Mechanisms Modulating Cytoskeletal Dynamics During Schwann Cell Myelination

雪旺细胞髓鞘形成过程中细胞骨架动力学的调节机制

基本信息

批准号：
7737261
负责人：
CRISTINA Maria FERNANDEZ-VALLE
金额：
$ 40.36万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-20 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7737261
关键词：
Actins Action Potentials Acute Affect Afferent Neurons Axon Basal lamina Cell membrane Cells Cellular Morphology Coculture Techniques Cues Cyclic AMP-Dependent Protein Kinases Cytoskeleton Data Demyelinating Diseases Development Disease Drug Delivery Systems Eating Electrons Extracellular Matrix F-Actin Foundations Genes Goals Image In Vitro Integrins LIM Domain Kinase 1 Laminin Life Ligands Light Link Maps Measures Mediating Mediator of activation protein Microscopic Modeling Molecular Morphology Myelin Myelin Sheath Nerve Nervous system structure Neuregulins Neurofibromatoses Neurofibromatosis 2 Neurofibromin 2 Neuroglia Outcome Pathology Pathway interactions Peptides Peripheral Nervous System Phosphorylation Phosphotransferases Positioning Attribute Process Proteins Publishing Ranvier&apos s Nodes Rattus Reporting Research Research Personnel Role Schwann Cells Schwannomatosis Sensory Signal Pathway Signal Transduction Staging Testing Time Tumor Suppressor Proteins Work cofilin combinatorial in vivo kinase inhibitor knock-down lentiviral-mediated myelination neurological pathology novel p21 activated kinase paxillin polymerization prevent public health relevance receptor research study response rho GTP-Binding Proteins tumor young adult

项目摘要

Myelination allows rapid propagation of action potentials in the nervous system. Dys- and demyelinating disorders are among the most common neurological pathologies affecting young adults. Myelinating glial cells such as Schwann cells of the peripheral nervous system undergo stage specific changes in morphology that enable them to elaborate myelin around an axon. The signaling pathways that regulate actin dynamics in response to extrinsic axonal and extracellular matrix cues are largely unknown. We recently reported that activation of ErbB and B1 integrin receptors induces phosphorylation of Schwannomin, the Neurofibromatosis type 2 tumor suppressor. Schwannomin links receptors to the actin cytoskeleton and modulates the activity of Cdc42/RacGTPase. Thus it is positioned to link receptor activity to actin dynamics and trigger changes in cellular morphology needed for myelination. We hypothesize that Sch modulates actin polymerization through a p21activated kinase (PAK) - LIM kinase - cofilin pathway. In Aim 1, we propose to elucidate the function of cofilin during Schwann cell myelination. We will compare the ability normal and cofilin-deficient Schwann cells to myelinate axons in vitro. In Aim 2, we will assess whether neuregulin and laminin regulate LlMK and cofilin phosphorylation. We will determine whether cofilin is needed for Schwann cells to remodel their plasma membrane in response to NRG and laminin stimulation by conducting live imaging experiments with normal and cofilin-deficient Schwann cells. The immediate outcome of this work will be to identify a novel pathway used by Schwann cells to produce receptor specific changes in morphology associated with myelination. If successful, this work will provide the first complete map of a signaling cascade initiated by axonal and basal lamina ligands that terminates at the final downstream effector protein, actin. This information will impact the identification of increasingly specific drug targets for development of single and combinatorial therapies for myelinating disorders and other Schwann cell disorders such as Neurofibromatosis and Schwannomatosis.

髓鞘形成允许神经系统中动作电位的快速传播。髓鞘发育不良和脱髓鞘疾病是影响年轻人的最常见的神经病理学疾病之一。周围神经系统的髓鞘神经胶质细胞（例如雪旺细胞）经历特定阶段的形态变化，使它们能够在轴突周围形成髓磷脂。响应外在轴突和细胞外基质信号而调节肌动蛋白动力学的信号通路在很大程度上是未知的。我们最近报道，ErbB 和 B1 整合素受体的激活会诱导 2 型神经纤维瘤病肿瘤抑制因子 Schwannomin 的磷酸化。 Schwannomin 将受体与肌动蛋白细胞骨架连接起来并调节 Cdc42/RacGTPase 的活性。因此，它的定位是将受体活性与肌动蛋白动力学联系起来，并触发髓鞘形成所需的细胞形态的变化。我们假设 Sch 通过 p21 激活激酶 (PAK) - LIM 激酶 - cofilin 途径调节肌动蛋白聚合。在目标 1 中，我们建议阐明丝切蛋白在雪旺细胞髓鞘形成过程中的功能。我们将比较正常和丝切蛋白缺陷的雪旺细胞在体外使轴突髓鞘化的能力。在目标 2 中，我们将评估神经调节蛋白和层粘连蛋白是否调节 LlMK 和丝切蛋白磷酸化。我们将通过对正常和肌动蛋白丝切蛋白缺陷的施万细胞进行活体成像实验，确定施万细胞是否需要肌动蛋白丝切蛋白来重塑其质膜以响应NRG和层粘连蛋白的刺激。这项工作的直接成果将是确定雪旺细胞使用的一种新途径，以产生与髓鞘形成相关的受体特异性形态变化。如果成功，这项工作将提供由轴突和基底层配体启动的信号级联的第一个完整图谱，该级联在最终下游效应蛋白肌动蛋白处终止。这些信息将影响越来越具体的药物靶标的确定，以开发针对髓鞘疾病和其他施万细胞疾病（例如神经纤维瘤病和神经鞘瘤病）的单一和组合疗法。