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

• 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
• 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

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.

与其他血管领域相比，我们对骨髓血管病变知之甚少