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: 10642963
• 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/10642963
• 关键词: Acceleration; 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; DNA Modification Methylases; Data; Disease; Epigenetic Process; Event; Fostering; General Hospitals; Genetic; Health; Hematopoiesis; Hematopoietic Cell Growth Factors; Hematopoietic stem cells; Histone Deacetylase; Human; Immune; Immune System Diseases; 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; 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.

睡眠是健康不可或缺的一部分，人类一生中应该有三分之一的时间处于睡眠状态。睡眠不佳或睡眠不足会引起 包括心血管疾病在内的许多病理疾病的风险。然而，潜在的生物学 将睡眠与心血管健康联系起来的机制尚不清楚。髓系白细胞，来源 来自骨髓(BM)的造血，在心血管病理中发挥核心作用，包括 动脉粥样硬化的形成。睡眠片断激活造血干细胞和祖细胞(HSPC)导致 单核细胞增多和扩大的小鼠动脉粥样硬化病变。这项拟议的研究旨在扩展这一点 观察和探索睡眠如何塑造造血干细胞的表观基因组，它们的克隆扩增， 血统承诺和先天免疫夹带。卡梅隆·麦克阿尔平博士研发出创新的鼠标 睡眠碎片化和干扰的模型。根据已公布和未公布的数据，这项提案 假设充足的睡眠对白细胞的表观基因组进行编程，促进表观遗传学特征 培养HSPC多样性，塑造HSPC谱系承诺，并影响先天免疫夹带。至 为了实现这些目标，将使用创新的机械和遗传小鼠睡眠碎片模型。 使用荧光HSPC标签系统，将监测特定HSPC克隆的种群动态 在睡眠碎片化期间。此外，受睡眠动态调整的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，睡眠对 将分析整个BM HSPC隔室及其细胞团。利用克隆性造血模型 以表观遗传调节剂中的体细胞突变为靶点，睡眠对克隆性造血驱动的影响 骨髓增殖和动脉粥样硬化将被确定。最后，睡眠如何塑造先天免疫力 由各种炎性刺激引起的夹带将受到质疑。总而言之，这项拟议的研究将 全面介绍睡眠的重要性及其对先天免疫系统--造血的影响 系统，和心血管疾病。卡梅隆·麦克阿尔平博士将在该中心内开展这项工作 马萨诸塞州总医院和哈佛医学院的系统生物学 菲利普·斯威斯基博士的导师和大卫·斯卡登博士的共同导师。麦克阿尔平博士已经组装了一个 由临床心脏病专家和克隆造血专家Peter Libby博士组成的咨询委员会； 凯特·杰弗里，白细胞表观遗传学专家；托马斯·斯卡梅尔博士，睡眠临床医生和 睡眠的神经生物学。这些导师将使他能够制定成功的研究战略和职业生涯 一名独立的生物医学调查员。