Project 3: Remote control of hematopoiesis in cardiovascular disease

项目三：远程控制心血管疾病造血

基本信息

批准号：
10238043
负责人：
Filip K Swirski
金额：
$ 39.99万
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/10238043
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 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

项目摘要

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，是脂质驱动的以脂蛋白和白细胞积累为特征的慢性炎性疾病船墙。除某些例外，所有白细胞均在骨髓中产生。在这里，我们将探索疾病位置与造血之间的长距离交流骨髓。我们将确定在动脉瘤和缺血性心肌中分泌的因素，以及然后针对那些由造血茎表达同源受体的因素，祖细胞。这种方法将揭示直接传输线的效应器位点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素将患病的心血管微环境与骨髓联系起来。我们将执行RNASEQ，以生成用于心肌梗塞和动脉粥样硬化的数据集在同一环境中识别配体 - 受体对表达。对于有前途的候选人，我们将用可用工具确认mRNA表达和蛋白质表达。对于每个候选人分子，我们将遵循使用我们的初步数据建立的蓝图，以适应策略介绍动脉粥样硬化病变和梗塞心肌中其他因素如何产生的因素可能会影响骨髓。在第二个目标中，我们将阐明长距离患病的微环境的机制具有对骨髓的遥控控制。我们将确定动脉粥样硬化病变中产生的候选因素以及骨髓中梗塞的心肌控制过程。总的来说，这些实验将确定患病部位（病变，梗死）之间的长距离通信的新线路，阐明基本机制，并为新的治疗方法铺平道路心血管疾病。