HUMAN TISSUE FACTOR AND ITS PLASMA INHIBITOR

人体组织因子及其血浆抑制剂

• 批准号: 2217552
• 负责人: GEORGE J BROZE
• 金额: $ 29.91万
• 依托单位: BARNES-JEWISH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-07-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2217552
• 关键词: anticoagulants; baboons; blood coagulation; blood lipoprotein; coagulation factor VII; coagulation factor X; dogs; hemophilia As; hemostasis; heparin; laboratory mouse; laboratory rabbit; monoclonal antibody; mucopolysaccharides; plasma; platelets; protease inhibitor; protein sequence; protein structure function; proteolysis; thromboembolism; thromboplastin; tissue /cell culture; vascular endothelium

The initiation of blood coagulation through the factor VII-tissue factor pathway is not only important for normal hemostasis, but is involved in pathological thrombosis as well. The cellular expression of tissue factor has been correlated with infectious, inflammatory, and neoplastic disease, and may be responsible in part for the thromboembolic complications of not only these illnesses, but also the venous thrombosis and pulmonary embolism occurring in otherwise normal individuals. Plasma contains an endogenous inhibitor of the factor VIIa/tissue factor complex, termed Tissue Factor Pathway Inhibitor (TFPI). One form of TFPI is bound to the lipoproteins in plasma, whereas another form is released into plasma (presumably from the endothelium) following the in vivo infusion of heparin. At physiologic concentrations, TFPI requires the presence of factor Xa to express feedback inhibition of the factor VIIa/tissue factor complex. We plan to extensively characterize lipoprotein-associated and heparin-- releasable forms of TFPI and investigate structure/function relationships in the TFPI molecule vis a vis its lipoprotein association, its inhibition of factor Xa, its inhibition of factor VIIa/tissue in the presence and absence of factor Xa, and the enhancement of its inhibitory activity by heparin and other glucosaminoglycans. Additional studies will investigate the mechanism of endogenous proteolysis of TFPI and the manner by which TFPI is associated with endothelial cells. Finally, to test the role of TFPI in a revised hypothesis of coagulation, we will determine whether the endogenous inhibition of TFPI ameliorates bleeding in dogs with hemophilia. The experiments are designed to provide information, now lacking, concerning the physiology of TFPI and its regulation of tissue factor-induced coagulation. The results should enhance our understanding of both normal hemostasis and pathological thromboembolism.

通过凝血因子VII-组织因子启动血液凝固 该通路不仅对正常止血很重要，而且参与 病理性血栓形成 组织的细胞表达 因子与感染、炎症和肿瘤相关 疾病，并可能是负责部分血栓栓塞 不仅这些疾病的并发症， 和肺栓塞发生在其他正常个体中。 血浆含有因子VIIa/组织因子的内源性抑制剂 复合物，称为组织因子途径抑制剂（TFPI）。 TFPI的一种形式 与血浆中的脂蛋白结合， 进入血浆（可能来自内皮）， 肝素输注。 在生理浓度下，TFPI需要 因子Xa的存在以表达因子的反馈抑制 VIIa/组织因子复合物。 我们计划对脂蛋白相关和肝素进行广泛的表征， TFPI的可释放形式，并研究结构/功能关系 在TFPI分子维斯维斯其脂蛋白缔合中， 因子Xa的抑制，其对因子VIIa/组织的抑制， 因子Xa的存在和不存在，以及其抑制性的增强， 肝素和其他葡糖胺聚糖的活性。 其他研究 将研究TFPI的内源性蛋白水解机制和TFPI的生物学活性。 TFPI与内皮细胞结合的方式。 最后为 为了检验TFPI在修正的凝血假说中的作用，我们将 确定TFPI的内源性抑制是否改善出血 在患有血友病的狗身上。 这些实验旨在提供信息，现在缺乏， 关于TFPI的生理学及其对组织的调节 因子诱导的凝血。 研究结果应该能增进我们对 正常止血和病理性血栓栓塞。