Oligodendrocytes, Glutamate Receptors, and Lead Neurotoxicity

少突胶质细胞、谷氨酸受体和铅神经毒性

• 批准号: 7337480
• 负责人: Wenbin Deng
• 金额: $ 47.46万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-22 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7337480
• 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; Chromosome Pairing; Cognitive deficits; Condition; 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; Personal Satisfaction; Phosphorylation; Physiological; Play; Predisposition; Principal Investigator; Process; RNA Interference; Regulation; Relative (related person); Research Personnel; Risk; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Slice; Synapses; Synaptic plasticity; Techniques; Thinking; Today; 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

DESCRIPTION (provided by applicant) 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. The investigators have previously demonstrated that environmentally relevant, low-level lead can disturb the survival, proliferation, and differentiation of oligodendrocytes at critical windows of development. The investigators have also demonstrated that developing oligodendrocytes are highly vulnerable to excitotoxicity mediated by Ca2+-permeable glutamate receptors (GluRs). Lead 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 dynamics and redox potential in developing oligodendrocytes, 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, the Principal Investigator proposes 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 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.

描述（由申请人提供） 铅 (Pb2+) 中毒仍然是当今美国最常见的环境疾病。长期目标是研究铅引起神经毒性的年龄特异性和细胞类型特异性机制。已知铅会导致髓磷脂缺陷，但其机制尚不清楚。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。研究人员此前已证明，环境相关的低水平铅会扰乱少突胶质细胞在关键发育窗口期的存活、增殖和分化。研究人员还证明，发育中的少突胶质细胞非常容易受到 Ca2+ 渗透性谷氨酸受体 (GluR) 介导的兴奋性毒性的影响。铅是一种二价金属离子，可以模拟 Ca2+ 并干扰 Ca2+ 敏感目标。线粒体在缓冲细胞内 Ca2+ 方面发挥着重要作用，并且是已知的 Pb2+ 靶标。在这里，我们建议检验以下假设：铅神经毒性的一个关键因素是 Ca2+ 通透性 GluR 功能的损害和发育​​性 GluR 表达的改变，同时信号机制的缺陷涉及发育中少突胶质细胞的线粒体动力学和氧化还原电位的改变，从而导致异常神经元-胶质细胞连接和功能障碍。该提案的目标 1 将检查 Pb2+ 是否会抑制少突胶质细胞发育过程中 Ca2* 渗透性 GluR 功能，并确定 GluR 亚型在 Pb2+ 毒性中的相对作用。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+ 是否会导致发育中少突胶质细胞线粒体功能、成熟、动态渗出和裂变以及氧化还原状态的改变。总体而言，首席研究员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，以提供重叠的方法来揭示铅对发育中的大脑产生毒性的新机制。该项目是第一个研究 GluR 和线粒体在少突胶质细胞发育过程中在铅毒性中的作用的项目。阐明这些以前未被认识的 Pb2+ 作用机制将为了解与铅暴露相关的风险以及制定针对 Ca2+ 渗透性 GluR 的干预策略和处理铅毒性的相关信号通路提供见解。