Oligodendrocytes, Glutamate Receptors, and Lead Neurotoxicity

铅（Pb 2+）中毒仍然是美国最常见的环境源性疾病。 今天的国家。长期目标是通过以下方式研究年龄特异性和细胞类型特异性机制 哪种铅会导致神经毒性铅已知会导致髓鞘缺陷，尽管其机制是 不清楚中枢神经系统中的髓鞘是由少突胶质细胞形成的，使这些细胞 可能是铅的目标我们以前已经证明，环境相关的，低水平的铅 可以干扰少突胶质细胞的存活、增殖和分化， 发展我们还证明了发育中的少突胶质细胞非常容易受到 由Ca 2+渗透性谷氨酸受体（GluRs）介导的兴奋性毒性。Pb 2+是二价金属离子， 可以模拟Ca 2+并干扰Ca 2+敏感的靶点。线粒体在缓冲中起主要作用 细胞内Ca 2+，并且是已知的Pb 2+靶。在这里，我们建议检查的假设，一个关键的 铅神经毒性的一个重要因素是Ca 2+渗透性GluR功能的损害和 发育性GluR表达，同时缺乏信号机制，涉及改变 发育中的少突胶质细胞的线粒体动力学和氧化还原电位，导致异常的神经元-胶质细胞 连接和功能障碍。本提案的目标1将检查Pb 2+是否抑制Ca 2 *- 渗透性GluR功能在发育中的少突胶质细胞，并确定GluR的相对作用 Pb 2+毒性的亚型。目的2将确定铅暴露是否改变GluR亚基的表达 和磷酸化状态，以及调节GluR功能的下游信号分子。目标3将 确定Pb 2+是否会导致线粒体功能、成熟、动力学渗出和 分裂和氧化还原状态。总的来说，我们建议结合使用 细胞和分子技术应用于铅暴露的体外和体内模型， 提供重叠的方法，以解开铅诱导的毒性对发展中国家的新机制， 个脑袋本项目首次研究了GluRs和线粒体在发育中的少突胶质细胞中的作用 铅中毒阐明这些以前未被认识到的Pb 2+作用机制将提供 深入了解与铅接触相关的风险， 针对Ca 2 +-可渗透GluRs和相关信号通路的干预策略， 处理铅中毒问题

Lead (Pb2+) poisoning remains the most common disease of environmental origin in the United States today. The long-term goal is to investigate age-specific and cell type-specific mechanisms by which lead causes its neurotoxicity. Lead is known to cause myelin defects, although the mechanism is unclear. Myelin in the central nervous system is formed by oligodendrocytes, making these cells a possible target for lead. We have previously demonstrated that environmentally relevant, low-level lead can disturb the survival, proliferation, and differentiation of oligodendrocytes at critical windows of development. We have also demonstrated that developing oligodendrocytes are highly vulnerable to excitotoxicity mediated by Ca2+-permeable glutamate receptors (GluRs). Pb2+ is a divalent metal ion that can mimic Ca2+ and interferes with Ca2+-sensitive targets. Mitochondria play a major role in buffering intracellular Ca2+, and are a known Pb2+ target. Here we propose to examine the hypothesis that a critical factor in lead neurotoxicity is the impairment of Ca2+-permeable GluR function and alteration of developmental GluR expression, concurrently with deficits in signaling mechanisms involving altered mitochondrial dynamicsand redox potential in developingoligodendrocytes,resulting in aberrant neuron-glia connectivity and functional impairments. Aim 1 of this proposal will examine whether Pb2+ inhibits Ca2*- permeable GluR function in developing oligodendrocytes, and determine the relative roles of GluR subtypes in Pb2+ toxicity. Aim 2 will determine whether lead exposure modifies GluR subunit expression and phosphorylation state, and downstream signaling molecules that regulate GluR function. Aim 3 will determine whether Pb2+ causes alterations in mitochondrial function, maturation, dynamics effusion and fission, and redox state in developing oligodendrocytes. Overall, we propose to use a combination of cellular and molecular techniques applied to both in vitro and in vivo models of lead exposure, to provide overlapping approaches to unravel novel mechanisms of lead-induced toxicity to the developing brain. This project is the first to study the role of GluRs and mitochondria of developing oligodendroglia in lead toxicity. Elucidating these previously unrecognized mechanisms of Pb2+ action will provide insights into the understanding the risks associated with lead exposure and the development of intervention strategies of targeting Ca2+-permeable GluRs and associated signaling pathways for dealing with lead toxicity.