FUNCTIONAL COMPARTMENTALIZATION OF NEURONS AND GLIA

描述本研究的最终目标是了解机制 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。 统一的主题是相互的 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 控制着每种细胞类型的功能反应，因此代表着 关键的治疗干预点。 具体假设涉及 小胶质细胞酪氨酸磷酸化的调节是一个重要的， 这是小胶质细胞对神经元损伤反应的必要步骤， 由淀粉样肽激活的小胶质细胞分泌可溶性因子， 介导神经元tau蛋白磷酸化为AD样状态， 可识别的潜在新途径。 一种神经元损伤的动物模型 其中小胶质细胞表现出酪氨酸的强烈上调的变性 在任何其他活化迹象之前进行磷酸化， 输注酪氨酸激酶抑制剂，将用于询问是否阻断 酪氨酸磷酸化阻止了小胶质细胞从 分支为阿米巴样的形式。 蛋白质印迹和凝胶激酶分析将 用于检查动力学，底物和酶参与这一过程 培养的海马神经元将用于检查调节 tau蛋白磷酸化的因子来源于小胶质细胞激活， 淀粉样肽的存在。 目前的数据显示， 磷酸化可以通过新的激酶和蛋白质印迹来实现， 凝胶激酶测定将用于确认和扩展这些结果。 激酶 抑制剂将被用来询问是否释放小胶质细胞因子， 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.