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.

项目概要/摘要 衰老会导致大脑功能逐渐衰退，是老年痴呆症的最大危险因素。 阿尔茨海默氏症和帕金森氏症等神经退行性疾病的发展。 研究重点关注影响衰老的基因，衰老的非基因调控正在取得进展 最近的几项研究表明基于染色质的表观遗传变化。 这是在衰老过程中发生的，并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有关，从而导致 基因表达和基因组结构的广泛干扰。 作为衰老标志的非基因调控可能开辟“逆转”的新途径 表观遗传变化改变了与年龄相关的疾病的发展轨迹，这是最有趣的方面之一。 衰老的非遗传控制的一个重要方面是“逆转”肌肉、大脑和心脏的衰老 异时性联体共生（老年动物和年轻动物之间的血液循环融合）。 我们小组最近的研究表明，老年小鼠接触年轻的血液可以 抵消和逆转大脑老化在分子、结构、功能和功能方面的现有影响 认知水平，并且小胶质细胞可能在这种恢复活力的效果中发挥作用。 表观遗传学分析 ChIP-seq 和 ATAC-seq 提供对衰老如何发生的全面了解 使用这些互补的表观基因组读数改变小胶质细胞染色质的可及性。 结果，该应用程序将确定 1) 小胶质细胞随着衰老和衰老而发生的表观遗传变化 2）年轻循环因子是否可以逆转小胶质细胞表观基因组的变化。