Mechanisms of Environmental and Nuclear and Mitochondrial Mutagenesis

环境、核和线粒体诱变机制

基本信息

批准号：
7985127
负责人：
Jason H Bielas
金额：
$ 59.72万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7985127
关键词：
Affect Age Aging Amyotrophic Lateral Sclerosis Apoptosis Base Pairing Biological Assay Brain Cell division Cell physiology Cells Characteristics Chemicals Cleaved cell Clinical Clonal Expansion Complex DNA DNA Damage DNA lesion Data Dermal Development Diagnosis Disease Dose Environment Environmental Pollutants Environmental Risk Factor Etiology Eukaryotic Cell Event Exposure to Failure Fibroblasts Figs - dietary Frequencies Functional disorder Generations Genes Genome Genotype Goals Health Human Hydrogen Peroxide Incidence Individual Induced Mutation Insecticides Kinetics Knowledge Lesion Life Longevity Malignant Neoplasms Mammalian Cell Measures Methodology Methods Mitochondria Mitochondrial DNA Modeling Molecular Monitor Mus Muscle Mutagenesis Mutagens Mutate Mutation Mutation Detection Normal Cell Nuclear Organelles Oxidative Phosphorylation Oxygen Consumption Parkinson Disease Pathology Peptides Pesticides Phenotype Physiological Play Point Mutation Population Prevention Process Production Reactive Oxygen Species Recombinants Refractory Research Resistance Risk Assessment Risk Factors Role Rotenone Sentinel Somatic Mutation Source T-Lymphocyte Techniques Temporal Lobe Testing Therapeutic Therapeutic Intervention Time Tissues Toxic Environmental Substances Transgenic Mice Work age related base catalase cell type design disease phenotype ebselen environmental agent environmental mutagens exposed human population fitness high throughput screening mitochondrial DNA mutation mitochondrial dysfunction mitochondrial genome mouse model mutant neoplastic cell novel peripheral blood prevent public health relevance repaired research study restriction enzyme sample fixation theories wasting

项目摘要

DESCRIPTION (provided by applicant): Mitochondria are functionally diverse organelles with a central role in many cellular processes, including oxidative phosphorylation and apoptosis. The mitochondrial theory of aging postulates that the lifelong accumulation of mitochondrial DNA (mtDNA) mutations in multiple tissues leads to mitochondrial failure, downstream processes such as apoptosis, and the progressive decline of tissue function (i.e., aging and disease). Moreover, mtDNA mutations are suspected to contribute to the etiology of a number of age-related disorders, including Parkinson's disease, muscle-wasting, and the metastatic potential of cancers. As eukaryotic cells contain many hundreds copies of mtDNA, it stands to reason that a minimum critical number of mutant mtDNAs must be present before tissue dysfunction and clinical signs become apparent. Yet, we do not fully understand the mechanisms underlying the amplification and fixation of these pathogenic mutant populations. There is evidence that these mutations pre-exist at extremely low frequency as random mutations in normal cells and tissues. Our working hypothesis is that the induction and accumulation of random mtDNA mutations fuels pathogenic mutant populations, aging, and age-related disease. Thus, environmental mutagens in particular may play a substantial role in the origin and incidence of aging and disease by damaging mtDNA and increasing the rate at which mitochondrial mutations accumulate. The goal of this proposal is to determine the molecular mechanisms of somatic mtDNA mutagenesis associated with DNA damaging agents and disease, under the direction of the following Aims: (1) test the hypothesis that the frequency of random mtDNA mutations increases with age in humans, (2) determine whether an environmental toxin can increase the rate at which mitochondrial mutations accumulate, (3) evaluate whether random mtDNA mutations precede and drive pathogenic mutant populations in human cells, and (4) reduce mtDNA mutations in human cells. Our Specific Aims are feasible, because of our dramatic advance in our ability to sensitively measure mitochondrial mutations, and important, given the critical role of mitochondria in aging and cancer. A mechanistic understanding of the environmental factors that accelerate mtDNA mutation should aid in the identification of risk factors and methods that prevent and/or slow age-related debilitation and disease. Ultimately, fulfillment of our proposed aims will help unravel the role of mitochondrial mutagenesis in human aging and potentially aid in the amelioration of age-related disease, extending the number of healthy and active years of life. PUBLIC HEALTH RELEVANCE: Mitochondrial mutations are suspected to contribute to the etiology of a number of age-related disorders, including Parkinson's disease, muscle-wasting, and the metastatic potential of cancers. Yet, we do not fully understand the mechanisms underlying the generation of mitochondrial mutations. Ultimately, fulfillment of our proposed aims, to elucidate mitochondrial mutagenesis, will aid in the amelioration of age-related disease, and extend the number of healthy active years of life.

描述（由申请人提供）：线粒体是功能多样的细胞器，在许多细胞过程中发挥核心作用，包括氧化磷酸化和细胞凋亡。衰老的线粒体理论假设，多个组织中线粒体 DNA (mtDNA) 突变的终生积累会导致线粒体衰竭、细胞凋亡等下游过程以及组织功能的逐渐衰退（即衰老和疾病）。此外，mtDNA突变被怀疑是导致许多与年龄相关的疾病的病因，包括帕金森病、肌肉萎缩和癌症的转移潜力。由于真核细胞含有数百个 mtDNA 拷贝，因此在组织功能障碍和临床症状变得明显之前，必须存在最低临界数量的突变 mtDNA，这是理所当然的。然而，我们并不完全了解这些致病突变体群体扩增和固定的机制。有证据表明，这些突变作为正常细胞和组织中的随机突变以极低的频率预先存在。我们的工作假设是，随机 mtDNA 突变的诱导和积累会加剧致病性突变群体、衰老和与年龄相关的疾病。因此，环境诱变剂尤其可能通过破坏线粒体DNA并增加线粒体突变积累的速度，在衰老和疾病的起源和发生中发挥重要作用。本提案的目标是在以下目标的指导下确定与 DNA 损伤剂和疾病相关的体细胞 mtDNA 突变的分子机制：（1）检验随机 mtDNA 突变频率随着人类年龄的增长而增加的假设， (2) 确定环境毒素是否会增加线粒体突变积累的速度，(3) 评估随机 mtDNA 突变是否先于并驱动人类细胞中的致病性突变群体，以及 (4) 减少人类细胞中的 mtDNA 突变。我们的具体目标是可行的，因为我们在灵敏测量线粒体突变的能力方面取得了巨大进步，而且考虑到线粒体在衰老和癌症中的关键作用，这一目标也很重要。对加速 mtDNA 突变的环境因素的机制理解应有助于识别风险因素以及预防和/或减缓与年龄相关的衰弱和疾病的方法。最终，实现我们提出的目标将有助于揭示线粒体突变在人类衰老中的作用，并可能有助于改善与年龄相关的疾病，延长健康和活跃的寿命。公共健康相关性：线粒体突变被怀疑是导致许多与年龄相关的疾病的病因，包括帕金森病、肌肉萎缩和癌症的转移潜力。然而，我们并不完全了解线粒体突变产生的机制。最终，实现我们提出的阐明线粒体突变的目标，将有助于改善与年龄相关的疾病，并延长健康活跃的寿命。