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

基本信息

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
项目类别：
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

项目摘要

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，人类应该在三分之一的生命中入睡。睡眠不足或不足多种病理包括心血管疾病的风险。但是，基础生物学将睡眠与心血管健康联系起来的机制尚不清楚。髓样谱系的白细胞来源从骨髓（BM）造血作用，在心血管病理学中起着核心作用，包括动脉粥样硬化。睡眠碎片激活造血茎和祖细胞（HSPC），导致单核细胞增多和鼠动脉粥样硬化病变。拟议的研究旨在扩展这一点观察并探索睡眠如何塑造造血干细胞的表观组，其克隆膨胀，血统的承诺和先天的免疫夹带。卡梅隆·麦卡尔丁（Cameron McAlpine）博士开发了创新的鼠标睡眠破碎和破坏的模型。根据已发布和未发表的数据，该提案假设有足够的睡眠程序为白细胞的表观基因组，促进了表观遗传学特征促进HSPC多样性，塑造HSPC谱系承诺，并影响先天的免疫夹带。到实现这些目标，将使用创新的机械和遗传小鼠模型的睡眠碎片模型。使用荧光HSPC标记系统，将监视特定HSPC克隆的种群动力学在睡眠破裂期间。此外，通过睡眠动态调节的HSPC克隆将具有他们的表观基因组和转录组介绍了。另外，使用单细胞RNA-seq，睡眠对将分析整个BM HSPC室及其细胞簇。使用克隆造血的模型靶向表观遗传修饰剂中的体细胞突变，睡眠对克隆造血的影响将确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多种炎症刺激引起的夹带将受到质疑。这项拟议的研究将在一起就睡眠的重要性及其对造血的影响（先天免疫）提供了全面的看法系统和心血管疾病。卡梅隆·麦卡尔平（Cameron McAlpine）博士将在中心内部进行这项工作马萨诸塞州综合医院和哈佛医学院的系统生物学菲利普·斯威斯基（Filip Swirski）博士的指导和大卫·斯卡德登（David Scadden）博士的授权。 McAlpine博士组装了咨询委员会由临床心脏病专家彼得·利比（Peter Libby）博士组成，克隆造血专家；博士凯特·杰弗里（Kate Jeffery），白细胞表观遗传学专家；以及托马斯·斯卡梅尔（Thomas Scammell）博士，睡眠临床医生，专家睡眠神经生物学。这些导师将使他能够制定成功的研究策略和职业独立的生物医学研究者。