Actomyosin motors and Mechanism of Myelin Formation

肌动球蛋白马达和髓磷脂形成机制

• 批准号: 7262553
• 负责人: Carmen V Melendez-Vasquez
• 金额: $ 26.66万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7262553
• 关键词: Actomyosin; Affect; Axon; Basal lamina; Cell Differentiation process; Cells; Cellular Morphology; Coculture Techniques; Cytoskeleton; Data; Defect; Demyelinating Diseases; Development; Disease; Doctor of Philosophy; Event; Failure; Goals; Immunofluorescence Immunologic; In Vitro; Laboratories; Length; Localized; Measures; Membrane; Molecular; Morphology; Motor; Multiple Sclerosis; Myelin; Myelin Sheath; Myosin Light Chain Kinase; Myosin Light Chains; Names; Neuroglia; Neurons; Neuropathy; Oligodendroglia; Optic Nerve; Pathway interactions; Pattern; Peripheral; Phosphorylation; Phosphotransferases; Play; Principal Investigator; Process; RNA; Regulation; Rho-associated kinase; Role; Schwann Cells; Techniques; Testing; Time; Western Blotting; in vivo; insight; myelination; novel; novel therapeutics; prevent; research study; rho

DESCRIPTION (provided by applicant): The myelin sheath forms by the spiral wrapping of a glial membrane around an axon. The; mechanisms responsible for this process are unknown but are likely to involve changes in the glial cell cytoskeleton. Recent data from our laboratory strongly suggest that regulation of actomyosin assembly via phosphorylation of myosin light chain (MLC) is an important aspect of this process. We have found that Rho-associated kinase (ROCK) and myosin light chain kinase (MLCK), two of the major kinases involved in MLC phosphorylation, have very distinct roles on myelination. In Schwann cell-neuron cocultures, inhibition of ROCK results in atypical Schwann cell morphology, with cells that branch aberrantly and form multiple, small independent myelin segments along the length of axons, each with associated nodes and paranodes. This organization partially resembles myelin formed by oligodendrocytes. By contrast, inhibition of MLCK appears to prevent myelination by interfering with the spiral wrapping of the myelin sheath around the axon. We have also found that MLC phosphorylation is robustly, but transiently, activated at the onset of myelination during development. In this study we will test the hypothesis that ROCK and MLCK, two of the major pathways regulating MLC phosphorylation and hence actomyosin activity, are directly involved in the control of myelin morphology and its wrapping around the axon. The overall goal of this project is to provide novel insights into the mechanisms that regulate myelin morphology and formation in the PNS and CNS. A basic understanding of the molecular machinery of myelination should aid in the development of new therapeutic strategies to promote remyelination in diseases; such as multiple sclerosis and peripheral demyelinating neuropathies.

描述（由申请人提供）：髓鞘由神经胶质膜围绕轴突螺旋包裹而形成。这;负责这一过程的机制尚不清楚，但可能涉及神经胶质细胞骨架的变化。 我们实验室的最新数据强烈表明，通过肌球蛋白轻链 (MLC) 磷酸化调节肌动球蛋白组装是该过程的一个重要方面。我们发现 Rho 相关激酶 (ROCK) 和肌球蛋白轻链激酶 (MLCK) 这两种参与 MLC 磷酸化的主要激酶在髓鞘形成中具有非常不同的作用。在施万细胞-神经元共培养中，抑制 ROCK 会导致非典型的施万细胞形态，细胞异常分支并沿着轴突长度形成多个小的独立髓鞘片段，每个片段都有相关的节点和旁节点。该组织部分类似于少突胶质细胞形成的髓磷脂。相比之下，抑制 MLCK 似乎可以通过干扰轴突周围髓鞘的螺旋包裹来阻止髓鞘形成。我们还发现，MLC 磷酸化在发育过程中髓鞘形成开始时被强烈但短暂地激活。在本研究中，我们将检验以下假设：ROCK 和 MLCK（调节 MLC 磷酸化和肌动球蛋白活性的两条主要途径）直接参与髓磷脂形态及其包裹轴突的控制。该项目的总体目标是为调节 PNS 和 CNS 中髓磷脂形态和形成的机制提供新的见解。对髓鞘形成分子机制的基本了解应有助于开发新的治疗策略，以促进疾病的髓鞘再生；例如多发性硬化症和周围脱髓鞘神经病。