Mechanisms of myelopoiesis after myocardial infarction

心肌梗死后骨髓生成机制

基本信息

批准号：
10625852
负责人：
Partha Dutta
金额：
$ 47.41万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625852
关键词：
Acceleration Acute Adoptive Transfer Apolipoprotein E Applications Grants Arterial Fatty Streak Atherosclerosis Binding Sites Biological Assay Blood Blood Platelets Blood Vessels Bone Marrow Bone Marrow Cells Bone Marrow Transplantation C57BL/6 Mouse Cardiac Myocytes Cell Count Cells Color Data Disease Distant Event Exposure to Flow Cytometry Generations HMGB1 gene Heart Hematopoietic stem cells In Vitro Infarction Inflammation Inflammatory Injury Interleukin-3 Receptor Ischemia Knockout Mice Knowledge Location Low Density Lipoprotein Receptor Luciferases Magnetic Resonance Imaging Measures Mediating Messenger RNA Methylcellulose MicroRNAs Molecular Mus Myelogenous Myeloid Cells Myelopoiesis Myocardial Infarction Oils Organ Pathogenesis Patients Process Production Proliferating Role Signal Transduction Sorting Stains Technology Testing Trichrome stain method cytokine drug development extracellular vesicles fluorescence molecular tomography hematopoietic differentiation improved in silico in vivo intravital microscopy ischemic injury migration mouse model necdin novel therapeutics overexpression progenitor reconstitution sham surgery stem cell proliferation stem cells transcription factor ultrasound

项目摘要

Project Summary/ Abstract: An acute injury, such as myocardial infarction (MI), induces exaggerated production of myeloid cells in the bone marrow. These newly generated myeloid cells are inflammatory and are crucial in disease pathogenesis, exacerbating underlying processes such as atherosclerosis. However, the systemic long distance signals and molecular mechanisms that trigger myelopoiesis in the bone marrow after an ischemic event at a distant organ, such as the heart, are poorly understood. Our preliminary data revealed that, following an MI, bone marrow hematopoietic stem and progenitor cells (HSPC) relocated into the vascular niches. Vascular niches confer distinct microenvironments promoting HSPC proliferation and differentiation. In investigating the long-distance signals produced after MI, we found increased levels of platelet-derived extracellular vesicles (pEV) in the blood of patients and mice after MI. These pEV increased the expression of PU.1, which is a myeloid transcription factor, and the receptor for interleukin-3 (IL-3R), which increases myeloid cell generation, in bone marrow HSPC. Additionally, pEV isolated from mice with MI contained high levels of miR-499, which increased bone marrow HSPC proliferation and differentiation in vitro. From these observations, we hypothesize that increased miR-499 in pEV following MI relocates HSPC to active vascular niches in the bone marrow, where they proliferate and differentiate into myeloid cells. We will test this hypothesis in two specific aims: (1) We will determine the role of pEV in relocation of HSPC to the vascular niches in the bone marrow. (2) We will investigate if increased miR-499 expression in pEV augments myelopoiesis and atherosclerosis after MI. To test the hypothesis, we will photoconvert KikGR+ HSPC, use mice deficient of miR-499 and two different mouse models of atherosclerosis. We will characterize pEV in patients and mice with MI using flow cytometry, ImageStream and NanoSight technologies. Additionally, we will determine the proliferation of HSPC exposed to pEV isolated from miR- 499+/+ and miR-499-/- mice after MI in vitro and in vivo. The proposed grant application will further our understanding of the mechanisms of MI-induced myelopoiesis, and explore new therapeutic avenues to diminish inflammation and atherosclerosis after MI.

项目摘要/摘要：急性损伤，例如心肌梗塞（MI），会导致骨髓细胞过度生成。骨髓。这些新生成的骨髓细胞具有炎症性，在疾病中至关重要发病机制，加剧动脉粥样硬化等潜在过程。然而，系统性的长期缺血后触发骨髓生成的距离信号和分子机制人们对远处器官（例如心脏）发生的事件知之甚少。我们的初步数据显示，心肌梗死后，骨髓造血干细胞和祖细胞 (HSPC) 重新定位到血管中利基市场。血管生态位赋予独特的微环境，促进 HSPC 增殖和分化。在研究心肌梗死后产生的长距离信号时，我们发现血小板衍生的信号水平增加 MI 后患者和小鼠血液中的细胞外囊泡（pEV）。这些 pEV 增加了表达 PU.1（一种骨髓转录因子）和白细胞介素 3 (IL-3R) 受体，可增加骨髓 HSPC 中的骨髓细胞生成。此外，从患有 MI 的小鼠中分离出的 pEV 含有高 miR-499 水平，可增加体外骨髓 HSPC 的增殖和分化。从这些根据观察，我们假设 MI 后 pEV 中 miR-499 的增加使 HSPC 重新定位为活性状态骨髓中的血管壁龛，它们在那里增殖并分化成骨髓细胞。我们将测试该假设有两个具体目标：（1）我们将确定 pEV 在 HSPC 迁移到骨髓中的血管壁龛。 (2) 我们将研究 pEV 中 miR-499 表达是否增加增强心肌梗死后的骨髓生成和动脉粥样硬化。为了检验这个假设，我们将对 KikGR+ 进行光转换 HSPC，使用缺乏 miR-499 的小鼠和两种不同的动脉粥样硬化小鼠模型。我们将使用流式细胞术、ImageStream 和 NanoSight 表征 MI 患者和小鼠的 pEV 技术。此外，我们将确定暴露于从 miR-分离的 pEV 中的 HSPC 的增殖情况。 MI 后的 499+/+ 和 miR-499-/- 小鼠体外和体内。拟议的赠款申请将进一步推动我们了解 MI 诱导的骨髓细胞生成机制，并探索新的治疗途径减少心肌梗死后的炎症和动脉粥样硬化。