Mechanisms and functional impact of genome instability in aging

衰老过程中基因组不稳定性的机制和功能影响

基本信息

批准号：
10431796
负责人：
JAN VIJG
金额：
$ 40.63万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-04-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10431796
关键词：
Address Affect Age Aging Aneuploidy Animals B-Cell Activation B-Lymphocytes Biological Assay Biological Markers Cell Aging Cell Differentiation process Cell physiology Cells Cellular Assay Centenarian Chromosome Segregation Chromosome abnormality Chronology Clonal Evolution Clustered Regularly Interspaced Short Palindromic Repeats Code Copy Number Polymorphism DNA DNA Damage DNA Repair DNA Sequence Alteration DNA biosynthesis Degenerative Disorder Disease Engineering FOXO3A gene Fibroblasts Frequencies Genetic Genome Genomic Instability Genotype Hepatocyte Human In Vitro Induced Mutation Liver Longevity Longitudinal cohort Longitudinal cohort study Lymphocyte Maintenance Malignant Neoplasms Measures Methods Modeling Mus Mutation Pattern Point Mutation Process RNA Reporter Retrotransposition Roentgen Rays Role Somatic Cell Somatic Mutation System Technology Testing Time Tissues Transgenic Mice Untranslated RNA Variant base cell type comorbidity computational network modeling disorder risk fitness gene network genome sequencing genome-wide genome-wide analysis healthy aging human old age (65+)in vivo indexing insight loss of function mouse model novel overexpression promoter repaired senescence single cell sequencing stem telomere transcriptome transcriptome sequencing whole genome

项目摘要

ABSTRACT – Project 2 Genome instability refers to the tendency of the genome to undergo a range of irreversible DNA mutations, from base substitutions to chromosomal alterations. In contrast to DNA damage, DNA mutations cannot be repaired and have been implicated as a cause of aging since the 1950s. However, it has proved very difficult to test whether genome instability underlies, at least in part, the gradual loss of function and increased degenerative disease risk associated with aging. This is because somatic mutations are difficult to detect in normal, non-clonal tissues. New, single-cell whole genome sequencing technology, developed by Project 2 as part of this PPG, makes it possible to study different types of somatic mutations and their distribution across the genome directly in human or mouse tissues. In Aim 1, Project 2 will first test the effects on genome instability of rare genome maintenance genotypes associated by Project 4 with accelerated or delayed aging in humans. Then, with Project 1, we will test the possible functional impact of genome instability on human aging (Aim 2). Finally, with Project 3 we will test the possible role of genome instability in cellular senescence (Aim 3). The results of Project 2 should, for the first time, provide insight into genome instability in human primary cells as a function of age and its possible causal contribution to aging.

摘要 - 项目2 基因组不稳定性是指基因组经历一系列不可逆的DNA突变的趋势，从基础取代到染色体改变。与DNA损伤相反，DNA突变不能是自1950年代以来，修复并隐含是衰老的原因。但是，事实证明很难测试基因组不稳定性是否构成至少部分的功能丧失和增加退化性疾病风险与衰老有关。这是因为很难在正常的，非悬式组织。由项目2开发的新型单细胞整体基因组测序技术该PPG的一部分，可以研究不同类型的体细胞突变及其分布直接在人或小鼠组织中的基因组。在AIM 1中，项目2将首先测试对基因组的影响项目4与加速或延迟衰老相关的稀有基因组维持基因型的不稳定性人类。然后，使用项目1，我们将测试基因组不稳定性对人衰老的功能影响（目标2）。最后，通过项目3，我们将测试基因组不稳定性在细胞感应中的可能作用（AIM 3）。项目2的结果首次应洞悉人类原代细胞中基因组不稳定性随着年龄的函数及其对衰老的可能因果贡献。