Influence of sleep on hematopoietic stem cell diversity and clonality in cardiovascular disease

睡眠对心血管疾病中造血干细胞多样性和克隆性的影响

• 批准号: 10408186
• 负责人: Cameron Stuart McAlpine
• 金额: $ 24.9万
• 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: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408186
• 关键词: Advisory Committees; Arterial Fatty Streak; Atherosclerosis; Behavior; Biological; Biology; Bone Marrow; CSF1 gene; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Carotid Arteries; Cell Compartmentation; Cell Lineage; Cells; Cellular biology; Chronic; Clinical; Clonal Expansion; Clonality; Clone Cells; Consequentialism; DNA Modification Methylases; Data; Epigenetic Process; Event; Fostering; General Hospitals; Genetic; Health; Hematopoiesis; Hematopoietic Cell Growth Factors; Hematopoietic stem cells; Histone Deacetylase; Human; Immune; Immunologic Memory; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Investigation; Lesion; Leukocytes; Life; Link; Massachusetts; Mechanics; Mediating; Mentors; Mentorship; Modeling; Monitor; Monocytosis; Mus; Mutation; Myelogenous; Myeloproliferation; Nature; Neurobiology; Neurons; Pathology; Pathway interactions; Persons; Phase; Play; Population Dynamics; Production; Publishing; Reporting; Research; Research Personnel; Risk; Role; Shapes; Sleep; Sleep Deprivation; Sleep Fragmentations; Sleep disturbances; Somatic Mutation; Source; Stimulus; Stress; System; Systems Biology; Testing; Work; adequate sleep; atherogenesis; base; cardiovascular disorder risk; cardiovascular health; career; epigenome; experimental study; innovation; medical schools; monocyte; mouse model; novel; poor sleep; programs; response; single-cell RNA sequencing; sleep quality; sleep regulation; transcriptome

Sleep is integral to health, and humans should be asleep for a third of their life. Poor or insufficient sleep raises the risk of a number of pathologies including cardiovascular disease. However, the underlying biological mechanisms that link sleep to cardiovascular health are unclear. Leukocytes of the myeloid lineage, sourced from bone marrow (BM) hematopoiesis, play a central role in cardiovascular pathology, including atherogenesis. Sleep fragmentation activates hematopoietic stem and progenitor cells (HSPCs) resulting in monocytosis and enlarged murine atherosclerotic lesions. The proposed research aims to extend this observation and explore how sleep shapes the epigenome of hematopoietic stem cells, their clonal expansion, lineage commitment, and innate immune entrainment. Dr. Cameron McAlpine has developed innovative mouse models of sleep fragmentation and disruption. Based on published and unpublished data, this proposal hypothesizes that adequate sleep programs the epigenome of leukocytes, promoting an epigenetic profile that fosters HSPC diversity, shapes HSPC lineage commitment, and influences innate immune entrainment. To achieve these aims, innovative mechanical and genetic mouse models of sleep fragmentation will be used. Using a fluorescent HSPC tagging system, the population dynamics of specific HSPC clones will be monitored during sleep fragmentation. Further, HSPC clones that are dynamically regulated by sleep will have their epigenome and transcriptome profiled. Additionally, using single-cell RNA-seq, the influence of sleep on the entire BM HSPC compartment and its cell clusters will be analyzed. Using models of clonal hematopoiesis targeting somatic mutations in epigenetic modifiers, the impact of sleep on clonal hematopoiesis driven myeloproliferation and atherosclerosis will be determined. Finally, how sleep shapes innate immune entrainment caused by diverse inflammatory stimuli will be questioned. Together, this proposed research will provide a comprehensive view on the importance of sleep and its impact on hematopoiesis, the innate immune system, and cardiovascular disease. Dr. Cameron McAlpine will conduct this work within the Center for Systems Biology at the Massachusetts General Hospital and Harvard Medical School under the primary mentorship of Dr. Filip Swirski and co-mentorship of Dr. David Scadden. Dr. McAlpine has assembled an Advisory Committee comprising of Dr. Peter Libby, clinical cardiologist and expert in clonal hematopoiesis; Dr. Kate Jeffery, an expert in leukocyte epigenetics; and Dr. Thomas Scammell, sleep clinician and expert on the neurobiology of sleep. These mentors will allow him to develop a successful research strategy and career as an independent biomedical investigator.

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。睡眠不足或睡眠不足会提高 包括心血管疾病在内的多种疾病的风险。然而，潜在的生物 将睡眠与心血管健康联系起来的机制尚不清楚。骨髓系白细胞，来源 来自骨髓（BM）造血，在心血管病理学中发挥核心作用，包括 动脉粥样硬化。睡眠碎片化会激活造血干细胞和祖细胞 (HSPC)，从而导致 单核细胞增多症和小鼠动脉粥样硬化病变扩大。拟议的研究旨在扩展这一 观察和探索睡眠如何塑造造血干细胞的表观基因组及其克隆扩张， 谱系承诺和先天免疫诱导。 Cameron McAlpine 博士开发出创新型鼠标 睡眠碎片化和破坏的模型。该提案基于已发表和未发表的数据 假设充足的睡眠对白细胞的表观基因组进行编程，促进表观遗传特征 促进 HSPC 多样性，塑造 HSPC 谱系承诺，并影响先天免疫夹带。到 为了实现这些目标，将使用睡眠碎片化的创新机械和基因小鼠模型。 使用荧光 HSPC 标记系统，将监测特定 HSPC 克隆的群体动态 睡眠碎片化期间。此外，受睡眠动态调节的 HSPC 克隆将具有其 表观基因组和转录组分析。此外，利用单细胞 RNA-seq，研究了睡眠对 将分析整个 BM HSPC 区室及其细胞簇。使用克隆造血模型 针对表观遗传修饰因子的体细胞突变，睡眠对克隆造血驱动的影响 将确定骨髓增殖和动脉粥样硬化。最后，睡眠如何塑造先天免疫 由多种炎症刺激引起的夹带将受到质疑。总之，这项拟议的研究将 全面了解睡眠的重要性及其对造血、先天免疫的影响 系统和心血管疾病。卡梅伦·麦卡尔平博士将在该中心开展这项工作 系统生物学在马萨诸塞州总医院和哈佛医学院下属小学 Filip Swirski 博士的指导和 David Scadden 博士的共同指导。麦卡尔平博士组装了一个 顾问委员会由临床心脏病专家和克隆造血专家 Peter Libby 博士组成；博士。 Kate Jeffery，白细胞表观遗传学专家；托马斯·斯卡梅尔 (Thomas Scammell) 博士，睡眠临床医生和专家 睡眠的神经生物学。这些导师将使他能够制定成功的研究策略和职业生涯 独立的生物医学研究者。