FUNCTIONAL COMPARTMENTALIZATION OF NEURONS AND GLIA

描述：这项研究的最终目的是了解机制 小胶质细胞和神经元在神经元损伤中的相互作用 和神经退行性疾病。统一的主题是互惠 小胶质细胞和神经元中蛋白磷酸化系统的调节 关于关键早期事件的神经元损伤和神经退行性疾病 管理每种细胞类型的功能反应，从而代表 关键的治疗干预点。提出了具体的假设。 小胶质细胞酪氨酸磷酸化的调节是一种开创性的和 小胶质细胞对神经元损伤反应的必要步骤 淀粉样多肽激活的小胶质细胞分泌可溶性因子 通过调节神经元tau蛋白的磷酸化，使其进入AD样状态 可识别的潜在的新途径。一种神经细胞的动物模型 小胶质细胞表现出强烈的酪氨酸上调的变性 在任何其他激活迹象之前的磷酸化，连同 输注酪氨酸激酶抑制剂，将用来询问是否阻断 酪氨酸磷酸化阻止小胶质细胞从 分支成阿米巴形状的。蛋白印迹和凝胶内蛋白激酶分析将 用于检测与此有关的动力学、底物和酶 培养中的反应性海马神经元将被用来检查调节 活化的小胶质细胞衍生的因子对tau磷酸化的影响 淀粉样多肽的存在。目前的数据表明，这 磷酸化可能受新的激酶、蛋白质印迹和蛋白的影响 凝胶激酶分析将用于确认和推广这些结果。激活剂 抑制剂将被用来询问小胶质细胞因子的释放是否 依赖于酪氨酸磷酸化。

DESCRIPTION The ultimate goal of this research is to understand mechanisms underlying the interactive role of microglia and neurons in neuronal injury and neurodegenerative disease. The unifying theme is the reciprocal regulation of protein phosphorylation systems in microglia and neurons in neuronal injury and neurodegenerative disease regarding key early events governing the functional response of each cell type, and thus represent critical therapeutic intervention points. The specific hypotheses addressed are that regulation of microglial tyrosine phosphorylation is a seminal and necessary step in the response of microglia to neuronal injury, and that microglia activated by amyloid peptides secrete soluble factors which mediate phosphorylation of neuronal tau proteins to an AD like state via identifiable potentially novel pathways. An animal model of neuronal degeneration in which microglia exhibit a robust upregulation of tyrosine phosphorylation prior to any other sign of activation, together with infusion of tyrosine kinase inhibitors, will be used to ask whether blocking tyrosine phosphorylation prevents the conversion of microglia from the ramified to the ameboid form. Western blot and in gel kinase analyses will be used to examine the dynamics, substrates and enzymes involved in this response Hippocampal neurons in culture will be used to examine regulation of tau phosphorylation by factors derived from microglia activated in the presence of amyloid peptides. Current data indicate that this phosphorylation may be effected by novel kinases, and Western blot and in gel kinase assays will be used to confirm and extend these results. Kinase inhibitors will be used to ask whether release of microglial factors is dependent on tyrosine phosphorylation.