Cardiovascular disease (CVD) and the endothelial bone marrow niche: Project 2

心血管疾病 (CVD) 和内皮骨髓生态位：项目 2

• 批准号: 10670733
• 负责人: Matthias Nahrendorf
• 金额: $ 39.09万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670733
• 关键词: Acceleration; Acute myocardial infarction; Apolipoprotein E; Area; Arterial Fatty Streak; Atherosclerosis; Back; Behavior; Biology; Blood; Blood Vessels; Blood flow; Bone Marrow; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cell physiology; Cells; Cessation of life; Circulation; Clinical Research; Clonality; Collaborations; Collagen; Data; Diet; Disease; Disease Progression; Emergency Situation; Endothelial Cells; Endothelium; Expression Profiling; Extravasation; Feedback; Gene Deletion; Gene Expression Profiling; Genes; Harvest; Heart failure; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Image; Individual; Inflammation; Instruction; Knockout Mice; Knowledge; Laboratories; Lasers; Leukocytes; Leukocytosis; Longevity; Marrow; Metabolic syndrome; Monitor; Mus; Myelogenous; Myeloid Cells; Myocardial Infarction; Myocardial Ischemia; Output; Pathology; Pathway interactions; Pattern; Pharmaceutical Preparations; Preparation; Production; Retrieval; Role; Shapes; Signal Transduction; Sorting; Surveys; Sympathectomy; Sympathetic Nervous System; Testing; Time; Tissues; Virus Activation; Wild Type Mouse; Work; angiogenesis; bone imaging; cardiovascular risk factor; cell motility; cohort; constriction; cortical bone; disease phenotype; endothelial dysfunction; experimental study; hypercholesterolemia; image guided; in vivo; innovation; intravital imaging; migration; monocyte; mortality; neutrophil; new technology; new therapeutic target; non-invasive imaging; non-invasive monitor; novel diagnostics; receptor; serial imaging; shear stress; stem cell proliferation; stem cells; transcriptome sequencing; whole genome

In contrast to other vascular territories, fairly little is known about bone marrow vasculature pathologies that occur in individuals with atherosclerosis and acute myocardial infarction (MI). This is an important gap in our knowledge because the bone marrow endothelium, as an integral contributor to the hematopoietic niche, regulates the output and phenotype of disease-promoting leukocytes. These leukocytes, especially monocytes and neutrophils, migrate to atherosclerotic lesions and ischemic myocardium to promote tissue destruction and death. Their life span in inflamed tissue can be less than a day. Hence, myeloid cell production must be considered a central driver of inflammation and disease. The causal relationship of systemic leukocytosis and cardiovascular disease (CVD) progression is well documented, and clinical studies show a strong association of leukocytosis with cardiovascular mortality. Our overarching hypothesis states that cardiovascular risk factors and disease modulate the function of the bone marrow vasculature. Based on bone marrow endothelial cells' role as an essential component of the hematopoietic niche, we hypothesize that acute MI and atherosclerosis modify the crosstalk between endothelial (EC) and hematopoietic stem and progenitor cells (HSPC), giving rise to CVD-accelerating positive feed back loops. We propose to identify the pathways that lead to altered endothelial instruction of HSPC, resulting in accelerated monocyte and neutrophil production and increased release of leukocytes into systemic circulation. Inhibiting these pathways will diminish the higher HSPC proliferation rates and myeloid lineage bias, will moderate the release of newly produced leukocytes from the bone marrow, and will ultimately counteract the increased systemic supply of CVD-promoting leukocytes. In collaboration with our PPG colleagues, we will pursue studies investigating endothelial and vascular biology in the marrow of mice with atherosclerosis or acute myocardial infarction. Selecting upregulated targets from gene expression profiling in mice with CVD, we propose to investigate hematopoiesis and leukocyte levels in EC-specific KO mice. We will then induce MI and atherosclerosis in KO mice, testing the hypothesis that they are protected against leukocyte overproduction and cardiovascular pathology. This work will identify novel therapeutic targets in the bone marrow endothelium. In collaboration with Dr. Lin, we will employ new technology to image bone marrow vascular function in mice with acute MI or atherosclerosis. Specifically, we will image blood flow to estimate shear stress, endothelial dysfunction (vascular ability to constrict and dilate), vascular-associated collagen, angiogenesis and vascular leakage. These parameters will be integrated with serial imaging of HSPC proliferation and leukocyte migration. The experiments will reveal how bone marrow vascular parameters change in CVD, and how these changes contribute to systemic oversupply of disease- promoting leukocytes in atherosclerosis and acute MI.

与其他血管领域相比，对骨髓血管病理学知之甚少， 发生在动脉粥样硬化和急性心肌梗死（MI）患者中。这是一个重要的差距， 知识，因为骨髓内皮细胞，作为造血生态位的一个组成部分， 调节促疾病白细胞的输出和表型。这些白细胞，尤其是单核细胞 和中性粒细胞，迁移到动脉粥样硬化病变和缺血心肌，促进组织破坏， 死亡它们在发炎组织中的寿命可能不到一天。因此，骨髓细胞的产生必须是 被认为是炎症和疾病的主要驱动因素。全身性白细胞增多症与 心血管疾病（CVD）进展有充分的文献记载，临床研究显示， 白细胞增多与心血管死亡率的关系。我们的总体假设指出，心血管危险因素 和疾病调节骨髓脉管系统的功能。基于骨髓内皮细胞的 作为造血生态位的重要组成部分，我们假设急性心肌梗死和动脉粥样硬化 修饰内皮细胞（EC）和造血干细胞和祖细胞（HSPC）之间的串扰， 到CVD加速正反馈回路。我们建议确定导致改变的途径， HSPC的内皮指令，导致单核细胞和中性粒细胞生成加速， 白细胞释放到体循环中。抑制这些途径将降低较高的HSPC 增殖率和髓系偏向，将缓和新产生的白细胞从 骨髓，并将最终抵消增加的CVD促进白细胞的全身供应。在 与我们的PPG同事合作，我们将继续研究内皮和血管生物学， 动脉粥样硬化或急性心肌梗死小鼠的骨髓。选择上调的靶点， 基因表达谱在CVD小鼠中的表达，我们建议研究CVD小鼠的造血和白细胞水平， EC特异性KO小鼠。然后，我们将在KO小鼠中诱导MI和动脉粥样硬化，测试它们是否会导致MI和动脉粥样硬化的假设。 防止白细胞过度产生和心血管病变。这项工作将确定新的 骨髓内皮细胞的治疗靶点。与林博士合作，我们将聘请新的 技术，以成像急性心肌梗死或动脉粥样硬化小鼠骨髓血管功能。我们特别 将对血流成像以估计剪切应力、内皮功能障碍（血管收缩和扩张的能力）， 血管相关胶原、血管生成和血管渗漏。这些参数将与 HSPC增殖和白细胞迁移的连续成像。实验将揭示骨髓 CVD中血管参数的变化，以及这些变化如何导致疾病的系统性供过于求- 促进动脉粥样硬化和急性心肌梗死中的白细胞。