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.

睡眠对于健康至关重要。人类一生中有三分之一的时间都在睡眠中，但我们的睡眠时间正变得越来越长。 睡眠不足或睡眠不足会增加多种疾病的风险，包括 然而，心血管疾病（CVD）在人的一生中会有所不同——睡眠时间和质量。 与老年人的睡眠质量恶化相一致，心血管疾病的风险随着年龄的增长而增加。 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？ 最近，我们探索了连接睡眠、衰老和心血管健康的生物途径。 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，调节前中性粒细胞生成骨髓生长因子集落 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 我们将通过创新的方法探索这一假设。 目标 1 探究年轻小鼠 (3-) 的造血微环境基质区室。 月龄）和老年（18 月龄）雌雄小鼠均暴露于 SF 16 周，我们将找出方法。 睡眠塑造生态位结构和组织并探索内皮细胞衰老的功能， 转录景观和这些表型中的 IL-6 信号传导 目标 2 研究下丘脑分泌素信号传导。 我们将使用创新的小鼠模型来分析年轻和老年小鼠的造血生态位。 BM 中的下丘脑分泌素产生细胞和反应细胞，并查询它们的转录和表观遗传程序。 目标 3 从 BM 转向血管壁，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。 我们将探讨血管细胞衰老和白细胞动力学在两种性别中的作用。 单细胞技术将用于识别细胞组成和稳定性。 该计划将应用最先进的技术来研究系统级。 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。