP) 信号传导和下调转录抑制剂，2) mTOR 通过在这两个过程中调节特定的细胞骨架靶标来促进髓鞘形成的启动 延伸和轴突包裹，3) rictor 通过促进胼胝体髓鞘形成 Akt473 磷酸化与 mTOR 和 ILK 协调。