Reversing age-related epigenetic changes and characterizing microglia heterogeneity in obesity and aging
逆转与年龄相关的表观遗传变化并表征肥胖和衰老中的小胶质细胞异质性
基本信息
- 批准号:10562551
- 负责人:
- 金额:$ 3.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-12-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAffinity ChromatographyAgeAgingAnimalsBODIPYBioinformaticsBiological AssayBiologyBlood VolumeBrainCaloric RestrictionCell NucleusCellsCommunicationDNADNA MethylationDNA Modification ProcessDataDevelopmentDiseaseElderlyElementsEnhancersEpigenetic ProcessFatty acid glycerol estersFluorescence-Activated Cell SortingFoundationsFunctional disorderFutureGene ExpressionGenesGenomicsGoalsGrantHeterogeneityHigh Fat DietHippocampus (Brain)ImpairmentInflammationInflammatoryInterventionKnowledgeLaboratoriesLifeLipidsMaintenanceManuscriptsMentorsMessenger RNAMethylationMicrogliaModelingMolecularMorphologyMusNeurodegenerative DisordersNuclearNutritionalObese MiceObesityOperative Surgical ProceduresOralPathologicPatternPhagocytesPhasePhenotypePhysiologicalPlasmaPopulationRNAResearchRibosomesRoleSalineScientistSiteStructureTechnical ExpertiseTechniquesTechnologyTestingThinnessTissuesTrainingTranslatingWritingage groupage relatedaging brainanti agingbasebisulfite sequencingcareercell typechemokinecytokinedesigndiet-induced obesitydietaryepigenomeepigenome editingepigenomicsexperiencefunctional declineimmune activationimprovedinnovationinsightinterestlaboratory experiencemacrophagemolecular phenotypemouse modelneuroinflammationnovel strategiespreventresponsesexsingle-cell RNA sequencingskillssystemic inflammatory responsetranscriptome sequencingtranscriptomicstranslational studytranslatomeuptakewhole genome
项目摘要
Project Summary
Neuroinflammation is a hallmark of brain aging that may contribute to declines in function and neurodegenerative
diseases. As the resident macrophage of the brain, microglial are crucial to brain maintenance but have been
demonstrated to take on pro-inflammatory phenotypes with aging. The proposed research will examine the role
of microglia-specific epigenetic mechanisms in aging and determine the effects of obesity and aging interactions
on microglia phenotypic heterogeneity. We will determine whether aberrant age-related microglia-specific
epigenetic patterns can be reversed by heterochronic plasma approaches. Additionally, we will determine how
microglia subpopulations differ with age and obesity at a single-cell level with special interests in lipid-droplet-
accumulating microglia (LDAM). The goals of the training are to: 1) obtain a strong knowledge and foundation
in animal and nutritional models of anti-aging and obesity 2) gain hands-on experience in technologies and
bioinformatic skills needed for various omics approaches in specific hippocampal cells and at a single-cell level
3) apply these skills to achieve the research aims outlined in this proposal and 5) gain experience and improve
oral and presentation skills, manuscript and grant writing to enable a transition to independence. In Aim 1, we
hypothesize that exposure of old mice to young plasma will reverse age-related microglia-specific DNA
modifications to restore ‘youthful’ epigenomic patterns. This is based on the premise that DNA modifications are
key regulators of the diverse phenotypes required for the fulfillment of microglia functions which are disrupted in
aging. We will determine whether the administration of plasma from young into old mice can reverse age-related
microglial-specific hippocampal epigenetic and transcriptomic changes in Cx3cr1:NuTRAP mice using whole
genome oxidative bisulfite sequencing (WGoxBS) and RNA sequencing, respectively. These studies will identify
specific genomic sites amenable to the rejuvenating interventions and serve as targets for future epigenome
editing studies. In Aim 2, we will determine how the interaction of obesity and aging affect microglia
heterogeneity. We hypothesize that high-fat diet leads to expansion of pathological LDAM resulting in impaired
microglial function, which can be reversed by late-life calorie restriction. We will use single-cell transcriptomic
analysis, bulk transcriptomics and microglia functional assays (phagocytic uptake and cytokine/chemokine
analysis) to determine changes in microglia subpopulations in dietary-induced obese mice with age. In addition,
we will determine whether starting calorie restriction at 12 months in dietary-induced obese mice can mitigate
the effects of obesity on microglia heterogeneity. This will help identify mechanistic insights into microglia
heterogeneity, LDAM and obesity-associated neuroinflammation. In total, the training goals and objectives will
provide the needed skills and expertise to pursue a research career focused on developing anti-aging
interventions.
项目摘要
神经炎症是大脑老化的标志,可能导致功能下降和神经退行性疾病。
疾病作为大脑的常驻巨噬细胞,小胶质细胞对大脑的维护至关重要,但一直受到
随着年龄的增长呈现出促炎表型。拟议中的研究将审查
小胶质细胞特异性表观遗传机制在衰老中的作用,并确定肥胖和衰老相互作用的影响
关于小胶质细胞表型异质性的研究我们将确定是否异常的年龄相关的小胶质细胞特异性
表观遗传模式可以通过异时等离子体方法逆转。此外,我们将确定如何
小胶质细胞亚群在单细胞水平上随年龄和肥胖而不同,对脂滴特别感兴趣,
累积小胶质细胞(LDAM)。培训的目标是:1)获得坚实的知识和基础
在抗衰老和肥胖的动物和营养模型中2)获得技术方面的实践经验,
在特定海马细胞和单细胞水平上进行各种组学方法所需的生物信息学技能
3)应用这些技能来实现本提案中概述的研究目标,5)获得经验并提高
口头和演讲技巧,手稿和赠款写作,使过渡到独立。目标1:
假设老年小鼠暴露于年轻血浆将逆转与年龄相关小胶质细胞特异性DNA
修改以恢复“年轻”的表观基因组模式。这是基于这样的前提,即DNA修饰是
小胶质细胞功能的实现所需的不同表型的关键调节因子,
衰老我们将确定将年轻小鼠的血浆注入老年小鼠是否可以逆转与年龄相关的衰老。
Cx 3cr 1:NuTRAP小鼠中小胶质细胞特异性海马表观遗传和转录组学变化
基因组氧化亚硫酸氢盐测序(WGoxBS)和RNA测序。这些研究将确定
特定的基因组位点适合复壮干预,并作为未来表观基因组的目标
编辑研究。在目标2中,我们将确定肥胖和衰老的相互作用如何影响小胶质细胞
异质性我们假设高脂饮食导致病理性LDAM的扩张,导致受损的
小胶质细胞功能,这可以通过晚年的热量限制来逆转。我们将使用单细胞转录组学
分析、批量转录组学和小胶质细胞功能测定(吞噬细胞摄取和细胞因子/趋化因子)
分析)以确定饮食诱导的肥胖小鼠中小胶质细胞亚群随年龄的变化。此外,本发明还提供了一种方法,
我们将确定饮食诱导的肥胖小鼠在12个月时开始热量限制是否能减轻
肥胖对小胶质细胞异质性的影响。这将有助于确定对小胶质细胞的机械见解
异质性、LDAM和肥胖相关的神经炎症。总的来说,培训目标和目的将
提供所需的技能和专业知识,以追求专注于开发抗衰老的研究事业
干预措施。
项目成果
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