Fibrin(ogen) Structure and Interactions

University Of Maryland Baltimore, Baltimore MD

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Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Fibrinogen (340 kDa) is a multifunctional plasma protein that after activation spontaneously polymerizes to form a fibrin gel. Fibrin prevents the loss of blood upon vascular injury and serves subsequently as a provisional matrix on which various cell types adhere, migrate and proliferate during wound healing and other physiological and pathological processes. The ability of fibrinogen to polymerize and degrade in a controllable fashion and to adhere to different cells makes it an ideal bioadhesive (fibrin sealant) that has been used increasingly in numerous surgical application for arrest of bleeding, gluing of tissues, delivery of bioactive substances, etc. Better understanding of the mechanisms underlying fibrin-dependent processes and more effective application of fibrin sealant require comprehensive knowledge of the structure and interactions of this complex molecule. Recent studies established a high resolution structure of about two-thirds of the molecule. The first aim of this application is to complete the high-resolution structure of the remaining regions and to further clarify conformational changes upon conversion of fibrinogen to fibrin. Our recent discoveries that fibrinogen alphaC-domains interact with high affinity with plasminogen, tPA and apo(a) suggest their involvement in fibrinolysis and atherogenesis. The second aim is to characterize these interactions and to clarify their role in regulation of these processes. Interactions of the other fibrin(ogen) regions, gamma-modules and the betaN-domains, with receptors on leukocytes and endothelial cells was shown to stimulate inflammation and angiogenesis. The third and fourth aims focus on further establishing the mechanisms of these interactions. These aims will be accomplished by preparation of various fibrin(ogen) domains and combinations thereof by limited proteolysis and recombinant techniques, and studying their structures and interactions by biochemical and biophysical methods. These studies will generate basic knowledge that will have an impact on the understanding of and ability to control the above mentioned fibrin(ogen)-dependent processes. They will also contribute to the development of improved fibrin sealants with desirable properties.