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: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10440470
• 关键词: Age; Aging; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Behavior; Biological; Biological Assay; Blood; Blood Vessels; Bone Marrow; Bone Marrow Cells; Cardiovascular Diseases; Cardiovascular system; Cell Aging; Cells; Cessation of life; Clinical; Communication; Confocal Microscopy; Coronary artery; Data; Deterioration; Disease; Elderly; Endothelial Cells; Epigenetic Process; Exposure to; Flow Cytometry; Gene Expression Profile; Genetic Transcription; Growth; Growth Factor; Health; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Heterogeneity; Human; Image; Immune; Incidence; Individual; Inflammation; Inflammatory; Interleukin-6; Knowledge; Leukocytes; Link; Longevity; Macrophage Colony-Stimulating Factor; Mediating; Molecular Analysis; Monocytosis; Mus; Myelogenous; Myocardial; Neuroimmune; Neuropeptides; Osteitis; Pathology; Pathway interactions; Persons; Phenotype; Population; Process; Production; Publishing; RNA; Receptor Cell; Reporting; Resolution; Risk; Role; Shapes; Signal Transduction; Sleep; Sleep Deprivation; Sleep Fragmentations; Sleep disturbances; Stromal Cells; Structure; System; Technology; Testing; Time; Work; XCL1 gene; age related; aged; atherogenesis; base; calcification; cardiovascular disorder risk; cardiovascular health; cell type; clinical translation; cytokine; human old age (65+); hypocretin; innovation; innovative technologies; intravital microscopy; monocyte; mouse model; neurotransmission; neutrophil; poor sleep; programs; receptor; senescence; sex; single cell technology; sleep regulation; stem cell proliferation; transcriptomics; vascular inflammation

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.

睡眠是健康不可或缺的。人类应该在三分之一的生活中睡着，但我们变得越来越 睡眠被剥夺。睡眠不足或不足会增加多种病理的风险 心血管疾病（CVD）。但是，睡眠在一个人的一生中各不相同 - 睡眠时间和质量 较早的情况下恶化。与睡眠定义一致，CVD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CVD？我们会在这里 探索连接睡眠，衰老和心血管健康的生物学途径。最近，我们 证明小鼠中的睡眠碎片（SF）增强了造血茎和祖细胞（HSPC） 骨髓（BM）的增殖，导致单核细胞增多症，中性粒细胞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，通过该轴，睡眠调节神经肽降压素 造血生态位的信号调节中性基质的产生髓样生长因子菌落的产生 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讨该假设 睡眠中断促进了造血生态位的生物年龄并增强血管 通过表观遗传和感觉程序进行炎症。我们将使用创新探讨这一假设 鼠标模型和技术。 AIM 1询问年轻的造血小众基质室（3- 一个月大的）和年龄（18个月大的）小鼠，暴露于16周的SF。我们将确定方式 睡眠塑造利基结构和组织，并探索内皮细胞感应的功能， 这些表型中的转录格局和IL-6信号传导。 AIM 2研究中的低载素信号传导 两性的年轻小鼠和老年小鼠的造血生态位。使用创新的鼠标模型，我们将介绍 BM中产生降蛋白素和反应性细胞，并查询其转录和表观遗传学程序。 AIM 3从BM移动到容器墙。我们将研究SF诱导的年轻人和老化的动脉粥样硬化 两性的apoe - / - 小鼠。我们将探讨血管细胞感应和白细胞动力学在 动脉瘤的生长和稳定性。单细胞技术将用于识别细胞组成和 转录景观。该计划将采用最新技术来调查系统级 通信网络。我们对BM中造血生态位的讯问，神经肽信号传导， 血管壁中的动脉粥样硬化将揭示与年龄相关的CVD中睡眠的功能，并将填充至关重要 知识差距直接临床翻译。