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.
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