CONTROL OF SCHWANN CELL DIFFERENTIATION

描述（来自申请人摘要）： 本提案的目的是了解雪旺细胞如何 在开发过程中整合各种环境信号， 从周围神经疾病或创伤中恢复。长期 目标是确定雪旺细胞如何响应来自 细胞外基质（ECM），轴突和邻近的雪旺细胞， 以协调生长和分化成髓鞘形成 细胞为了实现这一目标，Fernando-Valle博士和她的同事们 研究了由雪旺细胞粘附激活的ECM依赖性信号传导， 层粘连蛋白是雪旺细胞基底层中的ECM蛋白。期间 最后一个授权期，粘着斑激酶，桩蛋白，fyn激酶，和 merlin（一种由神经纤维瘤病2型基因编码的肿瘤抑制基因 产品）被发现参与β-1整合素依赖性 体外雪旺细胞髓鞘形成过程中的信号传导。的机制 梅林抑制肿瘤形成的神经系统是未知的。 这些结果暗示梅林在β-1整合素依赖的信号传导中起作用。 雪旺细胞分化过程中的信号通路。假设是 测试了梅林介导信号通路之间的“对话”; 通过与HER 2/HER 3受体结合的胶质生长因子激活， 另一个由层粘连蛋白与雪旺氏细胞上的β-1整合素结合激活， 细胞表面在本申请中，提出：1）映射β-1 通过检查rho GTP酶及其调节剂的整合素上游事件; 2)通过检测丝裂原激活的β 1整合素下游事件， 蛋白激酶和β-1整合素内吞作用; 3）寻找“串扰” 通过传导HER 2/HER 3受体和桩蛋白，梅林， 和FAK相互免疫共沉淀;和4）进行功能性 使用显性阴性和反义寡核苷酸的分析 战略布局 分离的雪旺细胞培养物和体外髓鞘形成模型 由与神经元共培养的许旺细胞组成。这些 是有用的范例，允许蛋白质的功能分析， 应用所有主要的生物化学、分子和细胞学 接近。这些信息可能与治疗的发展有关， a）外周神经损伤，B）努力使用雪旺细胞作为 中枢神经再生和髓鞘再生促进剂 创伤或疾病后的系统，以及3）治疗或预防 神经胶质或其他神经系统肿瘤，偶发于 人群或由2型神经纤维瘤病突变引起 基因

DESCRIPTION (from the applicant's abstract): The objective of this proposal is to understand how Schwann cells integrate diverse environmental signals during development of, and recovery from, disease or trauma to peripheral nerve. The long-term goals are to determine how Schwann cells respond to signals from extracellular matrix (ECM), axons, and neighboring Schwann cells in order to coordinate growth and differentiation into myelin-forming cells. Toward this goal, the Dr. Fernandez-Valle and her colleagues have studied ECM dependent signaling activated by Schwann cell adhesion to laminin, an ECM protein in the Schwann cell basal lamina. During the last grant period, focal adhesion kinase, paxillin, fyn kinase, and merlin (a tumor suppressor encoded by the neurofibromatosis type-2 gene product) were found to be involved in beta-1 integrin-dependent signaling during Schwann cell myelination in vitro. The mechanism by which merlin suppresses tumor formation the nervous system is unknown. The results implicate merlin in a beta-1 integrin dependent signaling pathway during Schwann cell differentiation. The hypothesis will be tested that merlin mediates a "dialogue" between signaling pathways; one activated by glial growth factor binding to HER2/HER3 receptors and another activated by laminin binding to beta-1 integrins on the Schwann cell surface. In this application, it is proposed to: 1) map beta-1 integrin upstream events by examining rho GTPases and their regulators; 2) map beta-1 integrin downstream events by examining mitogen-activated protein kinase and beta-1 integrin endocytosis; 3) look for "cross-talk" between pathways by conducting HER2/HER3 receptor and paxillin, merlin, and FAK reciprocal co-immunoprecipitations; and 4) carry out functional analyses using dominant negative and antisense oligonucleotide strategies. Isolated Schwann cell cultures and the in vitro myelination model consisting of Schwann cells co-cultured with neurons will be used. These are useful paradigms, allowing for functional analyses of proteins and application of all major biochemical, molecular, and cytological approaches. This information may relate to development of therapies for a) injuries to peripheral nerve, b) efforts to use Schwann cells as promoters of regeneration and remyelination in the central nervous system following trauma or disease, and 3) treatment or prevention of glial or other nervous system tumors occurring sporadically in the population or resulting from mutations in the neurofibromatosis type-2 gene.