Epigenomic analysis of neural circuits in Alzheimer's disease mouse models

阿尔茨海默病小鼠模型神经回路的表观基因组分析

• 批准号: 10380678
• 负责人: Carl Wayne Cotman
• 金额: $ 75.84万
• 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: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10380678
• 关键词: ATAC-seq; Affect; Age; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid Beta A4 Precursor Protein; Amyloid beta-Protein; Animals; Architecture; Atlases; Back; Behavior; Behavior Therapy; Behavioral; Cell Nucleus; Cells; Chromatin; Chromosomes; Coupled; DNA Methylation; DNA mapping; DNA methylation profiling; Data; Defect; Dementia; Development; Disease; Disease Progression; Dominant-Negative Mutation; Drug Targeting; Elderly; Exhibits; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genomics; Goals; HDAC3 gene; Health; Hippocampus (Brain); Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Impaired cognition; Impairment; Joints; Knock-in; Lead; Learning; Location; Maps; Measures; Memory; Memory Loss; Modeling; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathway interactions; Performance; Physical Exercise; Physiology; Population; Publishing; Regulator Genes; Research; Running; Shapes; Small Nuclear RNA; Technology; Testing; Untranslated RNA; Wild Type Mouse; Work; age related; base; behavior change; brain health; brain tissue; cell type; design; diagnostic tool; drug candidate; early detection biomarkers; effective therapy; epigenome; epigenomics; exercise intervention; histone modification; imaging approach; improved; in vivo calcium imaging; inhibitor; intervention effect; middle age; molecular marker; mouse model; multiple omics; mutant; neural circuit; new therapeutic target; optogenetics; programs; relating to nervous system; response; sedentary; targeted biomarker; transcriptome; transcriptome sequencing; treatment strategy

Project Summary / Abstract Alzheimer’s disease (AD) is the most common cause of progressive dementia (memory and cognitive loss) in older adults. Presently, more than 5.5 million Americans may have dementia caused by AD. There is no cure for this debilitating condition. It is increasingly critical that we develop better early diagnostic tools and new treatment strategies for this neurodegenerative disease. Previous gene expression studies using brain tissue and cross-sectional design identify genes whose expression correlates with AD progression. Gene expression is regulated by the cell’s epigenome comprising of DNA methylation, histone modification and non- coding RNAs. We propose to characterize the epigenome of key cell types in neural circuits responsible for learning and memory. Our goal is to determine how the epigenome shapes hippocampal circuit activity and behaviors during AD progression, using the latest single cell genomic technologies coupled with functional circuit mapping and behavioral analysis. We will use two AD mouse models that recapitulate neuropathological features and functional defects observed in human Alzheimer’s. Our guiding hypothesis is that AD neurodegeneration causes significant alterations in the epigenome of cells, including maladaptive changes in accessible chromatin landscape and gene expression programs in disease relevant cell types. This in turn causes defects in specific neural circuit functionality during AD pathogenesis. In Aim 1, we will generate a comprehensive epigenome- and transcription-based cell atlas for hippocampal CA1 and subiculum, and identify epigenomic changes that accompany AD progression in each cell type in AD model mice and age-matched control mice. Single nucleus ATAC-seq (snATAC-seq), single nucleus RNA-seq (snRNA-seq) and the newly developed Methyl-HI in single cells for joint mapping of DNA methylation and chromatin contacts will be key approaches. The proposed work will allow for creation of the first single cell multi-omics atlas of the hippocampal circuits, and will allow us to track the epigenomic changes exhibited by multiple specific cell populations at different AD-like neurodegeneration stages. In Aims 2 and 3, we will investigate the cell subtype specific epigenomic and gene expression basis of neural circuit activities and related memory behaviors in AD model mice of middle age. We will measure epigenomic and behavioral changes in response to genetically targeted ontogenetic hippocampal circuit manipulation and histone deacetylase inhibition. Further, we will determine the beneficial effects of simple behavioral interventions via physical exercise on AD-related epigenomic signatures in Aim 3. Together, our proposed research will provide a new framework to study the molecular underpinnings of neural circuit activities affected during the course of AD pathogenesis. It will also lead to the identification of new therapeutic targets and molecular biomarkers for early detection and better treatment of AD.

项目总结/摘要 阿尔茨海默病（AD）是进行性痴呆（记忆和认知障碍）的最常见原因。 失（老年人）。目前，超过550万美国人可能患有由AD引起的痴呆症。有 无法治愈这种虚弱的状况我们开发更好的早期诊断工具越来越重要， 这种神经退行性疾病的新治疗策略。以前的基因表达研究使用大脑 组织和横断面设计鉴定其表达与AD进展相关的基因。基因 表达受细胞的表观基因组调节，表观基因组包括DNA甲基化、组蛋白修饰和非甲基化。 编码RNA。我们建议表征神经回路中负责以下功能的关键细胞类型的表观基因组： 学习和记忆。我们的目标是确定表观基因组如何塑造海马电路活动， AD进展期间的行为，使用最新的单细胞基因组技术结合功能电路 映射和行为分析。我们将使用两种AD小鼠模型， 在人类阿尔茨海默氏症中观察到的特征和功能缺陷我们的指导假设是， 神经退行性变引起细胞表观基因组的显著改变，包括细胞内的适应不良变化。 在疾病相关细胞类型中的可访问的染色质景观和基因表达程序。这反过来 导致AD发病过程中特定神经回路功能的缺陷。在目标1中，我们将生成一个 海马CA 1和下托的综合表观基因组和基于转录的细胞图谱，并确定 在AD模型小鼠和年龄匹配的小鼠中，伴随AD进展的表观基因组变化 对照小鼠。单核ATAC-seq（snATAC-seq）、单核RNA-seq（snRNA-seq）和新的 在单细胞中开发甲基HI用于DNA甲基化和染色质接触的联合作图将是关键 接近。这项工作将允许创建第一个海马单细胞多组学图谱 电路，并将使我们能够跟踪多个特定的细胞群表现出的表观基因组变化， 不同的AD样神经变性阶段。在目标2和3中，我们将研究细胞亚型特异性 AD模型神经回路活动及相关记忆行为的表观基因组学和基因表达基础 中年老鼠我们将测量表观基因组和行为变化，以应对基因靶向 个体发育海马回路操纵和组蛋白去乙酰化酶抑制。此外，我们将确定 通过体育锻炼进行的简单行为干预对AD相关表观基因组特征的有益影响 目标3。总之，我们提出的研究将提供一个新的框架来研究分子基础 AD发病过程中神经回路活动受影响的程度。它还将导致确定 新的治疗靶点和分子生物标志物，用于早期检测和更好地治疗AD。