Characterization of Rac1 effectors in myelination.

髓鞘形成中 Rac1 效应器的表征。

基本信息

批准号：
9178762
负责人：
M. Laura Feltri
金额：
$ 0.52万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9178762
关键词：
Address Affect Apical Axon Back Basal lamina Binding Biological Biology Caliber Cell surface Cells Charcot-Marie-Tooth Disease Collection Congenital neurologic anomalies Data Defect Deformity Development Disease Dystroglycan Event Extracellular Matrix Funding Genes Genetic Epistasis Grant Guanosine Triphosphate Health Human Integrin Binding Integrins Joints Laminin Laminin Receptor Ligands Mass Spectrum Analysis Mediating Mediator of activation protein Movement Mus Muscle Weakness Muscular Atrophy Mutant Strains Mice Mutate Mutation Myelin Nerve Neuregulins Neuroglia Neuropathy Pain Pathway interactions Patients Peripheral Nerves Peripheral Nervous System Peripheral Nervous System Diseases Positioning Attribute Process Proteins Proteome Radial Reagent Role Schwann Cells Sensory Side Signal Transduction Sorting - Cell Movement Surface System Testing Tissues Work base cell type congenital muscular dystrophy dimer feeding gain of function in vivo myelination neurotransmission neurotrophic factor novel overexpression polarized cell receptor research study segregation

项目摘要

DESCRIPTION (provided by applicant): Laminins are fundamental for development of many tissues. Mutations in laminins and related genes cause Congenital Muscular Dystrophies that include multiple peripheral nervous system abnormalities. Laminins and laminin receptors also affect cytoskeletal and RhoGTPAse molecules mutated in Charcot-Marie-Tooth neuropathies. Impaired laminin signaling causes arrest in the developmental step of radial sorting of axons by Schwann cells. Radial sorting is a prerequisite for myelination and a sophisticated example of how cell-cell and cell-matrix interactions cooperate to induce cellular polarization. In the two previous grant periods we showed that axonal sorting is a multistep process, and that the early steps of axonal recognition, segregation and wrapping require the laminin receptors α6ß1 and α7ß1 integrins and Rac1 RhoGTPase, whereas the subsequent detachment of large caliber axons by pro-myelinating Schwann cells requires the laminin receptor dystroglycan. We now propose to address three fundamental cell biological questions and roadblocks to our understanding of sorting and myelination: how do laminins and integrins, at the basal surface of Schwann cells, promote interaction with axons that occurs at the opposite surface (apical-like surface, near axons)? How are signals from laminins integrated with signals from axonal neuregulins? How are contact and wrapping of axons by myelinating glia initiated, mechanically powered and advanced? By capitalizing on the remarkable collection of mouse mutants and reagents that we have generated, we are now in the unique position to address these issues and to identify novel mediators in myelination. These studies will address the critical functional relationship between opposing polarized surfaces, which is relevant to the biology of any polarized cell, but is also important for radial sorting and the initiation of myelination; and is impaired in several human neuropathies and other myelin diseases.

描述（由申请人提供）：层粘连蛋白和相关基因的突变导致先天性肌营养不良，包括多种周围神经系统异常，层粘连蛋白和层粘连蛋白受体也影响细胞骨架和 Charcot-Marie-突变的 RhoGTPAse 分子。牙齿神经病受损的层粘连蛋白信号导致施万轴突径向排序的发育步骤停滞。径向分选是髓鞘形成的先决条件，也是细胞-细胞和细胞-基质相互作用如何协同诱导细胞极化的复杂例子。在前两个资助期中，我们表明轴突分选是一个多步骤的过程，并且早期步骤。轴突识别、分离和包裹的过程需要层粘连蛋白受体 α6ß1 和 α7ß1 整合素和 Rac1 RhoGTPase，而随后的大口径轴突分离促髓鞘形成的施万细胞需要层粘连蛋白受体肌营养不良聚糖，我们现在提出解决三个基本的细胞生物学问题和我们理解分选和髓鞘形成的障碍：施万细胞基底表面的层粘连蛋白和整合素如何促进与轴突的相互作用。发生在相反的表面（顶端样表面，靠近轴突）？来自层粘连蛋白的信号如何与来自轴突神经调节蛋白的信号整合？通过利用我们所产生的大量小鼠突变体和试剂，我们现在处于解决这些问题并确定髓鞘形成中的新介质的独特位置。相对极化表面之间的关键功能关系，与任何极化细胞的生物学相关，但对于径向分选和髓鞘形成的起始也很重要，并且在几种人类神经病和其他髓鞘质中受到损害；疾病。