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

与其他血管领域相比，人们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。这是我们的一个重要差距 知识是因为骨髓内皮细胞作为造血利基不可或缺的贡献者， 调节致病白细胞的产量和表型。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，促进组织破坏和 死亡。它们在发炎组织中的寿命可能不到一天。因此，髓系细胞的产生必须是 被认为是炎症和疾病的主要驱动力。全身性白细胞增多症的因果关系 心血管疾病(CVD)的进展被很好地记录下来，临床研究表明两者之间存在很强的相关性 白细胞增多症与心血管死亡率的关系。我们的首要假设是心血管危险因素 疾病调节着骨髓血管系统的功能。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与动脉粥样硬化 修饰内皮细胞(EC)和造血干/祖细胞(HSPC)之间的串扰，产生 到CVD加速正反馈环路。我们建议找出导致改变的路径 HSPC的内皮调节，导致单核细胞和中性粒细胞的产生加速和增加 将白细胞释放到体循环中。抑制这些通路将降低较高的HSPC 增殖率和髓系偏向，将减缓新产生的白细胞从 最终将抵消全身增加的促进心血管疾病的白细胞的供应。在……里面 与PPG同事合作，我们将继续研究血管内皮细胞和血管生物学 动脉粥样硬化或急性心肌梗死小鼠的骨髓。从以下位置选择上调目标 CVD小鼠的基因表达谱，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小鼠中诱导心肌梗死和动脉粥样硬化，测试他们的假设 防止白细胞过度生产和心血管疾病。这部作品将使小说 骨髓内皮细胞的治疗靶点。在与林博士的合作下，我们将聘请新的 成像急性心肌梗死或动脉粥样硬化小鼠骨髓血管功能的技术。具体来说，我们 将血流成像以估计切应力、内皮功能障碍(血管收缩和扩张能力)、 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系列成像。这些实验将揭示骨髓如何 血管参数在心血管疾病中的变化，以及这些变化如何导致系统性疾病供应过剩- 促进白细胞在动脉粥样硬化和急性心肌梗塞中的作用。

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.