MECHANISMS OF ACTIVATION OF COAGULATION FACTOR XI

凝血因子 XI 的激活机制

• 批准号: 2210769
• 负责人: David Gailani
• 金额: $ 8.19万
• 依托单位: BARNES-JEWISH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 1995-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2210769
• 关键词: SDS polyacrylamide gel electrophoresis; activation product; autoradiography; blood coagulation; chimeric proteins; coagulation factor XI; coagulation factor XII; endopeptidases; hemostasis; human subject; human tissue; immunoprecipitation; intermolecular interaction; kallikreins; laboratory rabbit; monoclonal antibody; plasma; polymerase chain reaction; protein purification; protein structure function; recombinant DNA; surface property; thrombin; western blottings

The purpose of this research project is to investigate the mechanisms by which coagulation factor XI becomes an active serine protease. Factor XI is a plasma glycoprotein which is clearly required for normal hemostasis, as persons deficient in this protein have abnormal bleeding, particularly after surgical procedures. In vitro, factor XI is activated by factor XII in conjunction with high molecular weight kininogen and prekallikrein, however, congenital deficiencies of these "contact activation" proteins do not cause clinical hemostatic problems. This observation suggests that an alternative mechanism for factor XI activation exists. The recent findings that the serine protease thrombin is able to activate factor XI in vitro and that factor XI undergoes autoactivation in the presence of certain negatively charged surfaces suggests that factor XI may play a role in sustaining the hemostatic process after some thrombin has been generated at the site of a wound. The activation of factor XI by thrombin and by autoactivation will be studied in physiologic systems containing plasma and in the presence of various cells which may function in normal hemostasis. A search will be conducted for additional, previously undescribed, mechanisms of factor XI activation. Finally, factor XI mutants will be produced to study the interaction of thrombin with factor XI and the autoactivation process. The data obtained will provide far a better understanding of normal hemostasis and will provide a firmer knowledge base from which to study thromboembolic diseases.

这项研究项目的目的是通过以下方式来研究其机制 哪种凝血因子XI成为一种活性丝氨酸蛋白酶。第XI因子 是一种血浆糖蛋白，显然是正常止血所必需的， 由于缺乏这种蛋白质的人会出现异常出血，尤其是 在手术后。在体外，凝血因子XI被凝血因子XII激活 与高分子激肽原和前激肽释放酶结合， 然而，这些“接触激活”蛋白的先天缺陷 不会引起临床止血问题。这一观察结果表明， 存在另一种激活因子XI的机制。最近的 发现丝氨酸蛋白酶凝血酶能够激活凝血因子XI 在体外，该因子XI在有 某些带负电的表面表明，因子XI可能起到 某些凝血酶在维持止血过程中的作用 在伤口处产生。凝血酶对凝血因子XI的激活作用 通过自激活将在生理系统中进行研究，包括 血浆和可能在正常情况下发挥作用的各种细胞的存在 止血。将进行搜索，以了解以前 未描述的，因子XI激活的机制。最后，因素XI 将产生突变体来研究凝血酶与因子的相互作用 XI和自动激活过程。所获得的数据将提供一个遥远的 更好地了解正常止血，将提供更坚定的 用于研究血栓栓塞性疾病的知识库。