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: 10383858
• 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/10383858
• 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; 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.

睡眠是健康不可或缺的一部分，人类一生中有三分之一的时间应该在睡觉。睡眠不足或睡眠不足会增加 包括心血管疾病在内的多种疾病的风险。然而，潜在的生物学 睡眠与心血管健康之间的联系机制尚不清楚。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 动脉粥样硬化睡眠片段激活造血干细胞和祖细胞（HSPC）， 单核细胞增多症和扩大的鼠动脉粥样硬化病变。这项研究旨在扩大这一点。 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， 谱系定型和先天免疫诱导。卡梅隆麦卡尔平博士开发了一种创新的鼠标 睡眠碎片和中断的模型。根据已公布和未公布的数据， 假设充足的睡眠程序的表观基因组的白细胞，促进表观遗传概况， 促进HSPC多样性，形成HSPC谱系定型，并影响先天免疫夹带。到 为了实现这些目标，将使用创新的睡眠片段化的机械和遗传小鼠模型。 使用荧光HSPC标记系统，将监测特定HSPC克隆的群体动态 在睡眠碎片中。此外，由睡眠动态调节的HSPC克隆将具有其生物学特性。 表观基因组和转录组分析。此外，使用单细胞RNA-seq，睡眠对大脑皮层的影响， 将分析整个BM HSPC隔室及其细胞簇。利用克隆造血模型 靶向表观遗传修饰因子中的体细胞突变，睡眠对克隆造血驱动的影响 将测定骨髓增生和动脉粥样硬化。最后，睡眠如何塑造先天免疫 由不同的炎症刺激引起的夹带将受到质疑。总之，这项拟议的研究将 提供一个全面的观点，睡眠的重要性及其对造血，先天免疫， 系统和心血管疾病。卡梅隆麦卡尔平博士将在中心内开展这项工作， 系统生物学在马萨诸塞州总医院和哈佛医学院下小学 Filip Swirski博士的指导和大卫斯卡登博士的共同指导。麦卡尔平博士已经组织了一个 咨询委员会由临床心脏病专家和克隆造血专家彼得利比博士组成。 白细胞表观遗传学专家凯特·杰弗里和睡眠临床医生、睡眠问题专家托马斯·斯卡梅尔博士。 睡眠的神经生物学这些导师将使他能够制定一个成功的研究战略和职业生涯， 独立的生物医学调查员