Project 3: Remote control of hematopoiesis in cardiovascular disease

项目三：远程控制心血管疾病造血

• 批准号: 10469353
• 负责人: Filip K Swirski
• 金额: $ 39.98万
• 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/10469353
• 关键词: Affect; Arterial Fatty Streak; Atherosclerosis; Blood Circulation; Bone Marrow; CRISPR/Cas technology; Cardiovascular Diseases; Cells; Clonality; Collaborations; Communication; Data; Data Set; Disease; Endothelial Cells; Environment; Flow Cytometry; Gene Expression; Genes; Genetic Engineering; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor Receptors; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; IL3 Gene; Image; Immunohistochemistry; Infarction; Inflammation; Inflammatory; Lesion; Leukocytes; Ligands; Link; Lipids; Lipoproteins; Location; MPP3 gene; Mediator of activation protein; Mus; Myocardial Infarction; Myocardial Ischemia; Myocardium; Pathway interactions; Persons; Phenotype; Process; Production; Property; Proteins; Publishing; Reporter; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Role; Series; Shapes; Site; Source; Stroke; Testing; Tissues; Transplantation; Triage; Work; chronic inflammatory disease; conditional knockout; cytokine; experimental study; genome wide association study; insight; intravital microscopy; mRNA Expression; migration; monocyte; neutrophil; novel; novel therapeutic intervention; pre-clinical; protein expression; receptor; remote control; response; screening; tool; transcriptome sequencing; transmission process

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.

动脉粥样硬化是心肌梗塞和中风的根本原因，是一种脂质驱动的疾病 以脂蛋白和白细胞积聚为特征的慢性炎症性疾病 血管壁。除了一些例外，所有白细胞都是在骨髓中产生的。在这里，我们 将探索疾病部位和造血系统之间的远距离通讯 骨髓。我们将识别动脉粥样硬化和缺血心肌中分泌的因子，并且 然后针对那些其同源受体由造血干表达的因子 祖细胞。这种方法将揭示效应位点所通过的直接传输线 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 分泌的因子将患病的心血管微环境与骨髓联系起来。我们 将执行 RNAseq 生成心肌梗塞和动脉粥样硬化的数据集 识别同一环境中配体-受体对的表达。对于有前途的候选人，我们将 使用可用的工具确认 mRNA 表达和蛋白质表达。对于每位候选人 分子，我们将遵循根据我们的初步数据建立的蓝图，调整策略 分析其他因素如何在动脉粥样硬化病变和梗塞心肌中产生 可能会影响骨髓。在第二个目标中，我们将阐明长途 患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如何在动脉粥样硬化病变和动脉粥样硬化病变中产生。 骨髓中梗塞心肌的控制过程。总的来说，这些实验将 确定病变部位（病变、梗塞）之间新的长距离通讯线路， 阐明潜在机制，为新的治疗方法铺平道路 心血管疾病。