Oligodendrocytes, Glutamate Receptors, and Lead Neurotoxicity

少突胶质细胞、谷氨酸受体和铅神经毒性

基本信息

批准号：
7847872
负责人：
Wenbin Deng
金额：
$ 9.8万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-22 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847872
关键词：
Acids Affect Age Animals Astrocytes Biochemical Brain Buffers Ca(2+)-Calmodulin Dependent Protein Kinase Calcineurin Cell Nucleus Cell Transplants Cell physiology Cells Child Cognitive deficits D Aspartate Defect Development Developmental Process Disease Event Exposure to Feedback Gene Expression Gene Silencing Gene Transfer Glutamate Receptor Glutamates Goals Hippocampus (Brain)Image Impairment In Vitro Intervention Ions Kainic Acid Receptors Lead Lead Poisoning Learning Long-Term Potentiation Mediating Memory Microscopic Mitochondria Molecular Morphology Myelin N-Methyl-D-Aspartate Receptors N-Methylaspartate Neuraxis Neuroglia Neurologic Neurons Oligodendroglia Oxidation-Reduction Oxidative Stress Phosphorylation Physiological Play Predisposition Process RNA Interference Regulation Relative (related person)Research Personnel Risk Role Signal Pathway Signal Transduction Signaling Molecule Slice Synapses Synaptic plasticity Techniques Toxic effect United States Virus Work age related cell type cellular targeting coping divalent metal effusion excitotoxicity functional disability in vivo in vivo Model insight kainate lead exposure lead ion mitochondrial dysfunction neurobehavioral neurotoxicity neurotransmission novel oligodendrocyte precursor programs receptor research study toxicant

项目摘要

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.

铅 (Pb2+) 中毒仍然是美国最常见的环境原因疾病今天的国家。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其神经毒性。已知铅会导致髓磷脂缺陷，尽管其机制是不清楚。中枢神经系统中的髓磷脂由少突胶质细胞形成，使这些细胞成为铅的可能目标。我们之前已经证明，与环境相关的低含量铅可以扰乱少突胶质细胞在关键窗口期的存活、增殖和分化发展。我们还证明，发育中的少突胶质细胞非常容易受到由 Ca2+ 通透性谷氨酸受体 (GluR) 介导的兴奋性毒性。 Pb2+是二价金属离子可以模仿 Ca2+ 并干扰 Ca2+ 敏感目标。线粒体在缓冲中起重要作用细胞内 Ca2+ 是已知的 Pb2+ 靶标。在这里，我们建议检验以下假设：铅神经毒性的因素是 Ca2+ 通透性 GluR 功能的损害和发育性 GluR 表达，同时涉及涉及改变的信号传导机制的缺陷发育中的少突胶质细胞的线粒体动力学和氧化还原电位，导致异常的神经胶质细胞连接性和功能障碍。该提案的目标 1 将检查 Pb2+ 是否抑制 Ca2*- 发育少突胶质细胞中的渗透性 GluR 功能，并确定 GluR 的相对作用 Pb2+ 毒性的亚型。目标 2 将确定铅暴露是否会改变 GluR 亚基表达和磷酸化状态，以及调节 GluR 功能的下游信号分子。目标3将确定 Pb2+ 是否会导致线粒体功能、成熟、动力学渗出和线粒体功能的改变发育中的少突胶质细胞的裂变和氧化还原状态。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，提供重叠的方法来揭示铅对发展中国家的毒性的新机制脑。该项目是第一个研究 GluR 和线粒体在少突胶质细胞发育中的作用的项目在铅毒性方面。阐明这些以前未被认识的 Pb2+ 作用机制将提供深入了解与铅暴露相关的风险和发展针对 Ca2+ 渗透性 GluR 及相关信号通路的干预策略处理铅中毒。