Influence of sleep on the hematopoietic niche and atherosclerosis during aging
睡眠对衰老过程中造血生态位和动脉粥样硬化的影响
基本信息
- 批准号:10618378
- 负责人:
- 金额:$ 42.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAgeAgingAllyApolipoprotein EArterial Fatty StreakAtherosclerosisBehaviorBiologicalBiological AssayBloodBlood VesselsBone MarrowBone Marrow CellsCardiovascular DiseasesCardiovascular systemCell AgingCellsCessation of lifeClinicalCommunicationConfocal MicroscopyCoronary arteryDataDeteriorationDiseaseElderlyEndothelial CellsEpigenetic ProcessEventExposure toFlow CytometryGene Expression ProfileGenetic TranscriptionGrowthGrowth FactorHealthHematopoiesisHematopoieticHematopoietic stem cellsHeterogeneityHumanImageImmuneIncidenceIndividualInflammationInflammatoryInterleukin-6KnowledgeLeukocytesLinkLongevityMacrophage Colony-Stimulating FactorMediatingModelingMolecular AnalysisMonocytosisMusMyelogenousMyocardial InfarctionNeuroimmuneNeuropeptidesOsteitisPathologyPathway interactionsPersonsPhenotypePopulationProcessProductionPublishingReceptor CellReportingResolutionRiskRoleShapesSignal TransductionSleepSleep DeprivationSleep FragmentationsSleep disturbancesStromal CellsStructureSystemTechnologyTestingTimeWorkage relatedagedatherogenesiscalcificationcardiovascular disorder riskcardiovascular healthcell typeclinical translationcytokineepigenetic profilinghypocretininnovationinnovative technologiesintravital microscopymonocytemouse modelneurotransmissionneutrophilpoor sleepprogramsreceptorsenescencesexsingle cell technologysingle-cell RNA sequencingsleep regulationstem cell proliferationsystemic inflammatory responsetranscriptomic profilingvascular inflammation
项目摘要
Sleep is integral to health. Humans should be asleep for a third of their lives, yet we are becoming increasingly
sleep deprived. Poor or insufficient sleep increases the risk for a number of pathologies including
cardiovascular disease (CVD). Sleep, however, varies across an individual's lifetime — sleep time and quality
deteriorate in the elderly. Congruent with sleep deterioration, CVD risk increases with age. These observations
raise a fundamental question; does sleep disruption directly contribute to age-associated CVD? Here we will
explore the biological pathways that connect sleep, aging, and cardiovascular health. Recently, we
demonstrated that sleep fragmentation (SF) in mice augments hematopoietic stem and progenitor cell (HSPC)
proliferation in the bone marrow (BM), leading to monocytosis, neutrophillia, and larger atherosclerotic lesions.
We identified a neuro-immune communication axis whereby the sleep-regulating neuropeptide hypocretin
signals to the hematopoietic niche to regulate pre-neutrophils' production of the myeloid growth factor colony
stimulating factor-1. Here we build on our published findings and preliminary data to explore the hypothesis
that that sleep disruption advances the biological age of the hematopoietic niche and augments vascular
inflammation through epigenetic and senescent programs. We will explore this hypothesis using innovative
mouse models and technologies. Aim 1 interrogates the hematopoietic niche stromal compartment of young (3-
month-old) and aged (18-month-old) mice of both sexes exposed to 16 weeks of SF. We will identify ways in
which sleep shapes niche structure and organization and explore the function of endothelial cell senescence,
transcriptional landscape, and IL-6 signaling in these phenotypes. Aim 2 investigates hypocretin signaling in
the hematopoietic niche in young and aged mice of both sexes. Using innovative mouse models we will profile
hypocretin-producing and responsive cells in the BM and query their transcriptional and epigenetic programs.
Aim 3 moves from the BM to the vessel wall. We will investigate SF-induced atherogenesis in young and aged
Apoe-/- mice of both sexes. We will explore the role of vascular cell senescence and leukocyte dynamics in
atheromata growth and stability. Single cell technology will be used to identify cellular composition and
transcriptional landscapes. This program will apply state-of-the-art technologies to investigate systems-level
communication networks. Our interrogations into the hematopoietic niche, neuropeptide signaling in the BM,
and atherogenesis in the vessel wall will reveal the function of sleep in age-associated CVD and will fill crucial
knowledge gaps with direct clinical translation.
睡眠对健康是不可或缺的。人类一生中应该有三分之一的时间在睡觉,然而我们正变得越来越多
睡眠不足。睡眠质量差或睡眠不足会增加患多种疾病的风险,包括
心血管疾病(CVD)。然而,睡眠在人的一生中是不同的--睡眠时间和质量
在老年人中恶化。与睡眠恶化相一致的是,心血管疾病的风险随着年龄的增加而增加。这些观察结果
提出一个基本问题:睡眠障碍是否直接导致与年龄相关的心血管疾病?在这里,我们将
探索将睡眠、衰老和心血管健康联系起来的生物途径。最近,我们
小鼠睡眠碎裂(SF)可增强造血干/祖细胞(HSPC)
骨髓(BM)增殖,导致单核细胞增多、中性粒细胞增多和较大的动脉粥样硬化病变。
我们确定了一个神经免疫通信轴,通过这个轴,睡眠调节神经肽下丘脑
向造血细胞生态位发出信号,调节中性粒细胞前体产生髓系生长因子集落
刺激因子-1。在这里,我们以已发表的发现和初步数据为基础来探索这一假设
睡眠障碍会使造血区的生物学年龄提前,并增加血管
通过表观遗传和衰老程序引起的炎症。我们将使用Innovative来探索这个假设
鼠标模型和技术。目的1询问青年(3-6岁)的造血龛间质。
雌雄(18个月龄)和老龄(18个月龄)小鼠暴露于16周的SF。我们将找出方法在
睡眠塑造了壁龛的结构和组织,并探索了内皮细胞衰老的功能,
转录图谱,以及IL-6在这些表型中的信号传导。AIM 2研究下丘脑肌醇信号转导途径
幼龄和老龄小鼠的造血生态位。使用创新的鼠标模型,我们将介绍
并对其转录和表观遗传程序提出质疑。
AIM 3从BM移动到血管壁。我们将研究SF诱导的年轻人和老年人的动脉粥样硬化形成
APOE-/-雌雄小鼠。我们将探讨血管细胞衰老和白细胞动力学在
动脉粥样硬化症的生长和稳定。单细胞技术将用于识别细胞成分和
抄写的风景。该计划将应用最先进的技术来研究系统级
通信网络。我们对造血区的询问,骨髓中的神经肽信号,
血管壁的动脉粥样硬化将揭示睡眠在年龄相关性脑血管病中的作用,并将填补至关重要的
与直接临床翻译的知识差距。
项目成果
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Cameron Stuart McAlpine其他文献
Cameron Stuart McAlpine的其他文献
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{{ truncateString('Cameron Stuart McAlpine', 18)}}的其他基金
Influence of sleep on hematopoietic stem cell diversity and clonality in cardiovascular disease
睡眠对心血管疾病中造血干细胞多样性和克隆性的影响
- 批准号:
10408186 - 财政年份:2021
- 资助金额:
$ 42.25万 - 项目类别:
Influence of sleep on hematopoietic stem cell diversity and clonality in cardiovascular disease
睡眠对心血管疾病中造血干细胞多样性和克隆性的影响
- 批准号:
10383858 - 财政年份:2021
- 资助金额:
$ 42.25万 - 项目类别:
Influence of sleep on the hematopoietic niche and atherosclerosis during aging
睡眠对衰老过程中造血生态位和动脉粥样硬化的影响
- 批准号:
10270515 - 财政年份:2021
- 资助金额:
$ 42.25万 - 项目类别:
Influence of sleep on the hematopoietic niche and atherosclerosis during aging
睡眠对衰老过程中造血生态位和动脉粥样硬化的影响
- 批准号:
10440470 - 财政年份:2021
- 资助金额:
$ 42.25万 - 项目类别:
Influence of sleep on hematopoietic stem cell diversity and clonality in cardiovascular disease
睡眠对心血管疾病中造血干细胞多样性和克隆性的影响
- 批准号:
10642963 - 财政年份:2021
- 资助金额:
$ 42.25万 - 项目类别:
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