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

基本信息

批准号：
10238042
负责人：
Matthias Nahrendorf
金额：
$ 39.27万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/10238042
关键词：
Acute myocardial infarction Apolipoprotein E Area Arterial Fatty Streak Atherosclerosis Back Behavior Biology Blood Blood Circulation Blood Vessels Blood flow Bone Marrow Cardiovascular Diseases Cardiovascular Pathology Cardiovascular system Cell physiology Cells Cessation of life 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 Lasers Lead 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 Signal Transduction Sum Surveys Sympathectomy Sympathetic Nervous System Testing Time Tissues Virus Activation Wild Type Mouse Work angiogenesis base bone bone imaging cardiovascular risk factor cell motility cohort 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 transcriptome sequencing whole genome

项目摘要

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.

与其他血管区域相比，人们对骨髓血管病理学知之甚少。发生于患有动脉粥样硬化和急性心肌梗死 (MI) 的个体。这是我们的一个重要差距知识，因为骨髓内皮作为造血生态位不可或缺的贡献者，调节促进疾病的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至动脉粥样硬化病变和缺血心肌，促进组织破坏和死亡。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。系统性白细胞增多与系统性白细胞增多的因果关系心血管疾病 (CVD) 的进展已有充分记录，临床研究表明两者之间存在密切关联白细胞增多症与心血管死亡率的关系。我们的总体假设表明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改变内皮细胞 (EC) 与造血干细胞和祖细胞 (HSPC) 之间的串扰，从而产生 CVD 加速正反馈回路。我们建议找出导致改变的途径 HSPC 的内皮指令，导致单核细胞和中性粒细胞生成加速并增加将白细胞释放到体循环中。抑制这些途径将降低较高的 HSPC 增殖率和骨髓谱系偏差，将调节新产生的白细胞从骨髓，最终将抵消促进 CVD 的白细胞的全身供应增加。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患有动脉粥样硬化或急性心肌梗塞的小鼠的骨髓。选择上调目标通过对患有 CVD 的小鼠进行基因表达谱分析，我们建议研究小鼠中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，检验以下假设：免受白细胞过度生成和心血管病理的影响。这项工作将确定小说骨髓内皮细胞的治疗靶点。与林博士合作，我们将聘请新的对患有急性心肌梗塞或动脉粥样硬化的小鼠进行骨髓血管功能成像的技术。具体来说，我们对血流进行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），血管相关胶原蛋白、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。实验将揭示骨髓如何 CVD 中血管参数的变化，以及这些变化如何导致系统性疾病供应过剩促进动脉粥样硬化和急性心肌梗塞中的白细胞。