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:10380678
- 负责人:
- 金额:$ 75.84万
- 依托单位:
- 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:
- 关键词:ATAC-seqAffectAgeAlzheimer disease detectionAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmericanAmyloid Beta A4 Precursor ProteinAmyloid beta-ProteinAnimalsArchitectureAtlasesBackBehaviorBehavior TherapyBehavioralCell NucleusCellsChromatinChromosomesCoupledDNA MethylationDNA mappingDNA methylation profilingDataDefectDementiaDevelopmentDiseaseDisease ProgressionDominant-Negative MutationDrug TargetingElderlyExhibitsGene ExpressionGene Expression ProfileGenesGenetic TranscriptionGenomicsGoalsHDAC3 geneHealthHippocampus (Brain)Histone DeacetylaseHistone Deacetylase InhibitorHumanImpaired cognitionImpairmentJointsKnock-inLeadLearningLocationMapsMeasuresMemoryMemory LossModelingMolecularMusNerve DegenerationNeurodegenerative DisordersNeuronsPathogenesisPathway interactionsPerformancePhysical ExercisePhysiologyPopulationPublishingRegulator GenesResearchRunningShapesSmall Nuclear RNATechnologyTestingUntranslated RNAWild Type MouseWorkage relatedbasebehavior changebrain healthbrain tissuecell typedesigndiagnostic tooldrug candidateearly detection biomarkerseffective therapyepigenomeepigenomicsexercise interventionhistone modificationimaging approachimprovedin vivo calcium imaginginhibitorintervention effectmiddle agemolecular markermouse modelmultiple omicsmutantneural circuitnew therapeutic targetoptogeneticsprogramsrelating to nervous systemresponsesedentarytargeted biomarkertranscriptometranscriptome sequencingtreatment strategy
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Carl Wayne Cotman', 18)}}的其他基金
Investigating the interface of epigenetics and metabolism underlying memory formation in the adult, aging, and AD brain
研究成人、衰老和 AD 大脑中记忆形成的表观遗传学和代谢界面
- 批准号:
10420533 - 财政年份:2022
- 资助金额:
$ 75.84万 - 项目类别:
Comparative Single-Cell Epigenomic Analysis of AD-like Pathogenesis in Unconventional Animal Models
非常规动物模型中 AD 样发病机制的比较单细胞表观基因组分析
- 批准号:
10281740 - 财政年份:2021
- 资助金额:
$ 75.84万 - 项目类别:
Comparative Single-Cell Epigenomic Analysis of AD-like Pathogenesis in Unconventional Animal Models
非常规动物模型中 AD 样发病机制的比较单细胞表观基因组分析
- 批准号:
10478202 - 财政年份:2021
- 资助金额:
$ 75.84万 - 项目类别:
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:
10267725 - 财政年份:2020
- 资助金额:
$ 75.84万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 75.84万 - 项目类别:
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:
10468921 - 财政年份:2020
- 资助金额:
$ 75.84万 - 项目类别:
Exercise-induced epigenetic mechanisms underlying neuronal plasticity and cognition
运动诱发的神经元可塑性和认知的表观遗传机制
- 批准号:
9007752 - 财政年份:2016
- 资助金额:
$ 75.84万 - 项目类别:
A Novel Approach to Study Synaptic Plasticity in Isolated Synaptosomes using Flow Cytometry
使用流式细胞术研究分离突触体突触可塑性的新方法
- 批准号:
8891691 - 财政年份:2015
- 资助金额:
$ 75.84万 - 项目类别:
Gene Expression, Compensation Mechanisms, and Successful Cognitive Aging
基因表达、补偿机制和成功的认知衰老
- 批准号:
8119609 - 财政年份:2009
- 资助金额:
$ 75.84万 - 项目类别:
Gene Expression, Compensation Mechanisms, and Successful Cognitive Aging
基因表达、补偿机制和成功的认知衰老
- 批准号:
7737824 - 财政年份:2009
- 资助金额:
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