Role of ERK1/ERK2 MAP Kinase in Myelin Assembly and Maintenance

ERK1/ERK2 MAP 激酶在髓磷脂组装和维护中的作用

• 批准号: 8611978
• 负责人: RASHMI BANSAL
• 金额: $ 19.06万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2015-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8611978
• 关键词: Ablation; Address; Adult; Automobile Driving; Axon; Caliber; Cells; Complex; Data; Demyelinating Diseases; Development; Environment; Event; Foundations; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Growth; Human; In Vitro; Intervention; Investigation; Knockout Mice; Knowledge; Long-Term Effects; MAP Kinase Gene; MAPK1 gene; MAPK10 gene; MAPK3 gene; Maintenance; Mediating; Mediator of activation protein; Mitogen-Activated Protein Kinases; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; Myelin Sheath; Oligodendroglia; Pathway interactions; Phase; Phosphotransferases; Play; Process; Proliferating; Regulation; Role; Series; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Tamoxifen; Thick; Time; Transgenic Mice; base; clinically relevant; design; functional disability; gain of function; human FRAP1 protein; in vivo; insight; mouse model; myelin biogenesis; myelination; oligodendrocyte lineage; postnatal; progenitor; public health relevance; remyelination

DESCRIPTION (provided by applicant): Wrapping of the myelin sheath around axons by oligodendrocytes (OLs) is critical for the rapid conduction of electrical signals that are required for normal functioning of the CNS. Myelination is a multistep process involving the proliferation of OL progenitors (OPCs), timely differentiation into OLs, ensheathment of axons and finally rapid expansion of myelin sheath during the peak of myelination followed by gradual growth in adulthood. While many regulators of the early stages of OL development have been identified, there are significant gaps in our understanding of the specific intracellular signaling events that are integrated within the OLs that control later phases of myelinogenesis to increase its thickness in proportion to axon caliber. Understanding this mechanism is clinically relevant since it is unclear why the myelin that is formed during remyelination in Multiple Sclerosis fails to achieve normal thickness. This proposal primarily addresses the important question of how myelin assembly and maintenance are regulated in the CNS, hypothesizing that ERK1/2-MAPK (Extracelluar Signal Regulated Kinases-1/2), important mediators of multiple external signals, plays a central role in these processes. This is based on our recent findings that mice lacking OL-specific expression of ERK1/2 fail to up- regulate the transcription of major myelin genes and are unable to generate thick myelin sheaths. This is independent of OPC proliferation, differentiation and ensheathment of axons since these events remain unaffected in the Erk1/2 knockout mice. These results represent an important conceptual paradigm shift as they suggest that OL differentiation/initiation and subsequent increase in myelin thickness are distinctly regulated, in contrast to the PNS, where one signal controls both OL differentiation and myelination. To obtain further insights into the role of ERK1/2 in the complex in vivo environment, we seek to address the following specific questions using a series of transgenic mice models with genetic loss or gain of ERK1/2 function. In Aim I, using mice where ablation of Erk1/2 in mature OLs will be induced at a later point in development and in adulthood, we will examine the role of ERK1/2 on the long- term progression of myelin growth and maintenance in adulthood. In Aim II, using mice where ERK1/2 activity will be elevated in OPCs and OLs during development or in mature OLs during adulthood, we will elucidate the role of ERK1/2 in OL development and myelin assembly during active myelination and in adulthood. Overall, a combination of state-of-the-art genetic loss- and gain-of-function approaches as proposed here are expected to enhance our understanding of the functional significance of ERK1/2 signaling both during OL differentiation and active myelin biogenesis, as well as to sustain its gradual growth and maintenance in adulthood, and to apply this knowledge for an informed intervention in the treatment of demyelinating diseases such as MS.

描述（由申请人提供）：少突胶质细胞（OL）包裹轴突周围的髓鞘对于所需电信号的快速传导至关重要 维持中枢神经系统的正常功能髓鞘形成是一个多步骤的过程，涉及OL祖细胞（OPC）的增殖、及时分化成OL、轴突的鞘化以及最终在髓鞘形成高峰期间髓鞘的快速扩张，随后在成年期逐渐生长。虽然已经确定了OL发育早期阶段的许多调节因子，但我们对特定细胞内信号传导事件的理解存在重大差距， 整合在控制髓鞘形成后期的OL内，以与轴突口径成比例地增加其厚度。理解这种机制是临床相关的，因为目前还不清楚为什么在多发性硬化症髓鞘再生过程中形成的髓鞘不能达到正常厚度。该提案主要解决了髓鞘组装和维持在CNS中如何调节的重要问题，假设ERK 1/2-MAPK（细胞外信号调节激酶-1/2），多种外部信号的重要介质，在这些过程中发挥核心作用。这是基于我们最近的发现，即缺乏ERK 1/2的OL特异性表达的小鼠不能上调主要髓鞘基因的转录，并且不能产生厚的髓鞘。这是独立的OPC增殖，分化和鞘的轴突，因为这些事件在Erk 1/2敲除小鼠中保持不受影响。这些结果代表了一个重要的概念范式转变，因为它们表明，OL分化/启动和随后的髓鞘厚度的增加是明显调节的，与PNS相反，其中一个信号控制OL分化和髓鞘形成。为了进一步了解ERK 1/2在复杂的体内环境中的作用，我们试图使用一系列具有ERK 1/2功能遗传缺失或获得的转基因小鼠模型来解决以下具体问题。在目的I中，使用在发育后期和成年期诱导成熟OL中Erk 1/2消融的小鼠，我们将检查ERK 1/2对成年期髓鞘生长和维持的长期进展的作用。在目的II中，使用ERK 1/2活性将升高的小鼠在OPCs和OLs在发展过程中或在成熟的OLs在成年期，我们将阐明ERK 1/2在OL发展和髓鞘组装在活跃的髓鞘形成和成年期的作用。总体而言，本文提出的最先进的遗传功能丧失和获得方法的组合有望增强我们对ERK 1/2信号传导在OL分化和活性髓鞘生物合成期间的功能意义的理解，以及维持其在成年期的逐渐生长和维持，并将这些知识应用于脱髓鞘疾病（如MS）治疗中的知情干预。