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.

髓鞘化可以快速传播神经系统中的动作电位。 Dys和脱髓鞘性疾病是影响年轻人的最常见神经病学。神经胶质细胞（如周围神经系统的雪旺氏细胞）经历了形态学的特定阶段变化，使它们能够在轴突周围详细说明髓磷脂。响应外部轴突和细胞外基质提示，调节肌动蛋白动力学的信号传导途径在很大程度上未知。我们最近报道，ERBB和B1整联蛋白受体的激活诱导schwannomin，schwannomin，schwannomin，schwannomin，sneurofiromatsis 2型肿瘤抑制剂。 Schwannomin将受体与肌动蛋白细胞骨架联系起来，并调节CDC42/RACGTPase的活性。因此，它可以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活化激酶（PAK） - LIM激酶-Cofilin途径调节肌动蛋白聚合。在AIM 1中，我们建议阐明schwann细胞髓样期间Cofilin的功能。我们将在体外比较正常和缺陷型的Schwann细胞的能力与髓鞘轴突。在AIM 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Cofilin磷酸化。我们将确定是否需要使用正常和Cofilin缺乏的Schwann细胞进行实时成像实验来确定Schwann细胞是否需要对NRG和层粘连蛋白刺激进行重塑其质膜。这项工作的直接结果将是确定Schwann细胞用来产生与髓鞘形态有关的受体特定变化的新途径。如果成功的话，这项工作将提供由轴突和基底层配体启动的信号级联反应的第一个完整图，该轴突配体终止于最终下游效应蛋白肌动蛋白肌动蛋白。这些信息将影响鉴定越来越特定的药物靶标，用于开发单一和组合疗法的骨髓疾病和其他schwann细胞疾病，例如神经纤维瘤病和Schwannomatosis。