PLATELET BINDING SITES FOR BOVINE FACTOR VIII

牛因子 VIII 的血小板结合位点

• 批准号: 3339402
• 负责人: EDWARD P KIRBY
• 金额: $ 13.07万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-05-01 至 1986-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3339402
• 关键词: adenosine diphosphate; affinity chromatography; autoradiography; coagulation factor VIII; crosslink; electrofocusing; gel electrophoresis; hemostasis; human tissue; monoclonal antibody; phosphorylation; platelet aggregation; platelets; stoichiometry; thrombosis

Factor VIII is a high molecular weight plasma glycoprotein complex which is an important regulator of blood coagulation and is also required for the recognition of damaged endothelial surfaces by blood platelets. A convenient model for the function of Factor VIII in platelet-mediated hemostasis is provided by the binding of bovine Factor VIII to human platelets. We propose to identify and to isolate the protein(s) on the platelet surface to which Factor VIII binds. The purified binding protein(s) will be characterized by biochemical techniques and the mechanism of association with Factor VIII determined. Chemical and enzymatic modification of the isolated binding protein(s) will be used to identify the regions responsible for functional activity. The effects of agents, such as ADP, which alter the responsiveness of platelets to Factor VIII, will be examined for their effects on the availability of binding sites on the platelet surface. We will also examine the effects of Factor VIII binding on the metabolic and functional responses of platelets and will study how this binding alters the responsiveness of platelets to other agonists. A congenital deficiency of the Factor VIII protein in humans (von Willebrand's disease) can cause a severe bleeding syndrome, because of the resulting defect in platelet-mediated hemostasis. Replacement therapy with concentrates of Factor VIII can correct this defect. On the other hand, a deficiency of Factor VIII (in swine) has been shown to be associated with a decreased tendency to form atherosclerotic plaques - probably because of a decreased responsiveness of the platelets to the early stages of damage to the vascular intima. These observations suggest that the interaction of Factor VIII with platelets plays a key role not only in protective hemostatic mechanisms but also in those which could lead to thrombotic conditions. A better understanding of this interaction is thus essential for a rational approach to the therapeutic management of these conditions.

因子VIII是一种高分子量等离子体糖蛋白复合物，是 血液凝血的重要调节剂，也需要 通过血小板识别受损的内皮表面。 一个 血小板介导的因子VIII功能的方便模型 止血是由牛因子VIII与人的结合提供的 血小板。 我们建议识别和隔离蛋白质 VIII因子结合的血小板表面。 纯化的结合 蛋白质将以生化技术为特征 确定与因子VIII的关联机制。 化学和 分离的结合蛋白的酶促修饰将用于 确定负责功能活动的区域。 效果 代理，例如ADP，它改变了血小板对因素的响应能力 VIII，将检查其对绑定的可用性的影响 血小板表面的位置。 我们还将检查因素的影响 VIII对血小板的代谢和功能反应结合和 将研究这种约束力如何改变血小板对其他的反应性 激动剂。 人类VIII蛋白的先天性缺陷 （von Willebrand病）可能导致严重的出血综合症，因为 血小板介导的止血的缺陷。 替代疗法 浓缩因子VIII可以纠正此缺陷。 另一方面 手，已证明因子VIII（猪）缺乏 与形成动脉粥样硬化斑块的趋势降低有关 - 可能是由于血小板对 血管内膜损害的早期阶段。 这些观察表明 VIII因子与血小板的相互作用起着关键作用而不是 仅在保护性止血机制中，而且在那些可以领导的机制中 到血小板状况。 更好地理解这种互动是 因此，对于理性的方法进行治疗管理至关重要 这些条件。