Single-Cell Analysis of Aging-Associated 4D Nucleome in the Human Hippocampus

人类海马中与衰老相关的 4D 核组的单细胞分析

• 批准号: 10117612
• 负责人: Carl Wayne Cotman
• 金额: $ 60.7万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10117612
• 关键词: Affect; Age; Age-Months; Age-associated memory impairment; Aging; Alzheimer' s Disease; Animals; Architecture; Area; Atlases; Autopsy; Biological Process; Brain; Brain region; Brain-Derived Neurotrophic Factor; Caring; Cells; Chromatin; Chromatin Structure; Cognitive; Complement; DNA; DNA Methylation; Data; Diet; Enhancers; Exercise; Exhibits; Gene Expression; Gene Expression Profile; Genes; Genetic Fingerprintings; Genetic Transcription; Genomics; Goals; Health; Hippocampus (Brain); Human; Impaired cognition; Individual; Intervention; Joints; Longevity; Maps; Measures; Medical; Methods; Molecular; Molecular Profiling; Monitor; Mus; Neurodegenerative Disorders; Nuclear; Pattern; Physical Exercise; Physical activity; Population; Process; Regulation; Regulator Genes; Research; Resolution; Role; Running; Sampling Studies; Smoking; Testing; Uncertainty; United States; Work; age group; age related; aging brain; base; brain cell; cell type; cognitive function; cohort; epigenome; exercise intervention; genomic data; human data; human subject; improved; interest; lifestyle factors; methylome; mind control; mouse model; multiple omics; neural circuit; neurotrophic factor; new therapeutic target; normal aging; novel; novel strategies; programs; promoter; response; sedentary; single cell analysis; tool; transcriptome

Project Summary / Abstract Age-related cognitive decline is an important concern in the United States, as approximately 20% of the US population is expected to be age 65 or older by year 2030. Understanding the molecular mechansims of brain aging to prolong healthy cognitive function is therefore increasingly important as the population ages and older people remain in the work force. Brain cells exhibit profound and heterogeneous changes during aging at molecular and cellular levels. The simple intervention of physical exercise has emerged as a major positive modulator of cognitive function in aging. In response to RFA-RM-20-005, we have formed an interdisciplinary team with expertise in single-cell genomics, neural circuitry, and aging, to investigate age- and physical activity- related changes of 4D nucleome in post-mortem human brain hippocampus cells across the lifespan with single- cell resolution. We hypothesize that cell-type-specific re-organization of nucleome occurs in the human hippocampal brain region during aging and with physical activity. The changes in nucleome in turn control brain epigenome and transcriptome, modulating neural circuit functionality. The “Methyl-HiC”, a new approach for joint profiling of DNA methylation and chromatin contacts in single cells, combined with “Paired-seq”, an ultra- high-throughput method for single-cell joint analysis of open chromatin and transcriptome, will be used to interrogate the chromatin architecture along with DNA methylation, chromatin accessibility and gene expression in the human hippocampus. In Aim 1, we will determine changes in nucleome in major cell types of post-mortem human hippocampus across the life-span with 4 age ranges (20–39, 40–59, 60–79, and 80–99 years old). We will further correlate these changes in nucleome with epigenome and transcriptome in each cell type, to identify vulnerable cell types during aging, and uncover potential gene regulatory programs that could be impacted by aging. In Aim 2, we will determine how physical activity modifies and restores nucleome in specific human hippocampal cell types. We will study two age-matched cognitively–healthy cohorts (70-99 years old) with either high level or low level physical activity, as measured by wearable activity monitors. We will correlate restorative effects on nucleome with epigenome and transcriptome. In Aim 3, we will map how aging and exercise alter nucleome in specific hippocampal cell types with highly controlled quantifiable physical activity in the mouse model, for comparison with human data. These mouse studies allow the exercise variable to be investigated in isolation from effects of other lifestyle factors that can affect hippocampal nucleome, which is not possible with human subjects. The proposed research will help to transform our ability to understand the mechanisms of chromatin organization and function in the context of human brain aging.

项目摘要 /摘要 与年龄有关的认知下降是美国的重要问题，因为大约有20％ 预计到2030年，美国人口将年满65岁。了解分子机制 因此，随着人口年龄的年龄和 老年人仍然是劳动力。脑细胞在衰老期间暴露了深刻和异质变化 分子和细胞水平。体育锻炼的简单干预已成为主要的积极 衰老中认知功能的调节剂。为了响应RFA-RM-20-005，我们形成了一个跨学科 团队具有单细胞基因组学，神经回路和衰老方面的专业知识，以研究年龄和身体活动 - 尸体后人脑海马细胞中4D核心的相关变化，整个生命周期 细胞分辨率。我们假设核的细胞类型特异性重组发生在人 衰老和体育活动期间海马大脑区域。核心依次控制大脑的变化 表观基因组和转录组，调节神经回路功能。 “甲基-HIC”，一种新方法 单个细胞中DNA甲基化和染色质接触的联合分析，与“配对seq”结合，一种超高 用于开放染色质和转录组的单细胞关节分析的高通量方法将用于 询问染色质结构以及DNA甲基化，染色质访问性和基因表达 在AIM 1中，我们将确定主要细胞类型后核心的变化 人类海马遍布4岁范围（20-39、40-59、60-79和80-99岁）。 将进一步将核心中的这些变化与表观基因组和每个细胞类型的转录组相关联，以识别 衰老期间脆弱的细胞类型，并发现可能受到可能受到影响的潜在基因调节程序 老化。在AIM 2中，我们将确定体育活动如何修饰和恢复特定人类的核 海马细胞类型。我们将研究两个年龄匹配的认知 - 健康队列（70-99岁） 通过可穿戴活动监测器测量的高水平或低水平的体育活动。我们将关联恢复 对核心与表观基因组和转录组的影响。在AIM 3中，我们将绘制衰老和运动如何改变 特定海马细胞类型中具有高度控制的量化物理活动的核心 模型，用于与人类数据进行比较。这些小鼠研究允许在 与可能影响海马核心的其他生活方式因素的影响分离出来，这是不可能的 人类主题。拟议的研究将有助于改变我们了解的能力 在人脑衰老的背景下，染色质组织和功能。