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: 10618378
• 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/10618378
• 关键词: ATAC-seq; Age; Aging; Ally; 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; Event; 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; Modeling; Molecular Analysis; Monocytosis; Mus; Myelogenous; Myocardial Infarction; Neuroimmune; Neuropeptides; Osteitis; Pathology; Pathway interactions; Persons; Phenotype; Population; Process; Production; Publishing; Receptor Cell; Reporting; Resolution; Risk; Role; Shapes; Signal Transduction; Sleep; Sleep Deprivation; Sleep Fragmentations; Sleep disturbances; Stromal Cells; Structure; System; Technology; Testing; Time; Work; age related; aged; atherogenesis; calcification; cardiovascular disorder risk; cardiovascular health; cell type; clinical translation; cytokine; epigenetic profiling; hypocretin; innovation; innovative technologies; intravital microscopy; monocyte; mouse model; neurotransmission; neutrophil; poor sleep; programs; receptor; senescence; sex; single cell technology; single-cell RNA sequencing; sleep regulation; stem cell proliferation; systemic inflammatory response; transcriptomic profiling; 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.

睡眠对健康是不可或缺的。人类一生中应该有三分之一的时间是在睡眠中度过的，然而我们却变得越来越