Novel mechanisms of platelet modified monocyte phenotype

血小板修饰单核细胞表型的新机制

基本信息

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
项目类别：
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

项目摘要

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.

概括血小板与免疫细胞的直接和间接相互作用加速了以下疾病的发病机制血管炎症和感染性疾病。受刺激的血小板释放大量免疫分子。我们发现了一种独立于任何血栓功能的炎症驱动机制。血小板引发的先天免疫细胞反应；血小板衍生的 Beta2 微球蛋白 (β2M) 是一种免疫细胞使用我们的新型血小板特异性 β2M-/- 小鼠介导促炎单核细胞表型的分子。我们现在发现血小板是血浆β2M的主要来源，并且血小板衍生的β2M具有直接作用这促使我们提出血小板、血浆 β2M、和免疫细胞反应，特别是血小板驱动的单核细胞促炎症反应。假设：β2M 是一种新型血小板衍生的促炎单核细胞表型介质。具体目标#1. 证明血小板介导的单核细胞炎症表型的机制我们将使用体外细胞研究来展示血小板衍生的 β2M 如何诱导单核细胞亲- 炎症反应。具体目标#2. 证明血小板衍生的 β2M 如何介导单核细胞反应和我们将使用我们建立的心肌梗塞模型来观察缺血性心肌损伤模型的结果。证明β2M介导的缺血性组织损伤的病理生理机制。该提案将证明血小板介导的单核细胞激活的新机制我们的研究结果将直接影响全球发病率和死亡率的主要原因。该提案由我们的一系列雄心勃勃的研究组成。研究团队具有独特的追求。