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Influence of sleep on the hematopoietic niche and atherosclerosis during aging

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
负责人:
Cameron Stuart McAlpine
金额:
$42.25万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-07-01 至 2026-05-31

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中文摘要
翻译
睡眠对于健康至关重要。人类一生中三分之一的时间都应该在睡眠中度过,但我们正变得越来越 睡眠不足。睡眠不佳或不足会增加多种疾病的风险,包括 心血管疾病(CVD)。然而,睡眠在人的一生中会有所不同——睡眠时间和质量 老年人病情恶化。与睡眠恶化相一致,心血管疾病风险随着年龄的增长而增加。这些观察 提出一个基本问题;睡眠中断是否直接导致与年龄相关的心血管疾病?在这里我们将 探索连接睡眠、衰老和心血管健康的生物途径。最近,我们 证明小鼠的睡眠碎片化 (SF) 会增强造血干细胞和祖细胞 (HSPC) 骨髓 (BM) 增殖,导致单核细胞增多、中性粒细胞增多和更大的动脉粥样硬化病变。 我们确定了一个神经免疫通讯轴,通过该轴调节睡眠的神经肽下丘脑分泌素 向造血生态位发出信号,调节前中性粒细胞产生骨髓生长因子集落 刺激因子-1。在这里,我们根据已发表的研究结果和初步数据来探索这一假设 睡眠中断会提前造血生态位的生物学年龄并增强血管 通过表观遗传和衰老程序产生炎症。我们将使用创新的方法来探索这个假设 鼠标模型和技术。目标 1 询问年轻人(3- 月龄)和老年(18 月龄)雌雄小鼠均暴露于 16 周的 SF。我们将确定方法 睡眠塑造生态位结构和组织并探索内皮细胞衰老的功能, 这些表型中的转录景观和 IL-6 信号传导。目标 2 研究下丘脑分泌素信号传导 年轻和老年小鼠的造血生态位。我们将使用创新的鼠标模型进行分析 BM 中产生下丘脑分泌素和反应的细胞,并查询它们的转录和表观遗传程序。 目标 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 Apoe-/- 两性小鼠。我们将探讨血管细胞衰老和白细胞动力学在 粥样斑块的生长和稳定性。单细胞技术将用于识别细胞组成和 转录景观。该计划将应用最先进的技术来研究系统级 通信网络。我们对造血生态位、骨髓中神经肽信号传导的探究, 血管壁中的动脉粥样硬化形成将揭示睡眠在与年龄相关的心血管疾病中的作用,并将填补关键的空白。 直接临床翻译的知识差距。
英文摘要
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.
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Influence of sleep on hematopoietic stem cell diversity and clonality in cardiovascular disease
Influence of sleep on hematopoietic stem cell diversity and clonality in cardiovascular disease
Influence of sleep on the hematopoietic niche and atherosclerosis during aging
Influence of sleep on the hematopoietic niche and atherosclerosis during aging
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