Reversing epigenetic changes in aged microglia via young circulatory factors

通过年轻循环因子逆转衰老小胶质细胞的表观遗传变化

• 批准号: 9812746
• 负责人: David Gate
• 金额: $ 0.66万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-23 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9812746
• 关键词: Age; Aging; Alzheimer' s Disease; Animals; Antibodies; Architecture; Attention; Biological Assay; Blood; Blood Circulation; Brain; Cardiovascular system; Cells; ChIP-seq; Chromatin; Chromatin Remodeling Factor; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive; Communication; Computer Analysis; DNA; DNA-Binding Proteins; Data; Development; Disease; Environment; Environmental Risk Factor; Epigenetic Process; Exhibits; Exposure to; Gene Expression; Gene Expression Alteration; Genes; Genetic Transcription; Genome; Genomics; Heart; Heritability; Histones; Human; Immune; In Vitro; Individual; Invaded; Knowledge; Libraries; Location; Longevity; Lysine; Mediator of activation protein; Methods; Microglia; Molecular; Molecular Structure; Mus; Muscle; NF-kappa B; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Nucleosomes; Parabiosis; Parkinson Disease; Pathway interactions; Pattern; Pattern recognition receptor; Phenotype; Play; Proteins; Regulation; Rejuvenation; Risk Factors; Role; Structure; Tissues; Toll-like receptors; Transposase; Twin Studies; Variant; Work; age related; aged; aging brain; base; cell type; epigenome; epigenomics; experimental study; genome-wide; healthspan; histone methylation; histone modification; juvenile animal; neurotoxic; new therapeutic target; non-genetic; p65; pathogen; sensor; therapeutic target

Project Summary/Abstract Aging leads to a progressive decline in brain function and is the greatest risk factor for the development of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. While myriad studies have focused on the genes that impact aging, the nongenetic regulation of aging is gaining increasing attention. Several recent studies have demonstrated chromatin-based epigenetic changes that occur during aging, and have highlighted the role of chromatin modifiers in regulating lifespan. Specifically, aging is associated with profound changes to the epigenome, resulting in alterations of gene expression and broad disturbances in genome architecture. Delineating the environmental, nongenetic regulation that occurs as a hallmark of aging could open new avenues that ‘reverse’ epigenetic changes to alter the trajectory of age-related diseases. One of the most intriguing aspects of the nongenetic control of aging is the ‘reversal’ of aging in muscle, brain, and heart by heterochronic parabiosis (fusion of the blood circulation between an old animal and a young animal). Recent studies from our group demonstrate that exposure of an aged mouse to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive levels and that microglia may play a role in this rejuvenation effect. This study will utilize the epigenetic assays ChIP-seq and ATAC-seq to provide a comprehensive understanding of how aging alters microglial chromatin accessibility genome-wide. Using these complimentary epigenomic read- outs, this application will determine 1) the epigenetic changes that occur in microglia with aging and 2) whether changes to the microglial epigenome can be reversed by young circulatory factors.

项目总结/摘要 衰老导致大脑功能的逐渐衰退，是大脑功能衰退的最大危险因素。 神经退行性疾病的发展，如阿尔茨海默氏症和帕金森氏症。虽然无数 研究主要集中在影响衰老的基因上，衰老的非遗传调节正在获得 越来越多的关注。最近的几项研究表明，基于染色质的表观遗传变化 这一发现强调了染色质修饰剂在调节寿命中的作用。 具体来说，衰老与表观基因组的深刻变化相关，导致表观基因组的改变。 基因表达和基因组结构的广泛干扰。描绘环境， 作为衰老标志的非遗传调节可能会开辟“逆转”衰老的新途径。 表观遗传变化来改变与年龄有关的疾病的轨迹。最有趣的方面之一 衰老的非遗传控制是通过以下方式“逆转”肌肉、大脑和心脏的衰老 异时共生（年老动物和年轻动物之间血液循环的融合）。 我们小组最近的研究表明，将老年小鼠暴露于年轻血液中， 从分子、结构、功能和组织层面抵消和逆转大脑老化的既存影响 认知水平，小胶质细胞可能在这种返老还童效应中发挥作用。本研究将利用 表观遗传学检测ChIP-seq和ATAC-seq，以全面了解衰老如何 改变了全基因组的小胶质细胞染色质可及性。使用这些互补的表观基因组读数- 此外，该应用程序将确定1）随着年龄的增长发生在小胶质细胞中的表观遗传变化， 2)小胶质细胞表观基因组的变化是否可以被年轻的循环因子逆转。