Tissue-specific somatic mutations during development and aging

发育和衰老过程中的组织特异性体细胞突变

• 批准号: 8728963
• 负责人: Matthew Aaron Hibbs
• 金额: $ 41.81万
• 依托单位: MOUNT DESERT ISLAND BIOLOGICAL LAB
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8728963
• 关键词: Adult; Age; Aging; Aging-Related Process; Apoptosis; Biological Models; Birth; Cell Aging; Cell Death; Cell Lineage; Cell Proliferation; Cell physiology; Cells; Comparative Biology; Complex; Control Animal; Coupled; DNA; DNA Damage; DNA Repair; Data; Data Analyses; Development; Elderly; Female; Functional disorder; Gene Mutation; Genetic; Genetic Anticipation; Genome; Genomic DNA; Genomic Instability; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Hemophilia A; High-Throughput Nucleotide Sequencing; Homeostasis; Human; Immune response; Individual; Instruction; Laboratory mice; Lead; Life; Link; Longevity; Maintenance; Malignant Neoplasms; Mammalian Cell; Mammals; Measurement; Measures; Methods; Mosaicism; Mus; Mutation; Myelogenous; Natural regeneration; Newborn Infant; Organ; Pharmacological Treatment; Phenotype; Replication Error; Reporter; Research; Resolution; S-Phase Fraction; Single Nucleotide Polymorphism; Sirolimus; Somatic Mutation; Statistical Methods; Stem cells; Technology; Testing; Time; Tissues; Variant; aged; anti aging; base; cell type; cohort; experience; functional decline; granulocyte; immune function; improved; innovation; insertion/deletion mutation; mTOR inhibition; macrophage; metaplastic cell transformation; monocyte; neutrophil; postnatal; progenitor; repaired; senescence; theories; tissue repair

PROJECT SUMMARY (See instructions): The accumulation of somatic (non-heritable) DNA mutations over time is a hallmark and potential mechanism of aging. Current theory postulates that un-repaired, stochastic DNA damage results in random DNA mutations that accumulate over time within individual cells, and are passed on as these cells replicate. These mutations are thought to impair cellular function, or to induce cell death or senescence, leading to impaired organ function and aging. Alternately, rare mutations may lead to cellular transformation and cancer. These theories depend upon the extent of mutations accumulated in tissues with age, but we do not have an accurate measurement of the mammalian somatic mutation rate. In the this study, we will utilize high-throughput sequencing and rigorous statistical methods to empirically measure the whole-genome somatic mutation rate in cells of the hematopoietic lineage from genetically identical mice collected at birth, sexual maturity, and old age. Our analyses of these data will determine the extent to which somatic mutations are associated with age, cellular turnover, proliferation, and functional decline. Further, we will explore the potential mechanisms of lifespan extension conferred by treatment with rapamycin by measuring the whole-genome somatic mutation rate in treatment animals and controls. This multi-factorial study of somatic mutations will provide the most accurate measurement of the mammalian somatic mutation rate to date, will begin to define the parameters that control the accumulation of mutations with age, and will begin to empirically test common theories of cancer and aging.

项目摘要（请参阅说明）： 随着时间的流逝，体细胞（无孔）DNA突变的积累是衰老的标志性和潜在的机制。当前的理论假设未修复的随机DNA损伤会导致随机DNA突变，这些突变会随着单个细胞内的时间而积聚，并随着这些细胞复制而传递。这些突变被认为会损害细胞功能，或诱导细胞死亡或衰老，从而导致器官功能和衰老受损。或者，罕见的突变可能导致细胞转化和癌症。这些理论取决于随着年龄的增长而在组织中积累的突变程度，但是我们没有准确测量哺乳动物的体细胞突变率。 在这项研究中，我们将利用高通量测序和严格的统计方法来凭经验测量来自遗传性相同小鼠的造血谱系的整个基因组体细胞突变率，该小鼠在出生时收集，性成熟和年龄。我们对这些数据的分析将决定体细胞突变与年龄，细胞更新，增殖和功能下降有关的程度。此外，我们将通过测量治疗动物和对照组中的全基因组体细胞突变率来探讨用雷帕霉素治疗赋予的寿命延长的潜在机制。这项对体细胞突变的多因素研究将提供迄今为止哺乳动物的体细胞突变率的最准确测量，将开始定义控制突变随着年龄的积累的参数，并将开始在经验上检验癌症和衰老的常见理论。