Novel mechanisms of platelet modified monocyte phenotype

血小板修饰单核细胞表型的新机制

• 批准号: 10377113
• 负责人: CRAIG N MORRELL
• 金额: $ 36.45万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377113
• 关键词: Age; Antigens; Arthritis; Atherosclerosis; Biological Assay; Biological Markers; Biological Response Modifiers; Blood Platelets; Blood Vessels; Cell membrane; Cells; Communicable Diseases; Complex; Data; Disease; Erythrocytes; Fibrosis; Hemorrhage; Histocompatibility; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Lead; Learning; Link; Mediating; Mediator of activation protein; Medicine; Membrane; Memory; Messenger RNA; Modeling; Molecular Chaperones; Morbidity - disease rate; Mus; Myocardial Infarction; Nature; Outcome; Pathogenesis; Phenotype; Plasma; Platelet Activation; Proteins; Proteomics; Publishing; Research; Research Project Grants; Risk; Role; Sepsis; Signal Transduction; Source; Work; base; cytokine; heart function; in vivo; injury and repair; monocyte; mortality; mouse model; myocardial injury; novel; novel therapeutics; receptor; response; response to injury; thrombotic; tissue injury; trafficking; transcriptome sequencing; vascular inflammation

Summary Platelet interactions with immune cells – both direct and indirect – accelerate the pathogenesis of vascular inflammatory and infectious diseases. Stimulated platelets release numerous immune molecules that drive inflammation independent of any thrombotic functions. We have discovered a novel mechanism of platelet initiated innate immune cell responses; platelet derived Beta2 microglobulin (β2M) is an immune molecule that mediates a pro-inflammatory monocyte phenotype. Using our novel platelet specific β2M-/- mice we have now found that platelets are a major source of plasma β2M, and that platelet derived β2M has direct pro-inflammatory effects. This leads us to propose a novel mechanistic link between platelets, plasma β2M, and immune cell responses, particularly platelet driven monocyte pro-inflammatory responses. Hypothesis: β2M is a novel platelet derived mediator of a pro-inflammatory monocyte phenotype. Specific Aim # 1. To demonstrate mechanisms of platelet mediated monocyte inflammatory phenotype in vitro. We will use in vitro cell based studies to show how platelet derived β2M induces monocyte pro- inflammatory responses. Specific Aim # 2. To demonstrate how platelet-derived β2M mediates monocyte responses and outcomes in an ischemic myocardial injury model. We will use our established myocardial infarction model to demonstrate the pathophysiologic mechanism of β2M mediated ischemic tissue injury. This proposal will demonstrate novel mechanisms for platelet mediated monocyte activation that have direct impacts on major causes of morbidity and mortality worldwide. Results of our studies will influence the work of many other groups and research projects. This proposal consists of an ambitious set of studies that our research team is uniquely situated to pursue.

总结 血小板与免疫细胞的直接和间接相互作用加速了 血管炎性和感染性疾病。刺激血小板释放大量免疫分子， 不依赖于任何血栓形成功能而驱动炎症。我们发现了一种新的机制 血小板引发的先天性免疫细胞反应;血小板衍生的β 2微球蛋白（β 2 M）是一种免疫细胞， 介导促炎单核细胞表型的分子。使用我们的新型血小板特异性β 2 M-/-小鼠 我们现在发现血小板是血浆β 2 M的主要来源，血小板衍生的β 2 M具有直接的 促炎作用。这使我们提出血小板、血浆β 2 M 和免疫细胞反应，特别是血小板驱动的单核细胞促炎反应。 假设：β 2 M是一种新的促炎单核细胞表型的血小板衍生介质。 具体目标#1。阐明血小板介导的单核细胞炎症表型的机制 体外我们将使用基于体外细胞的研究来显示血小板衍生的β 2 M如何诱导单核细胞前体细胞增殖。 炎症反应。 具体目标#2。为了证明血小板源性β 2 M如何介导单核细胞应答， 缺血性心肌损伤模型的结果。我们将使用我们建立的心肌梗死模型 探讨β 2 M介导缺血性组织损伤的病理生理机制。 这一提议将证明血小板介导的单核细胞活化的新机制， 对全世界发病率和死亡率的主要原因产生直接影响。我们的研究结果将影响 许多其他团体和研究项目的工作。这项建议包括一系列雄心勃勃的研究， 研究团队是唯一处于追求。