CONTROL OF SCHWANN CELL DIFFERENTIATION

施万细胞分化的控制

• 批准号: 2519978
• 负责人: CRISTINA Maria FERNANDEZ-VALLE
• 金额: $ 11.96万
• 依托单位: ORLANDO REGIONAL MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2519978
• 关键词: Schwann cells; actins; antisense nucleic acid; blocking antibody; cell differentiation; developmental neurobiology; electron microscopy; embryo /fetus cell /tissue; enzyme activity; extracellular matrix; immunoprecipitation; in situ hybridization; integrins; intermolecular interaction; laboratory mouse; laboratory rat; myelin; oligonucleotides; phosphorylation; protein tyrosine kinase; tissue /cell culture; western blottings

The mechanisms by which the extracellular matrix influences a cell's decision to proliferate or differentiate are poorly understood. During the last decade, many extracellular matrix-binding proteins were described and they are now known to be members of a large family of integrin receptor II IL it is becoming appreciated that integrins not only bind to matrix components but also interact with.the cytoskeleton and initiate signal transduction pathways that may be critical for cellular proliferation and differentiation. The Schwann cell (SC), the myelin forming cell of the peripheral nervous system, is an example of a cell that is absolutely dependent on the deposition of extracellular matrix in order to differentiate in response to axonal signals expressed by neurons. Although this observation was made nearly 15 years ago, we are only now ready to delineate the molecular mechanisms underlying this interdependence of extracellular matrix deposition and SC differentiation. This proposal provides experimental strategies that will allow ascertainment of the following: 1) whether the alpha6beta1 and alpha 6 Beta4 integrins, known to be expressed by SCs, play a role in SC differentiation into myelin-forming cells, 2) whether Beta1 or Beta4 integrin activation, or the actin-based cytoskeleton, are associated with expression of myelin-specific proteins or their mRNAs, 3) whether Beta1 or Beta4 integrins interact with actin, actin binding proteins, and signaling molecules such as the newly-described focal adhesion kinase, to form a stable transmembrane complex that forms upon SC binding to the extracellular matrix, and 4) whether tyrosine phosphorylation events are associated with and necessary for integrin-mediated signal transduction. These studies will be conducted in co-cultures of SCs with sensory neurons that allow 1) precise control of SC proliferation and differentiation, 2) perturbation of the expression of single molecules hypothesized to play critical roles in SC differentiation, and 3) that are amenable to analysis using cellular, molecular, biochemical, and morphological techniques. The information provided by these studies is crucial to our understanding of the mechanisms controlling normal cell development and will be directly applicable to efforts to control tumorigenesis in diseases such as neurofibromatosis, as well as to develop therapeutic strategies to alleviate demyelination caused by injury to the nervous system or by attack on the nervous system by immune mechanisms.

细胞外基质影响细胞的机制 人们对增殖或分化的决定知之甚少。期间 在过去的十年中，许多细胞外基质结合蛋白被 描述，现在已知他们是一个大家庭的成员 整合素受体 II IL 人们逐渐认识到整合素不 不仅与基质成分结合，还与细胞骨架相互作用 并启动可能至关重要的信号转导途径 细胞增殖和分化。施万细胞 (SC) 周围神经系统的髓磷脂形成细胞是一个例子 绝对依赖于细胞外沉积的细胞 矩阵以便区分所表达的轴突信号 由神经元。尽管这一观察是在近 15 年前做出的，但我们 现在才准备好描述其背后的分子机制 细胞外基质沉积和 SC 的相互依赖性 差异化。该提案提供了实验策略，将 允许确定以下内容： 1) 是否 alpha6beta1 和 已知由 SC 表达的 α 6 Beta4 整合素在 SC 中发挥作用 分化为髓磷脂形成细胞，2) 无论是 Beta1 还是 Beta4 整合素激活或基于肌动蛋白的细胞骨架与 髓磷脂特异性蛋白或其 mRNA 的表达，3) 是否 Beta1 或 Beta4 整合素与肌动蛋白、肌动蛋白结合蛋白相互作用，并且 信号分子，例如新描述的粘着斑激酶， 形成稳定的跨膜复合物，该复合物在 SC 与 细胞外基质，4) 酪氨酸磷酸化事件是否 与整合素介导的信号转导相关且是必需的。 这些研究将在 SC 与感官的共培养中进行 神经元可以 1）精确控制 SC 增殖和 分化，2）单分子表达的扰动 假设在 SC 分化中发挥关键作用，并且 3) 适合使用细胞、分子、生物化学和 形态学技术。这些研究提供的信息是 对于我们理解控制正常细胞的机制至关重要 的发展并将直接应用于控制工作 神经纤维瘤病等疾病的肿瘤发生，以及 制定治疗策略以减轻由脱髓鞘引起的脱髓鞘 神经系统损伤或免疫系统攻击神经系统 机制。