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 对扩散或区分的决定知之甚少。期间 在过去的十年中，许多细胞外基质结合蛋白是 描述的，现在他们是一个大家庭的成员 整联蛋白受体II IL已被整合蛋白而不是 仅与基质组件结合，但也可以与细胞骨架相互作用。 并启动可能对 细胞增殖和分化。 Schwann Cell（SC）， 外周神经系统的髓鞘形成细胞，是 绝对取决于细胞外沉积的细胞 矩阵以响应于表达的轴突信号而分化 由神经元。尽管这一观察结果是在大约15年前进行的 直到现在才准备描述这一点的分子机制 细胞外基质沉积和SC的相互依存关系 分化。该建议提供了实验策略 允许确定以下内容：1）是否alpha6beta1和 alpha 6 beta4整合素（已知由SC表示）在SC中起作用 分化为髓磷脂形成细胞，2）beta1还是beta4 整联蛋白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）beta1是否 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，例如新描述的局灶性粘附激酶， 形成一个稳定的跨膜复合物，该复合物在与SC结合时形成 细胞外基质和4）酪氨酸磷酸化事件是否为 与整联蛋白介导的信号转导相关，必要。 这些研究将在具有感觉的SC的共同文化中进行 允许1）精确控制SC增殖的神经元和 分化，2）单分子表达的扰动 假设在SC差异化中扮演关键角色，以及3） 使用细胞，分子，生化和 形态学技术。这些研究提供的信息是 对于我们对控制正常细胞的机制的理解至关重要 开发，将直接适用于控制的努力 诸如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 神经系统受伤或通过免疫对神经系统的攻击 机制。