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Anticoagulant Function of Arterial Endothelial Cells

动脉内皮细胞的抗凝功能

基本信息

批准号：
11671003
负责人：
FUKUDOME Kenji
金额：
$ 2.3万
依托单位：
Saga Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671003/
关键词：
Protein C receptor thrombomodulin endothelial cells thrombosis blood coagulation モノクローナル抗体梗塞

项目摘要

Plasma protein C is an indispensable regulator of blood coagulation. Deficiencies in this molecule are associated with thrombotic disease, and knockout mice lacking protein C suffered lethal thromboses within 24 hours after birth. Protein C is a serine protease that circulates as a zymogen form, and functions only when converted into the active protease form. Protein C activation is promoted by thrombin on the endothelial cell surface. Two associate endothelial cell surface molecules have been identified. One is thrombomodulin (TM), which is capable of high-affinity specific binding of thrombin. We identified another endothelial cell surface molecule involved in the activation mechanism of protein C.The endothelial cell protein C receptor (EPCR) specifically binds protein C, and enables effective protein C activation mediated by the thrombin/TM complex. Knockout of the gene for EPCR or TM caused embryonic lethality, and did not allow in vivo analysis of the anticoagulant activities of these molecules. Here, we generated function blocking monoclonal antibodies (mAbs) against all these key murine factors. Anti-protein C mAbs, which specifically prevent the binding to EPCR, caused lethal thrombosis in injected mice. An anti-EPCR mAb induced severe thrombosis. We also generated function-blocking mAb against murine TM.This antibody again caused lethal thrombosis. These mAbs will be powerful tools for analyzing in vivo protein C pathway function.

血浆蛋白C是血液凝固不可或缺的调节剂。这种分子的缺陷与血栓性疾病有关，缺乏蛋白C的基因敲除小鼠在出生后24小时内就会发生致命的血栓形成。蛋白质C是一种丝氨酸蛋白酶，其作为酶原形式循环，并且仅在转化为活性蛋白酶形式时起作用。内皮细胞表面的凝血酶促进蛋白C活化。已经鉴定了两种相关的内皮细胞表面分子。一种是血栓调节蛋白（TM），它能够高亲和力特异性结合凝血酶。我们确定了另一种参与蛋白C激活机制的内皮细胞表面分子。内皮细胞蛋白C受体（EPCR）特异性结合蛋白C，并使凝血酶/TM复合物介导的有效蛋白C激活成为可能。敲除EPCR或TM基因导致胚胎死亡，并且不允许对这些分子的抗凝活性进行体内分析。在这里，我们产生了针对所有这些关键鼠因子的功能阻断单克隆抗体（mAb）。特异性阻止与EPCR结合的抗蛋白C mAb在注射小鼠中引起致命血栓形成。抗EPCR mAb诱导严重血栓形成。我们还产生了功能阻断单克隆抗体对小鼠TM。这种抗体再次引起致命的血栓形成。这些单克隆抗体将成为分析体内蛋白C通路功能的有力工具。