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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：
9192200
负责人：
Alan Tseng
金额：
$ 4.86万
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/9192200
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 Electrons Endoplasmic Reticulum Extracellular Protein Fibrin Fibrinogen Generations Hemorrhage Hemostatic Agents Hemostatic function Imaging technology Impairment In Vitro Injury Integrin beta3 Integrins Isomerase Knockout Mice Lasers Lead Life Ligand Binding Mediating Megakaryocytes Membrane Proteins Modeling Modification Morbidity - disease rate Mus Natural regeneration Oxidation-Reduction Oxidoreductase Pathology Pathway interactions Peripheral arterial disease Platelet Activation Platelet aggregation Play Protein Disulfide Isomerase Proteins Recombinants Recruitment Activity Regulation Reporting Research Risk Role Signal Transduction Site Stroke Sulfhydryl Compounds Surface Tail Testing Thrombosis Thrombus Time Tissues Transient Ischemic Attack acute coronary syndrome disulfide bond extracellular in vivo in vivo imaging inhibitor/antagonist innovation insight intravital fluorescence microscopy intravital microscopy mortality mutant new therapeutic target novel novel therapeutics polyclonal antibody protein folding receptor research study therapeutic target

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/文摘