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Thrombotic Diathesis: Molecular Biology and Clinical Investigation.

血栓素质：分子生物学和临床研究。

基本信息

批准号：
03304049
负责人：
AOKI Nobuo
金额：
$ 15.3万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Co-operative Research (A)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

The study was focused mainly on the four subjects : Regulatory components of thrombus formation, initiation steps of extrinsic coagulation system, sugar chains of coagulation-related components, and platelet membrane. 1. Reguratory components of thrombus formation : Thrombomodulin, anticoagulant protein on surface membrane of endothelial cells, is increased by many stimulants. Its increase was found to be caused mainly by the increase of a high molecular weight type (a sugar-rich type). Four genetic abnormalities causing protein-C deficiency in 3 independent families were elucidated.The deficiency was found to be caused by failure of intracellular transport and secretion of the abnormal proteins produced. Structurally and functionally abnormal protein S, a cofactor of activated protein C, was newly discovered and characterized. 2. Initiation steps of extrinsic coagulation system : Cloning of cDNA for tissue factor in coagulation and its expression were successfully carried out. Monoclonal antibodies to recombinant tissue factor were produced, and the antibodies were used for the study on tissue factor antigen levels in circulation under various disease states. 3. Sugar chains of coagulation-related proteins : Sugar chains of coagulation factors VII, IX, XII and von Willebrand factor were characterized. ABO(H) blood type sugar chains were found to be present in von Willebrand factor and alpha 2 macroglobulin. 4. Cloning and structural characterization of cDNA for platelet membrane GPV were carried out. GPV was found to contain leucin-rich repeated structure and be released into plasma as a soluble form by thrombin. Interaction reaction of platelet and collagen was analyzed, and platelet membrane glycoprotein p62 (GP VI) was suggested to be involved in the reaction leading to the platelet activation. Platelet membrane receptor for thromboxane A2, a powerful agonist for platelet aggregation, was cloned and purified.

本文主要从血栓形成的调节成分、外源性凝血系统的启动步骤、凝血相关成分的糖链和血小板膜四个方面进行研究。1.血栓形成的调节成分：血栓调节蛋白，内皮细胞表面膜上的抗凝蛋白，被许多刺激物增加。发现其增加主要由高分子量类型（富含糖的类型）的增加引起。在3个独立家系中发现了4种引起蛋白C缺乏症的遗传异常，其原因是异常蛋白质不能在细胞内转运和分泌。结构和功能异常的蛋白S是活化蛋白C的辅因子，是新发现和表征的。2.外源性凝血系统的启动步骤：成功克隆了凝血组织因子cDNA并进行了表达。制备了重组组织因子的单克隆抗体，并将该抗体用于研究各种疾病状态下循环中组织因子抗原水平。3.凝血相关蛋白质的糖链：凝血因子VII、IX、XII和血管性血友病因子的糖链进行了表征。ABO（H）血型糖链存在于血管性血友病因子和α 2巨球蛋白中。4.对血小板膜GPV的cDNA进行了克隆和结构分析。GPV含有富含亮氨酸的重复结构，可被凝血酶以可溶性形式释放到血浆中。分析了血小板与胶原的相互作用，提示血小板膜糖蛋白p62（GP VI）参与了导致血小板活化的反应。血小板膜受体血栓素A2，一个强大的血小板聚集激动剂，克隆和纯化。