Temporal control of mitochondrial mutagenesis

线粒体诱变的时间控制

基本信息

批准号：
10587905
负责人：
Marc Vermulst
金额：
$ 50.72万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587905
关键词：
Address Affect Age Age-Months Aging Alleles Animals Autophagocytosis Biology Brain Cell Aging Cells Childhood Complement DNA biosynthesis DNA polymerase gamma Development Disease Enzymes Event Genetic Genome Health Heart Human Induced Mutation Inherited Intestines Lead Life Liver Longevity Malignant Neoplasms Mammalian Cell Mediating Mitochondria Mitochondrial DNA Modeling Molecular Motion Mus Muscular Atrophy Mutagenesis Mutation Mutation Detection Natural History Nerve Degeneration Pathogenicity Pathology Predisposition Premature aging syndrome Process Production Risk Factors Skeletal Muscle Societies Somatic Cell Testing Time Tissues age related combat detection method driving force experimental study insight mitochondrial DNA mutation mitochondrial genome mouse model novel prevent single cell sequencing therapy development tool

项目摘要

ABSTRACT To fully understand the basic biology that underlies human aging, and accurately time potential treatments that are aimed at preventing age-related pathology, it will be of vital importance to determine when the events that precipitate human aging occur. One of the processes that drives human aging is mitochondrial mutagenesis. Mitochondrial DNA (mtDNA) mutations accumulate as we grow older, which accelerates the natural aging process and contributes to various age-related diseases, including cancer, muscle wasting and neurodegeneration. However, due to the multiplicity of mitochondrial genomes in a cell, de novo mtDNA mutations are initially harmless. MtDNA mutations need to clonally expand to cause disease. Because this expansion process takes time, we hypothesize that the mutations that precipitate age-related pathology arise relatively early in life, and that the pace of mitochondrial aging is set long before pathology becomes apparent. We propose to test this hypothesis with a new mouse model of DNA polymerase gamma (PolgA), the enzyme that replicates the mitochondrial genome. This model expresses an error prone version of DNA polymerase gamma that can be replaced with a WT allele at will. Accordingly, we can turn off mitochondrial mutagenesis at any time during the animal’s lifespan and determine how mutations that occur early in life affect pathology later in life. In addition, we will use various mutation detection techniques, including random mutation capture, single cell sequencing and duplex sequencing to track the fate of these mutations over the lifespan of our mice. These experiments will describe the natural history of every possible mtDNA mutation in various tissues, effectively dissecting the parameters that control the impact of mtDNA mutations on human health. Finally, we propose to rejuvenate somatic cells and aging mice by manipulating mitochondrial fusion and mitophagy, in an attempt to cure them from deleterious mtDNA mutations. If successful, this strategy could provide a potential treatment for multiple pediatric mtDNA diseases, as well as the mitochondrial component of age-related diseases. Accordingly, our experiments have the potential to revolutionize our understanding of the relationship between mitochondrial mutagenesis and aging, and provide powerful new tools to combat both inherited and age-related diseases that are associated with mtDNA mutations.

抽象的充分了解人类衰老的基础生物学，并准确地确定潜在的治疗时间旨在预防与年龄相关的病理学，因此确定这些事件何时发生至关重要促使人类衰老发生的过程之一是线粒体突变。随着年龄的增长，线粒体 DNA (mtDNA) 突变不断积累，从而加速自然衰老过程并导致各种与年龄相关的疾病，包括癌症、肌肉萎缩和然而，由于细胞中线粒体基因组的多样性，线粒体DNA从头开始。 MtDNA 突变需要克隆扩展才能引起疾病。扩张过程需要时间，我们发现导致年龄相关病理的突变出现线粒体衰老的速度早在病理变得明显之前就已确定。我们建议用 DNA 聚合酶 γ (PolgA) 的新小鼠模型来检验这一假设。该模型表达了一种容易出错的 DNA 聚合酶版本。可以随意用 WT 等位基因替换的 gamma，因此，我们可以关闭线粒体诱变。动物一生中的任何时间，并确定生命早期发生的病理学突变如何影响以后另外，在生活中我们会用到各种突变检测技术，包括随机突变捕获、单一突变。细胞测序和双工测序来追踪这些突变在小鼠一生中的命运。这些实验将描述各种组织中每种可能的 mtDNA 突变的自然历史，有效剖析控制 mtDNA 突变对人类健康影响的参数。提出通过操纵线粒体融合和线粒体自噬来恢复体细胞和衰老小鼠的活力，如果成功的话，这一策略可能会提供一种潜在的治疗方法。治疗多种儿童线粒体DNA疾病，以及与年龄相关的线粒体成分因此，我们的实验有可能彻底改变我们对这种关系的理解。线粒体突变和衰老之间的关系，并提供强大的新工具来对抗遗传和衰老与 mtDNA 突变相关的年龄相关疾病。