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: 10615701
• 负责人: Bing Ren
• 金额: $ 74.88万
• 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/10615701
• 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; Histone Deacetylase Inhibitor; Human; Impaired cognition; Impairment; Joints; Knock-in; 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; Technology; Testing; Untranslated RNA; Wild Type Mouse; Work; age related; 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; neural circuit; neuropathology; neuroregulation; new therapeutic target; novel therapeutic intervention; optogenetics; programs; response; sedentary; single nucleus RNA-sequencing; targeted biomarker; transcriptome; transcriptome sequencing

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.

项目摘要 /摘要 阿尔茨海默氏病（AD）是进行性痴呆的最常见原因（记忆和认知） 老年人的损失）。目前，超过550万美国人可能患有AD引起的痴呆症。有 无法治愈这种衰弱的状况。我们开发更好的早期诊断工具和 这种神经退行性疾病的新治疗策略。先前使用大脑的基因表达研究 组织和横截面设计鉴定其表达与AD进展相关的基因。基因 表达受到细胞的表观基因组完成DNA甲基化，Hisstone修饰和非 - 编码RNA。我们建议在负责的神经回路中表征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和 AD进展过程中的行为，使用最新的单细胞基因组技术与功能电路结合 映射和行为分析。我们将使用两个概括神经病理学的AD鼠标模型 在人类阿尔茨海默氏症中观察到的功能和功能缺陷。我们的指导假设是广告 神经变性会导致细胞表观基因组发生显着改变，包括适应不良的变化 疾病相关细胞类型中的可访问染色质景观和基因表达程序。反过来 在AD发病机理期间导致特定神经回路功能的缺陷。在AIM 1中，我们将产生一个 全面的表观基因组和基于转录的细胞地图集，用于海马CA1和下丘脑，并识别 表观基因组变化可容纳AD模型小鼠中每种细胞类型的AD进展并匹配年龄 控制小鼠。单核ATAC-SEQ（SNATAC-SEQ），单核RNA-Seq（SnRNA-Seq）和新的 在单细胞中开发的甲基Hi用于DNA甲基化和染色质接触的关节图将是钥匙 方法。拟议的工作将允许创建海马的第一个单细胞多媒体图集 圆圈，将使我们能够跟踪多个特定细胞种群暴露的表观基因组变化 不同的广告样神经退行性阶段。在目标2和3中，我们将研究细胞亚型特异性 AD模型中神经回路活动和相关记忆行为的表观基因组和基因表达基础 中年的老鼠。我们将根据遗传靶向响应 个体发生海马电路操纵和组蛋白脱乙酰基酶抑制。此外，我们将确定 通过体育锻炼对简单行为干预的有益影响对与广告相关的表观基因组特征 在AIM 3中。我们提出的研究将提供一个新的框架来研究分子基础 在AD发病机理过程中影响的神经回路活性。这也将导致识别 新的治疗靶标和分子生物标志物，用于早期检测和更好的AD治疗。