权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
9099535
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
项目类别：
财政年份：
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/9099535
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 DNA Sequence Alteration Data Data Analyses Development Elderly Female Functional disorder Genetic Genetic Anticipation 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 whole genome

项目摘要

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.

项目总结（见说明）：随着时间的推移，体细胞（不可遗传的）DNA突变的积累是衰老的标志和潜在机制。目前的理论假设，未修复的随机DNA损伤导致随机DNA突变，这些突变随着时间的推移在单个细胞内积累，并随着这些细胞的复制而传递。这些突变被认为会损害细胞功能，或诱导细胞死亡或衰老，导致器官功能受损和衰老。或者，罕见的突变可能导致细胞转化和癌症。这些理论依赖于随着年龄的增长，组织中积累的突变程度，但我们没有一个准确的测量哺乳动物体细胞突变率。在本研究中，我们将利用高通量测序和严格的统计方法来经验性地测量出生、性成熟和老年时收集的遗传相同小鼠的造血谱系细胞的全基因组体细胞突变率。我们对这些数据的分析将确定体细胞突变与年龄、细胞更新、增殖和功能衰退相关的程度。此外，我们将通过测量治疗动物和对照动物的全基因组体细胞突变率来探索雷帕霉素治疗所赋予的寿命延长的潜在机制。这项多因素的体细胞突变研究将提供迄今为止最准确的哺乳动物体细胞突变率的测量，将开始定义控制随年龄增长的突变积累的参数，并将开始经验性地测试癌症和衰老的常见理论。