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Role of Mitochondrial DNA Mutations in Aging in Neuronal Cells

线粒体 DNA 突变在神经细胞衰老中的作用

基本信息

批准号：
7371075
负责人：
Yidong Bai
金额：
$ 28.68万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7371075
关键词：
Age Aging Aging-Related Process Apoptosis Applications Grants Biochemical Biogenesis Brain Brain region Cell Culture System Cell Line Cell model Cell physiology Cells DNA Electron Transport Energy Supply Evaluation Exhibits Functional disorder Gene Mutation Generations Genes Genetic Genetic Transcription Goals Individual Lipids Measures Methods Mitochondria Mitochondrial DNA Molecular Molecular Genetics Monitor Mus Mutation Nerve Endings Neuroblastoma Neurons Nuclear Oxidative Phosphorylation Oxidative Stress Phenotype Physiological Proteins Reactive Oxygen Species Regulation Relative (related person)Reporting Respiration Role Sequence Analysis Signal Transduction Synaptosomes System Techniques Technology Testing Time Tissues Translations age group age related established cell line human tissue improved insight middle age mitochondrial DNA mutation mitochondrial dysfunction mitochondrial genome mutant programs respiratory theories

项目摘要

Our long-term goal is to study the role of mitochondria in aging. The overall goal of this grant application is to test the mitochondria! theror/ of aging and, in particular, to investigate the role of mitochondrial DNA(mtDNA) mutations in mouse brain during aging. As one of the most favored hypotheses, the mitochondrial theory of aging, predicts that somatic mitochondria DNA (mtDNA) mutations accumulate with time, and the compromised mitochondrial function resulting from these mutations is then responsible for various aging phenotypes. However, there has been no comprehensive study of the overall accumulation of mtDNA mutations during aging, and the physiological consequences of aging-related mtDNA mutations are largely unclear. We recently established a method to transfer mtDNA from mouse nerve endings, i.e., synaptosomes to a cell system, and we have improved methods to isolate and characterize mtDNA mutations. Combined with established mitochondrial molecular genetic and biochemical technologies, we can, for the first time, investigate the accumulation of mtDNA mutations in neuronal cells during aging by evaluating individual mtDNA from the synaptosomes.The particular hypothesis to be tested in this proposal is that mutations in the mitochondrial genome accumulate during aging in mouse neuronal cells; these mtDNA mutations in turn compromise mitochondrial function and may result in oxidative damage to various cellular components including mtDNA in neuronal cells. We will perform genetic and functional analyses of aging-related mtDNA mutations by transferring synaptosomal mtDNA to a cell line system. This will reveal low frequncy mtDNA mutations that could not be identified by other methods. By generating neuronal cell models that carry aging-related mtDNA mutations, we will also charaterize the physiological consequences of the mutations, in particular those related to oxidative damage. The successful completion of this project will not only help to test the mitochondrial theory of aging, but could also provide insights into the underlying mechanisms of the aging process.

我们的长期目标是研究线粒体在衰老中的作用。这项拨款申请的总体目标是检测线粒体研究衰老的机制，特别是研究线粒体DNA（mtDNA）的作用老鼠大脑在衰老过程中的突变。作为最受欢迎的假设之一，线粒体理论衰老，预测体细胞线粒体DNA（mtDNA）突变随时间积累，这些突变导致线粒体功能受损，表型然而，还没有关于线粒体DNA的总体积累的全面研究衰老过程中的突变，以及衰老相关的mtDNA突变的生理后果在很大程度上是不清楚我们最近建立了一种从小鼠神经末梢转移mtDNA的方法，即，突触体我们已经改进了分离和表征mtDNA突变的方法。结合建立了线粒体分子遗传和生化技术，我们可以，第一次，研究衰老过程中神经细胞mtDNA突变的积累，在这个提议中要检验的特殊假设是，线粒体基因组在小鼠神经元细胞衰老过程中积累;这些mtDNA突变反过来损害线粒体功能，并可能导致各种细胞成分的氧化损伤包括神经细胞中的线粒体DNA。我们将对与衰老相关的线粒体DNA进行遗传和功能分析，通过将突触体mtDNA转移到细胞系系统中进行突变。这将揭示低频率mtDNA 其他方法无法识别的突变。通过生成携带有与衰老相关的mtDNA突变，我们还将描述突变的生理后果，特别是与氧化损伤有关的那些。这个项目的成功完成不仅有助于测试衰老的线粒体理论，但也可以提供对衰老的潜在机制的见解，过程