Genome Dynamics in Aging -- AECM

衰老中的基因组动力学——AECM

• 批准号: 8377449
• 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
• 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/8377449
• 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

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损坏驱动了主要组成部分 衰老过程，通过直接不良影响，但更有可能通过诱导基因组维持反应， 导致衰老，凋亡和/或基因组和表观基因组误差。长期目标 项目2是为了检验以下假设：体细胞DMA改变，包括基因组重排和 表观基因组变化，因果关系促进衰老，通过逐渐失调的基因表达失调导致细胞 功能下降和变性，最终与年龄有关的病理学，包括但不限于 癌症。在续签应用的特定目的1中，我们首先计划显着扩大 到目前为止，已经分析了分子终点。为此，通过项目1合作，我们将衡量 自发的DMA损伤，CpG岛甲基化的变化以及在组织中的转录噪声水平 正常和DMA修复缺陷，过早老化小鼠。在特定目标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性的潜在重要中间体，失调 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（带有项目3，4 和5）。在特定目标3中，我们建议将单个细胞的功能评估与全基因组结合在一起 分析其转录组，表观基因组和基因组。成功追求这些特定目标应该 对基因组维持的作用作为衰老的决定因素提供新的见解，重点是 各种分子和细胞端点之间的关系。