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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：
7632253
负责人：
Wenbin Deng
金额：
$ 33.96万
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 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7632253
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 Principal Investigator 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

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）