Project 3: Remote control of hematopoiesis in cardiovascular disease

动脉粥样硬化是心肌梗死和中风的根本原因， 以脂蛋白和白细胞积聚为特征的慢性炎性疾病 血管壁除了一些例外，所有的白细胞都是在骨髓中产生的。这里我们 将探索疾病部位和造血之间的远距离通信， 骨髓我们将确定动脉粥样硬化和缺血心肌中分泌的因子， 然后靶向造血干细胞表达其同源受体的那些因子， 祖细胞这种方法将揭示直接的传输线， 可能控制白细胞的产生、动员和功能。在第一个目标中，我们将筛选 将患病的心血管微环境与骨髓联系起来的分泌因子。我们 将执行RNAseq以生成心肌梗死和动脉粥样硬化的数据集， 在相同的环境中鉴定配体-受体对的表达。对于有前途的候选人，我们将 用可用的工具确认mRNA表达和蛋白质表达。针对每个候选 分子，我们将遵循我们的初步数据建立的蓝图， 分析动脉粥样硬化病变和梗死心肌中其他因子的产生方式， 可能会影响骨髓在第二个目标中，我们将阐明远距离 疾病微环境对骨髓进行远程控制的机制。 我们将确定候选因子是如何在动脉粥样硬化病变中产生的， 心肌梗死的骨髓控制过程。总的来说，这些实验 识别患病部位（病变、梗塞）之间的长距离通信的新线路， 阐明潜在的机制，并为新的治疗方法铺平道路， 心血管疾病

Atherosclerosis, the underlying cause of myocardial infarction and stroke, is a lipid-driven chronic inflammatory disease characterized by lipoprotein and leukocyte accumulation in the vessel wall. With some exceptions, all leukocytes are produced in the bone marrow. Here, we will explore long-distance communication between disease locations and hematopoiesis in the bone marrow. We will identify factors secreted in the atheroma and ischemic myocardium, and then target those factors whose cognate receptor is expressed by hematopoietic stem and progenitor cells. Such an approach will reveal direct transmission lines by which effector sites might control leukocyte production, mobilization, and function. In the first aim, we will screen for secreted factors that link diseased cardiovascular microenvironments with the bone marrow. We will perform RNAseq to generate data sets for myocardial infarction and atherosclerosis to identify ligand-receptor pair expression in the same milieu. For promising candidates, we will confirm mRNA expression and protein expression with available tools. For each candidate molecule, we will follow the blueprint established with our preliminary data, adapting the strategy to profile how other factors produced in atherosclerotic lesions and in the infarcted myocardium might influence the bone marrow. In the second aim, we will elucidate long-distance mechanisms by which diseased microenvironments exert remote control of the bone marrow. We will determine how candidate factors produced in the atherosclerotic lesion and in the infarcted myocardium control processes in the bone marrow. Collectively, these experiments will identify new lines of long-distance communication between diseased sites (lesion, infarct), elucidate the underlying mechanisms, and pave the way for new therapeutic approaches for cardiovascular disease.