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

基本信息

批准号：
8463182
负责人：
Joel Newman Meyer
金额：
$ 35.4万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8463182
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

项目摘要

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.

描述（由申请人提供）：本研究的长期目标是阐明持续性线粒体 DNA 损伤在神经退行性变中的作用。现在有强有力的证据表明，大多数帕金森病病例中的神经变性是遗传差异与环境暴露相互作用（基因-环境相互作用）的结果，但所涉及的基因和环境暴露都尚未得到充分了解。我们正在研究一个新的假设，即一些重要的环境毒素通过引起持续的线粒体 DNA 损伤而导致神经退行性变，而处理此类损伤的过程中的遗传缺陷会导致更大的易感性。线粒体 DNA 对许多损伤比核 DNA 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（如多环芳烃和紫外线辐射）引起的线粒体 DNA 损伤。我们将测试这种损害在关键发育时期因暴露而导致神经退行性变的作用。这种效应的特异性将使用秀丽隐杆线虫的创新转基因菌株进行测试。我们还将利用秀丽隐杆线虫中可用的遗传和分子工具来检验以下假设：参与线粒体融合和自噬的特定基因可以防止此类损伤。与公共卫生相关性的描述目前有强有力的证据表明，大多数帕金森病病例中的神经变性是遗传差异和环境暴露（基因-环境相互作用）综合影响的结果，但所涉及的基因和环境暴露都尚未得到充分了解。我们将检验以下假设：重要的常见环境毒素通过在发育的脆弱时期引起持续的线粒体 DNA 损伤而导致神经退行性变，而处理此类损伤的过程中的遗传缺陷会导致更大的易感性。如果是这样的话，对此类化学物质进行更好的监管可以大大降低帕金森病以及其他神经退行性疾病的发病率。