FIBRINOGEN/FIBRIN STRUCTURAL AND FUNCTIONAL DOMAINS

这个项目的长期目标是澄清 止血过程中的纤维蛋白原和纤维蛋白。为了贡献于 为此，我们将探讨纤维蛋白原转化的机制。 纤维蛋白和凝块的组装过程包括：纤维蛋白原纤维的形成， 分支和侧向联合以及纤维蛋白交联化(目标1)。我们 预计将确定第XIII因子结合位点在 纤维蛋白原，并了解凝血酶如何与其底物纤维蛋白原相互作用， 和纤维蛋白来调节纤维蛋白的生成、纤维蛋白的组装和 激活因子XIII(目标2)。我们也希望研究先天 与血栓栓塞症或出血相关的纤维蛋白原异常 障碍(目标3)，因为对这种障碍的结构和功能进行了分析 纤维蛋白原性异常将使我们更好地理解 正常纤维蛋白原和纤维蛋白的结构域。为了实现这些目标，我们将 利用最近关于纤维蛋白支化和交联化的几项发现， 以及凝血酶与纤维蛋白的结合和相互作用，在发展我们的 这些问题的实验策略。我们将雇佣各种不同的 方法包括生化、免疫学、生物物理学、电子学 显微技术和分子生物学技术。即将提供的信息 这些调查将有助于更全面地 对凝血酶、因子正常生理功能的认识 13、纤维蛋白原和纤维蛋白在止血中的作用。

The long range goal of this project is to clarify the roles played by fibrinogen and fibrin in the hemostatic process. In order to contribute to this objective, we will investigate the mechanism of fibrinogen conversion to fibrin and the clot assembly process including: fibrin fibril formation, branching and lateral association, and fibrin crosslinking (Aim 1). We expect to determine the location of the factor XIII binding site in fibrinogen, and learn how thrombin interacts with its substrate fibrinogen, and with fibrin to regulate fibrin generation, fibrin assembly, and the activation of factor XIII (Aim 2). We also wish to study congenital fibrinogen abnormalities associated with thromboembolic or hemmorhagic disorders (Aim 3), since structural and functional analysis of such dysfibrinogenemias will lead to a better understanding of the functional domains of normal fibrinogen and fibrin. To achieve these goals, we will exploit several recent discoveries on fibrin branching and crosslinking, and thrombin binding and interaction with fibrin, in developing our experimental strategies to these questions. We will employ a variety of methods including biochemical, immunological, biophysical, electron microscopic, and molecular biological techniques. Information forthcoming from these investigations will contribute to a more comprehensive understanding of the normal physiological functions of thrombin, factor XIII, fibrinogen and fibrin in hemostasis.