Molecular and Physiological Responses to Persistent Mitochondrial DNA Damage

对持续性线粒体 DNA 损伤的分子和生理反应

基本信息

批准号：
7828197
负责人：
Joel Newman Meyer
金额：
$ 19.5万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7828197
关键词：
Adult Animal Model Aromatic Polycyclic Hydrocarbons Autophagocytosis Autosomal Dominant Optic Atrophy Biological Caenorhabditis elegans Charcot-Marie-Tooth Disease Chemicals Clear Cell DNA DNA Adducts DNA Damage DNA Repair Pathway DNA copy number DNA lesion Data Dependence Development Developmental Delay Disorders Disease Dose Elderly Event Excision Exposure to Functional disorder Genes Genetic Genetic Transcription Genome Goals Grant Health Human Knock-out Lead Life Malignant Neoplasms Measures Mediating Mitochondria Mitochondrial DNA Mitochondrial Diseases Mitotic Modeling Molecular Mutagens Mutation Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Nuclear Nucleotide Excision Repair Outcome Oxygen Consumption Pathway interactions Phenotype Physiological Population Process Production Proteins RNA Interference Radiation Reactive Oxygen Species Research Staging Study models Technology Testing Time Toxic effect Transgenic Organisms Translations Ultraviolet C Radiation Work adduct dopaminergic neuron early life exposure gene function insight knock-down mitochondrial dysfunction mitochondrial genome mutant novel public health relevance repaired response tool toxicant

项目摘要

DESCRIPTION (provided by applicant): The goal of this research is to elucidate the physiological and molecular responses that occur in response to persistent mitochondrial DNA (mtDNA) damage. Mitochondrial DNA integrity is critical for human health, and mtDNA is more sensitive than nuclear DNA (nDNA) to many chemicals that cause DNA damage. However, the consequences of unrepaired mtDNA damage are poorly understood. Furthermore, since mitochondria apparently lack the repair proteins that would handle such damage in the nuclear genome, the fate of mtDNA damaged by environmental genotoxins, such as ultraviolet C radiation (UVC) and polycyclic aromatic hydrocarbons, is also poorly understood. This project will elucidate the fate of mtDNA damage and test the hypothesis that severely damaged mtDNA is cleared from the powerful model organism Caenorhabditis elegans by fission/fusion and autophagy. We have recently observed that early life stage exposure to bulky (UVC-induced) mtDNA lesions causes developmental delay in C elegans, and also leads to neurodegeneration in adults, suggesting that C elegans will be an appropriate as well as powerful model for the mammalian response to such damage. To better understand the temporal progression and mechanistic details of the toxicological response to such damage, we will also examine the molecular and physiological consequences of early-life exposure to persistent mtDNA damage. This work will be accomplished via the following three Specific Aims: Specific Aim 1. Test the hypothesis that exposure during early development to persistent mtDNA damage leads to mitochondrial dysfunction. We will measure mitochondrial function and dysfunction in C elegans carrying persistent mtDNA damage. Specific Aim 2. Test the hypothesis that exposure during early development to persistent mtDNA damage leads to neurodegeneration in adults. Many neurodegenerative diseases have environmental components, and exposure to mitochondrial toxicants is associated with neurodegenerative disease. We will test whether early-life exposure of C elegans to persistent mtDNA damage leads to neurodegeneration in later life. Specific Aim 3. Test the hypothesis that bulky DNA adducts present in mitochondrial genomes are removed via mitochondrial fusion, fission and autophagy. This hypothesis will be tested via the use of gene knock-out and gene knock-down technologies. PUBLIC HEALTH RELEVANCE: Mitochondrial DNA integrity is critical for human health, but the mechanisms by which persistent mtDNA damage causes physiological outcomes, and the pathways by which such damage is handled, are unclear. This research will yield information critical to our understanding of the genetic and environmental contributors to diseases caused by mitochondrial dysfunction.

描述（由申请人提供）：本研究的目标是阐明针对持续性线粒体 DNA (mtDNA) 损伤而发生的生理和分子反应。线粒体 DNA 的完整性对于人类健康至关重要，而且 mtDNA 对许多导致 DNA 损伤的化学物质比核 DNA (nDNA) 更敏感。然而，人们对未修复的线粒体DNA损伤的后果知之甚少。此外，由于线粒体显然缺乏处理核基因组中此类损伤的修复蛋白，因此我们对环境基因毒素（例如紫外线 C 辐射 (UVC) 和多环芳烃）损伤线粒体 DNA 的命运也知之甚少。该项目将阐明线粒体DNA损伤的命运，并测试严重受损的线粒体DNA通过裂变/融合和自噬从强大的模式生物秀丽隐杆线虫中清除的假设。我们最近观察到，生命早期暴露于大量（UVC 诱导的）mtDNA 损伤会导致线虫发育迟缓，并且还会导致成年神经变性，这表明线虫将是哺乳动物反应的合适且强大的模型造成这样的损害。为了更好地了解对此类损伤的毒理学反应的时间进展和机制细节，我们还将检查生命早期暴露于持续性线粒体 DNA 损伤的分子和生理后果。这项工作将通过以下三个具体目标来完成：具体目标 1. 检验以下假设：早期发育过程中暴露于持续性 mtDNA 损伤会导致线粒体功能障碍。我们将测量携带持续线粒体 DNA 损伤的线虫的线粒体功能和功能障碍。具体目标 2. 检验以下假设：早期发育过程中暴露于持续性 mtDNA 损伤会导致成人神经变性。许多神经退行性疾病都有环境因素，接触线粒体毒物与神经退行性疾病有关。我们将测试线虫在生命早期暴露于持续性线粒体 DNA 损伤是否会导致晚年的神经退行性变。具体目标 3. 检验线粒体基因组中存在的大量 DNA 加合物通过线粒体融合、裂变和自噬被去除的假设。这一假设将通过使用基因敲除和基因敲除技术进行检验。公共卫生相关性：线粒体 DNA 完整性对人类健康至关重要，但持续性 mtDNA 损伤导致生理结果的机制以及处理此类损伤的途径尚不清楚。这项研究将为我们了解线粒体功能障碍引起的疾病的遗传和环境因素提供至关重要的信息。