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Platelet ERO1alpha in thrombosis and hemostasis

血小板ERO1α在血栓形成和止血中的作用

基本信息

批准号：
10093117
负责人：
Alan Tseng
金额：
$ 1.5万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10093117
关键词：
Affect Agonist Animal Model Binding Biological Assay Bleeding time procedure Blocking Antibodies Blood Platelets Blood Vessels Cardiovascular Diseases Cell Surface Proteins Cell surface Cells Cessation of life Development Disease susceptibility Disulfides Endoplasmic Reticulum Extracellular Protein Fibrin Fibrinogen Generations Hemorrhage Hemostatic Agents Hemostatic function ITGB3 gene Imaging technology Impairment In Vitro Injury Integrins Isomerase Knockout Mice Lasers Lead Ligand Binding Mediating Megakaryocytes Membrane Proteins Modeling Modification Morbidity - disease rate Mus Natural regeneration Oxidants Oxidation-Reduction Oxides Oxidoreductase Pathology Pathway interactions Peripheral arterial disease Platelet Activation Platelet aggregation Play Protein Disulfide Isomerase Proteins Recombinants Regulation Reporting Research Risk Role Signal Transduction Site Stroke Sulfhydryl Compounds Surface Tail Testing Thrombosis Thrombus Time Tissues Transient Ischemic Attack acute coronary syndrome conditional knockout disulfide bond experimental study extracellular in vivo in vivo imaging inhibitor/antagonist innovation insight intravital fluorescence microscopy intravital microscopy mortality mutant new therapeutic target novel novel therapeutic intervention platelet function polyclonal antibody protein folding receptor recruit therapeutic target vascular injury

项目摘要

PROJECT SUMMARY/ABSTRACT It was reported that in 2009 alone, 32% of all deaths in the US resulted from cardiovascular disease, including acute coronary syndrome, stroke/transient ischemic attack, and peripheral artery disease. Underlying these pathologies is increased platelet activity. Platelets play an essential role in hemostasis and thrombosis. Following vascular and tissue damage, platelets rapidly adhere to the site of injury and secrete granular contents that recruit and activate additional platelets, culminating in the formation of thrombi through the interaction between integrin αIIbβ3 and fibrinogen. Because of the essential role of integrin αIIbβ3 in platelet thrombus formation, antagonists of the integrin have been developed. However, direct inhibition of ligand binding to integrin αIIbβ3 could impair hemostasis and increase the risk of bleeding. Thus, many efforts have been put forward to develop inhibitors blocking integrin αIIbβ3 function or signaling. Numerous studies have now characterized the role of thiol-disulfide bond exchange as a regulatory mechanism for integrin αIIbβ3. Using real-time intravital microscopy, we and others demonstrated that the isomerase activity of cell surface protein disulfide isomerase (PDI), a prototypical thiol isomerase, plays a critical role in regulating integrin β3 activation and thrombus formation at the site of vascular injury, thereby suggesting PDI to be a novel therapeutic target for the treatment of thrombosis. However, blocking extracellular PDI compromised hemostatic function in mice as assessed by tail bleeding times. These results warrant the need for further research into how extracellular PDI activity is regulated following vascular injury. In the endoplasmic reticulum (ER), PDI catalyzes thiol-disulfide oxidation, reduction, and isomerization during protein folding and ER oxidoreductin 1α (ERO1α) is the key protein responsible for accepting the electrons from reduced PDI to oxidize PDI, regenerating its activity. In this comprehensive proposal, we will test the hypothesis that platelet surface ERO1α modulates the ligand-binding function of integrin αIIbβ3 by controlling PDI activity and facilitates platelet aggregation during thrombosis. The proposed studies will provide mechanistic insight into an innovative approach to downregulate the ligand-binding function of integrin αIIbβ3 by inhibition of the ERO1α-PDI signaling axis and may lead to the development of novel therapeutic strategies.

项目总结/摘要据报道，仅在2009年，美国32%的死亡是由心血管疾病引起的，急性冠状动脉综合征、中风/短暂性脑缺血发作和外周动脉疾病。在这些病理学是血小板活性增加。血小板在止血和血栓形成中起重要作用。以下血管和组织损伤时，血小板迅速粘附在损伤部位并分泌颗粒状内容物，募集并激活额外的血小板，最终通过血小板与血小板之间的相互作用形成血栓。整合素αIIbβ3和纤维蛋白原。由于整合素αIIbβ3在血小板血栓形成中的重要作用，已经开发了整联蛋白的拮抗剂。然而，直接抑制配体与整合素αIIbβ3的结合，可能影响止血并增加出血风险。因此，已经提出了许多努力来开发阻断整合素αIIbβ3功能或信号传导的抑制剂。许多研究已经将巯基-二硫键交换作为一种调节机制整合素αIIbβ3。使用实时活体显微镜，我们和其他人证明了异构酶活性细胞表面蛋白质二硫键异构酶（PDI）是一种典型的巯基异构酶，在调节整合素β3活化和血管损伤部位血栓形成，从而表明PDI是一种新的用于治疗血栓形成的治疗靶点。然而，阻断细胞外PDI会损害止血，通过尾部出血时间评估小鼠的功能。这些结果证明需要进一步研究如何细胞外PDI活性在血管损伤后受到调节。在内质网（ER）中，PDI在细胞内催化硫醇-二硫化物氧化、还原和异构化。蛋白质折叠和ER氧化还原蛋白1α（ERO 1 α）是负责接受电子的关键蛋白质，还原PDI，氧化PDI，使其活性再生。在这份全面的提案中，我们将检验假设血小板表面ERO 1 α通过控制PDI活性调节整合素αIIbβ3的配体结合功能，在血栓形成期间促进血小板聚集。拟议的研究将提供一个机制的见解，通过抑制ERO 1 α-PDI下调整合素αIIbβ3配体结合功能的创新方法信号轴，并可能导致新的治疗策略的发展。