The Role of Mitochondrial DNA Damage in Neurodegeneration

线粒体 DNA 损伤在神经退行性变中的作用

• 批准号: 8182618
• 负责人: Joel Newman Meyer
• 金额: $ 37.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-16 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8182618
• 关键词: Aromatic Polycyclic Hydrocarbons; Autophagocytosis; Biological Assay; Caenorhabditis elegans; Chemicals; DNA; DNA Damage; DNA Repair; Data; Development; Disease; Environmental Exposure; Environmental Pollutants; Environmental Pollution; Environmental Risk Factor; Excision; Exposure to; Generations; Genes; Genetic; Genetic Determinism; Goals; Incidence; Lead; Mediating; Mitochondria; Mitochondrial DNA; Molecular Genetics; Mutagens; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Oxidative Phosphorylation; Oxidative Stress; Paraquat; Parkinson Disease; Pathway interactions; Play; Predisposition; Process; Public Health; Regulation; Research; Role; Rotenone; Specificity; Testing; Time; Toxic Environmental Substances; Transgenic Organisms; Ultraviolet Rays; disorder control; early life exposure; environmental agent; gene environment interaction; in vivo; innovation; mitochondrial autophagy; mitochondrial dysfunction; neuron loss; novel; oxidative DNA damage; repaired; tool

DESCRIPTION (provided by applicant): The long-range goal of this research is to elucidate the role of persistent mitochondrial DNA damage in neurodegeneration. There is now strong evidence that neurodegeneration in the majority of Parkinson's Disease cases is the result of the interplay of genetic differences with environmental exposures (gene-environment interactions), but neither the genes nor the environmental exposures involved are well understood. We are investigating the novel hypothesis that some important environmental toxins contribute to neurodegeneration by causing persistent mitochondrial DNA damage, and that genetic deficiencies in the processes that handle such damage lead to greater susceptibility. Mitochondrial DNA is more sensitive than nuclear DNA to many insults, and there is no apparent repair pathway for handling mitochondrial DNA damage caused by important environmental genotoxins such as polycyclic aromatic hydrocarbons and ultraviolet radiation. We will test the role of such damage in causing neurodegeneration as a result of exposure during key developmental time periods. The specificity of this effect will be tested using innovative new transgenic strains of Caenorhabditis elegans. We will also test the hypothesis that specific genes involved in mitochondrial fusion and autophagy protect against such damage, taking advantage of the genetic and molecular tools available in Caenorhabditis elegans. Description of relevance to public health There is now strong evidence that neurodegeneration in most Parkinson's Disease cases is the result of the combined effects of genetic differences and environmental exposures (gene- environment interactions), but neither the genes nor the environmental exposures involved are well understood. We will test the hypothesis that important, common environmental toxins contribute to neurodegeneration act by causing persistent mitochondrial DNA damage during vulnerable periods of development, and that genetic deficiencies in the processes that handle such damage lead to greater susceptibility. If this is the case, better regulation of such chemicals could greatly reduce the incidence of Parkinson's Disease, and possibly other neurodegenerative diseases as well. PUBLIC HEALTH RELEVANCE: There is now strong evidence that neurodegeneration in most Parkinson's Disease cases is the result of the combined effects of genetic differences and environmental exposures (gene- environment interactions), but neither the genes nor the environmental exposures involved are well understood. We will test the hypothesis that important, common environmental toxins contribute to neurodegeneration act by causing persistent mitochondrial DNA damage during vulnerable periods of development, and that genetic deficiencies in the processes that handle such damage lead to greater susceptibility. If this is the case, better regulation of such chemicals could greatly reduce the incidence of Parkinson's Disease, and possibly other neurodegenerative diseases as well.

描述（由申请人提供）：这项研究的远程目标是阐明持续性线粒体DNA损伤在神经变性中的作用。现在有强有力的证据表明，大多数帕金森氏病病例中的神经退行性病例是遗传差异与环境暴露（基因环境相互作用）的相互作用的结果，但涉及的基因或环境暴露均未得到充分了解。我们正在研究以下新的假设，即某些重要的环境毒素通过引起持续的线粒体DNA损伤来促进神经退行性，并且在处理这种损伤的过程中遗传缺陷会导致更大的敏感性。线粒体DNA比核DNA对许多损伤更敏感，并且没有明显的修复途径来处理由重要的环境基因毒素（如多环芳族烃和紫外线辐射）引起的线粒体DNA损伤。我们将测试由于关键发育期间暴露而导致神经退行性变化的作用。这种效果的特异性将使用秀丽隐杆线虫的创新新转基因菌株进行测试。我们还将检验以下假设：利用秀丽隐杆线虫可用的遗传和分子工具，参与线粒体融合和自噬保护这种损害的特定基因。与公共卫生相关的描述现在有强有力的证据表明，在大多数帕金森氏病病例中，神经退行性病例是遗传差异和环境暴露（基因环境相互作用）的综合作用的结果，但是所涉及的基因或环境暴露均未得到充分了解。我们将检验以下假设：重要的，常见的环境毒素在脆弱的发育时期造成持续的线粒体DNA损伤，以及在处理这种损害的过程中遗传缺陷会导致更大的易感性。如果是这种情况，对此类化学物质的更好调节可能会大大减少帕金森氏病的发病率，也可能会减少其他神经退行性疾病。 公共卫生相关性：现在有强有力的证据表明，在大多数帕金森氏病病例中，神经退行性病例是遗传差异和环境暴露（基因环境相互作用）的综合作用的结果，但是所涉及的基因或环境暴露均未得到充分了解。我们将检验以下假设：重要的，常见的环境毒素在脆弱的发育时期造成持续的线粒体DNA损伤，以及在处理这种损害的过程中遗传缺陷会导致更大的易感性。如果是这种情况，对此类化学物质的更好调节可能会大大减少帕金森氏病的发病率，也可能会减少其他神经退行性疾病。