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: 7487876
• 负责人: Wenbin Deng
• 金额: $ 46.86万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487876
• 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原因疾病。长期目标是研究特定年龄和特定细胞类型的铅导致其神经毒性的机制。众所周知，铅会导致髓鞘缺陷，尽管其机制尚不清楚。中枢神经系统中的髓鞘是由少突胶质细胞形成的，这使得这些细胞可能成为铅的目标。研究人员先前已经证明，与环境相关的低水平铅可以干扰发育关键窗口的少突胶质细胞的存活、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钙离子通透性谷氨酸受体(GluRs)介导的兴奋毒性的影响。铅是一种二价金属离子，可以模拟钙离子并干扰钙敏感靶点。线粒体在缓冲细胞内钙离子方面起主要作用，也是已知的Pb2+靶标。在此，我们提出了一个假设，即铅神经毒性的一个关键因素是钙离子通透性GluR功能的损害和发育中GluR表达的改变，同时伴随着信号机制的缺陷，涉及发育中的少突胶质细胞线粒体动力学和氧化还原电位的改变，导致神经元-胶质细胞连接和功能异常。本研究的目的1将研究Pb2+是否抑制发育中的少突胶质细胞的钙通透性GluR功能，并确定GluR亚型在Pb2+毒性中的相对作用。目的2将确定铅暴露是否改变GluR亚单位的表达和磷酸化状态，以及调节GluR功能的下游信号分子。目的3确定Pb2+是否导致发育中的少突胶质细胞线粒体功能、成熟、动力学渗出和分裂以及氧化还原状态的改变。总体而言，首席研究员建议将细胞和分子技术结合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造成毒性的新机制。本项目首次研究了发育中的少突胶质细胞GluRs和线粒体在铅中毒中的作用。阐明这些以前未知的Pb2+作用机制将有助于理解与铅暴露相关的风险，并制定针对钙离子通透性GluRs和相关信号通路的干预策略来应对铅中毒。