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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。脱髓鞘疾病是影响年轻人的最常见的神经系统疾病。周围神经系统的髓鞘形成神经胶质细胞（如许旺细胞）经历形态学的阶段特异性变化，这使得它们能够在轴突周围产生髓鞘。调节肌动蛋白动力学的信号转导途径，以响应外部轴突和细胞外基质的线索在很大程度上是未知的。我们最近报道，ErbB和B1整合素受体的激活可诱导神经纤维瘤病2型肿瘤抑制因子Schwannomin的磷酸化。Schwannomin将受体连接到肌动蛋白细胞骨架并调节Cdc 42/RacGT 3的活性。因此，它被定位为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变化。我们推测，Sch通过p21激活激酶（PAK）- LIM激酶- cofilin途径调节肌动蛋白聚合。在目的1中，我们建议阐明cofilin在雪旺细胞髓鞘形成过程中的功能。我们将比较正常和cofilin缺陷的雪旺细胞体外髓鞘轴突的能力。在目的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。我们将通过对正常和cofilin缺陷的雪旺细胞进行活体成像实验，确定雪旺细胞是否需要cofilin来重塑其质膜以响应NRG和层粘连蛋白刺激。这项工作的直接结果将是确定一种新的途径，用于许旺细胞产生与髓鞘形成相关的受体特异性形态变化。如果成功的话，这项工作将提供第一个完整的地图的信号级联启动轴突和基底层配体，终止于最后的下游效应蛋白，肌动蛋白。这些信息将影响越来越多的特定药物靶点的识别，用于开发髓鞘形成疾病和其他雪旺细胞疾病（如神经纤维瘤病和雪旺细胞瘤病）的单一和组合疗法。