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：
10166903
负责人：
CRAIG N MORRELL
金额：
$ 46.44万
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/10166903
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.

概括血小板与直接和间接的免疫电池相互作用 - 加速了血管炎症和传染病。刺激的血小板释放了许多免疫分子驱动炎症与任何血栓功能无关。我们发现了一种新颖的机制血小板引发了先天免疫细胞反应；血小板衍生的β2微球蛋白（β2M）是免疫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β2m - / - 小鼠现在，我们发现血小板是血浆β2M的主要来源，而该血小板衍生的β2M具有直接促炎作用。这使我们提出了血小板之间的新机械联系，等离子体β2M，和免疫球反应，尤其是血小板驱动的单核细胞促炎反应。假设：β2M是促炎单核细胞表型的新型血小板衍生的介体。具体目的＃1。证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β2M如何诱导单核细胞促进炎症反应。特定目的＃2。证明血小板来源的β2M如何介导单核细胞反应和缺血性心肌损伤模型的结果。我们将使用我们已建立的心肌梗塞模型证明β2M介导的缺血组织损伤的病理生理机制。该提案将证明具有血小板介导的单核细胞激活的新机制直接影响全球发病率和死亡率的主要原因。我们的研究结果将影响许多其他小组和研究项目的工作。该提议包括一系列雄心勃勃的研究研究团队独特地购买。