Influence of sleep on the hematopoietic niche and atherosclerosis during aging

睡眠是健康不可或缺的。人类一生中有三分之一的时间应该在睡觉，但我们越来越多地 睡眠不足睡眠不好或睡眠不足会增加一些疾病的风险，包括 心血管疾病（CVD）。然而，睡眠在每个人的一生中是不同的-睡眠时间和质量 在老年人中恶化。与睡眠恶化一致，CVD风险随着年龄的增长而增加。这些观察结果 提出了一个基本的问题：睡眠中断是否直接导致年龄相关的CVD？这里我们将 探索连接睡眠、衰老和心血管健康的生物学途径。最近我们 研究表明，小鼠的睡眠片段（SF）增加了造血干细胞和祖细胞（HSPC） 骨髓（BM）中的增殖，导致单核细胞增多症、嗜中性粒细胞增多症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，通过它，睡眠调节神经肽下丘脑泌素 向造血小生境发出信号，以调节前中性粒细胞产生髓样生长因子集落 刺激因子-1。在这里，我们建立在我们发表的研究结果和初步数据，以探讨这一假设 睡眠中断使造血小生境生物学年龄提前， 炎症通过表观遗传和衰老程序。我们将使用创新的方法来探索这一假设。 小鼠模型和技术。目的1询问年轻人（3- 月龄）和老龄（18月龄）小鼠。我们会找出方法， 其睡眠形态、微生态位结构和组织以及探索内皮细胞衰老的功能， 转录景观和IL-6信号在这些表型。目的2研究下丘脑泌素信号通路， 年轻和老年小鼠的造血生态位。使用创新的小鼠模型， 在BM中的下丘脑泌素产生和响应细胞，并查询它们的转录和表观遗传程序。 Aim 3从BM移动到血管壁。我们将研究SF诱导的动脉粥样硬化在年轻人和老年人 两种性别的Apoe-/-小鼠。我们将探讨血管细胞衰老和白细胞动力学在 动脉粥样硬化的生长和稳定性。单细胞技术将用于鉴定细胞组成， 转录景观。该计划将应用最先进的技术来调查系统级 通信网络。我们对造血系统的研究，骨髓中的神经肽信号， 血管壁动脉粥样硬化的发生将揭示睡眠在年龄相关性心血管疾病中的作用， 直接临床翻译的知识差距。

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.