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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目概要/摘要阿尔茨海默病 (AD) 是进行性痴呆（记忆和认知障碍）的最常见原因目前，超过 550 万美国人可能患有 AD 引起的痴呆症。这种使人衰弱的疾病无法治愈，我们开发更好的早期诊断工具和技术变得越来越重要。先前使用大脑进行的基因表达研究是针对这种神经退行性疾病的新治疗策略。组织和横截面设计确定了其表达与 AD 进展相关的基因。表达受到细胞表观基因组的调节，包括 DNA 甲基化、组蛋白修饰和非我们建议表征神经回路中负责的关键细胞类型的表观基因组。我们的目标是确定表观基因组如何塑造海马回路活动和 AD 进展期间的行为，使用最新的单细胞基因组技术与功能电路相结合我们将使用两种 AD 小鼠模型来概括神经病理学。我们在人类阿尔茨海默病中观察到的特征和功能缺陷是AD。神经变性导致细胞表观基因组的显着改变，包括适应不良的变化疾病相关细胞类型中可访问的染色质景观和基因表达程序。在 AD 发病过程中导致特定神经回路功能缺陷。在目标 1 中，我们将生成一个海马 CA1 和下托的基于表观基因组和转录的综合细胞图谱，并识别 AD 模型小鼠和年龄匹配的每种细胞类型中伴随 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) 和新的小鼠。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绘图将是关键拟议的工作将允许创建第一个海马单细胞多组学图谱。电路，并使我们能够跟踪多个特定细胞群表现出的表观基因组变化在目标 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我们将测量中年小鼠对基因靶向的反应的表观基因组和行为变化。个体发生海马回路操作和组蛋白脱乙酰酶抑制。通过体育锻炼进行简单行为干预对 AD 相关表观基因组特征的有益影响目标 3。我们提出的研究将共同提供一个新的框架来研究分子基础 AD 发病过程中受影响的神经回路活动也将导致识别。用于早期检测和更好治疗 AD 的新治疗靶点和分子生物标志物。