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Mechanisms of myelopoiesis after myocardial infarction

心肌梗死后骨髓生成机制

基本信息

批准号：
10415059
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10415059
关键词：
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 Cell Differentiation process Cells Color Data Disease Distant Event Exposure to Flow Cytometry Generations HMGB1 gene Heart Hematopoietic stem cells In Vitro Inflammation Inflammatory Injury Interleukin Receptor 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 Stains Technology Testing Trichrome stain method base 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：