CELL BIOLOGY OF A NEUROTROPHIC PROTEIN FROM GLIAL CELLS

神经胶质细胞神经营养蛋白的细胞生物学

• 批准号: 3123124
• 负责人: LINDA J VAN ELDIK
• 金额: $ 14.62万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-15 至 1995-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3123124
• 关键词: G protein; affinity chromatography; astrocytes; biological signal transduction; calcium flux; cell growth regulation; electrophoresis; glia; laboratory rat; membrane activity; nerve /myelin protein; protein structure function; protein tyrosine kinase; radiotracer; receptor binding; receptor sensitivity; tissue /cell culture; western blottings

The long term goal is to increase understanding of molecular mechanisms involved in development and maintenance of the nervous system, and how perturbations of these processes might be involved in certain disease states, especially inherited diseases and age-related disorders. The focus of the research is on S100beta, a glial cell protein that has neurotrophic activity; i.e., S100beta can selectively stimulate neurite outgrowth and enhance survival of CNS neurons. Feasibility data indicate that S100beta also stimulates glial cell proliferation. Thus, S100beta may be involved in the coordinate development and maintenance of the CNS by synchronously stimulating the differentiation of neurons and the proliferation of glia. However, nothing is known about the mechanisms which enable these cell types to respond differentially to S100beta. It is the goal of this proposal to fill a void in our knowledge of the molecular mechanisms by which S100beta stimulates glial cell proliferation. The two questions being addressed are: 1. what are the characteristics of the cell surface components that recognize S100beta; i.e. the receptor? and 2. how does binding of S100beta bring about stimulation of cell proliferation; i.e., signal transduction pathways? By addressing these two mechanistically coupled questions, insight will be gained into how molecular recognition of S100beta by the glial cell is transduced through intracellular signal transduction events to the eventual proliferative response. These studies will provide the necessary knowledge to pursue longer-term studies aimed at probing molecular mechanisms at a more detailed level, in order to understand how the cell surface events are coupled mechanistically to the nuclear events (changes in gene expression) and vice versa, and what distinguishing features of these pathways determine the specific biological responses of glial vs neuronal cells to S100beta stimulation. This research also has the potential to increase understanding of the neuropathologies associated with age-related disorders such as Down syndrome and Alzheimer's disease. Clearly, because S100beta can affect both glial and neuronal cells, aberrant S100beta gene expression and protein production/targeting during critical periods of development could have profound effects on nervous system function. In this regard, the abnormally high levels of S100beta found in the brains of patients with these diseases may be linked directly to the observed gliosis and abnormal neuritic outgrowth, and to the cascade of neuropathological events that with aging lead to mental retardation and dementia. This research has the potential to provide the basic knowledge necessary for future approaches to diagnostics and therapeutics for these age-related disorders.

长期目标是增加对分子机制的理解 参与神经系统的发展和维护，以及如何 这些过程的扰动可能与某些疾病有关 州，特别是遗传疾病和与年龄有关的疾病。 重点 这项研究是关于具有神经营养性的神经胶质细胞蛋白S100Beta的 活动;即S100beta可以选择性地刺激神经突生长和 增强中枢神经系统神经元的存活率。 可行性数据表明S100BETA 还刺激神经胶质细胞增殖。 因此，S100beta可能涉及 通过同步的协调开发和维护中枢神经系统 刺激神经元的分化和神经胶质的增殖。 但是，对启用这些细胞的机制一无所知 对S100BETA的反应类型。 这是目标的目标 提议在我们了解分子机制中填补空白的提议 S100BETA刺激神经胶质细胞的增殖。 这两个问题 被解决的是：1。细胞表面的特征是什么 识别S100beta的组件；即受体？ 和2。如何 S100beta的结合带来了细胞增殖的刺激； IE。， 信号转导途径？ 通过机械机械地解决这两个 耦合的问题，将获得分子识别的洞察力 神经胶质细胞通过细胞内信号转导S100beta 将事件转移到最终的增殖反应。 这些研究 将提供必要的知识来从事针对的长期研究 以更详细的水平探测分子机制 了解细胞表面事件如何机械耦合到 核事件（基因表达的变化），反之亦然，什么 这些途径的区分特征决定了特定的生物学 神经胶质细胞对S100BETA刺激的反应。 这 研究还有可能提高对 与年龄有关的疾病（例如下降）相关的神经病理学 综合征和阿尔茨海默氏病。 显然，因为s100beta会影响 神经胶质细胞和神经元细胞，异常S100BETA基因表达和 在关键开发期间的蛋白质生产/靶向可能 对神经系统功能有深远的影响。 在这方面， 在患者的大脑中发现了异常高的S100BETA 这些疾病可以直接与观察到的神经胶质变性和异常有关 神经产物的生长，以及一系列神经病理事件 衰老会导致智力低下和痴呆。 这项研究有 提供未来方法必要的基本知识的潜力 这些与年龄有关的疾病的诊断和治疗剂。