Genome Dynamics in Aging -- AECM

衰老中的基因组动力学——AECM

基本信息

批准号：
8234992
负责人：
Jan Vijg
金额：
$ 34.91万
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：
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/8234992
关键词：
Adenoviruses Adverse effects Affect Aftercare Age Aging Aging-Related Process Apoptosis Biological Assay Cardiac Myocytes Cell Aging Cell physiology Cells Cessation of life Chromatin Collaborations CpG Islands DNA Damage DNA Repair DNA Sequence Rearrangement Defect Disease Double Strand Break Repair Down-Regulation Embryo Fibroblasts Frequencies Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Genome Genome Stability Genomic Instability Genomics Genotoxic Stress Grant Heart Hepatocyte Housekeeping Human Hydrogen Peroxide Image Individual Induced Mutation Intervention Ionizing radiation Knockout Mice LacZ Genes Lead Life Link Liver Loss of Heterozygosity Maintenance Malignant Neoplasms Measures Methylation Microscopic Modeling Molecular Mus Mutation Nature Noise Normal tissue morphology Nucleotide Excision Repair Organ Pathology Premature aging syndrome Primary Cell Cultures Reporter Role System Techniques Testing Time Tissues Transcript Variant XRCC5 gene age related base computerized tools epigenomics functional decline genome-wide healthy aging in vivo insight mutant overexpression prevent programs repaired response restriction enzyme senescence single cell analysis

项目摘要

The rationale of this Program Project is that spontaneous DMA damage drives major components of the aging process, through direct adverse effects, but more likely by inducing genome maintenance responses, resulting in senescence, apoptosis and/or genomic and epigenomic errors. The long-term objectives of Project 2 are to test the hypothesis that somatic DMA alterations, including genome rearrangements and epigenomic changes, causally contribute to aging by gradually dysregulating gene expression leading to cell functional decline and degeneration and eventually to age-related pathologies, including but not limited to cancer. In Specific Aim 1 of the renewal application we first plan to significantly broaden the scope of the molecular endpoints thus far analyzed. For that purpose, in collaboration with Project 1, we will measure spontaneous DMA damage, changes in CpG island methylation and transcriptional noise levels in tissues of normal and DMA repair-deficient, prematurely aging mice. In Specific Aim 2 we will further study DMA double-strand breaks, as a potentially important intermediate in generating genome instability, dysregulated gene expression and cellular senescence in mouse and human primary fibroblast cultures (with projects 3, 4 and 5). In Specific Aim 3, we propose to combine functional assessment of a single cell with genome-wide analyses of its transcriptome, epigenome and genome. Successful pursuit of these Specific Aims should provide new insight into the role of genome maintenance as a determinant of aging, with a focus on the relationships among various molecular and cellular end points.

该计划项目的基本原理是自发的 DMA 损坏驱动了衰老过程，通过直接的不利影响，但更有可能通过诱导基因组维持反应，导致衰老、细胞凋亡和/或基因组和表观基因组错误。的长期目标项目 2 旨在检验体细胞 DMA 改变（包括基因组重排和表观基因组变化，通过逐渐失调的基因表达导致细胞衰老，从而导致衰老功能衰退和退化，最终导致与年龄相关的病理，包括但不限于癌症。在续展申请的具体目标 1 中，我们首先计划大幅扩大迄今为止分析的分子终点。为此，我们将与项目 1 合作测量自发 DMA 损伤、CpG 岛甲基化变化和组织中的转录噪音水平正常小鼠和 DMA 修复缺陷、过早衰老的小鼠。在具体目标2中我们将进一步研究DMA 双链断裂，作为产生基因组不稳定、失调的潜在重要中间体小鼠和人类原代成纤维细胞培养物中的基因表达和细胞衰老（项目 3、4 和5)。在具体目标 3 中，我们建议将单细胞的功能评估与全基因组的功能评估结合起来对其转录组、表观基因组和基因组进行分析。成功追求这些具体目标应该提供了关于基因组维护作为衰老决定因素的作用的新见解，重点是各种分子和细胞终点之间的关系。