FIBRINOGEN/FIBRIN STRUCTURAL AND FUNCTIONAL DOMAINS

本项目的长期目标是阐明 纤维蛋白原和纤维蛋白在止血过程中。 以促进 为此，我们将探讨纤维蛋白原转化的机制 纤维蛋白和凝块组装过程包括：纤维蛋白原纤维形成， 分支和侧向缔合以及纤维蛋白交联（目的1）。 我们 期望确定因子XIII结合位点的位置， 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， 并与纤维蛋白一起调节纤维蛋白的产生、纤维蛋白的组装， 因子XIII的活化（Aim 2）。 我们也希望研究先天性的 与血栓栓塞或出血相关的纤维蛋白原异常 疾病（目的3），因为结构和功能分析， 异常纤维蛋白原血症将导致更好地了解功能性 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分支和交联的几个发现， 以及凝血酶与纤维蛋白的结合和相互作用， 这些问题的实验策略。 我们将采用各种 方法包括生物化学、免疫学、生物物理学、电子 显微镜和分子生物学技术。 即将提供资料 这些调查将有助于更全面地了解 了解凝血酶的正常生理功能，因子 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.