Fibrinogen is a multifunctional protein involved in a number of important physiological and pathological processes. The formation of a fabrin matrix at sites of tissue injury (or other places) prevents blood loss and provides a provisional stroma that interacts with different cell types to promote their deposition, migration and proliferation. Thus, besides its prominent function in hemostasis, fibrinogen is recognized as a cell adhesion molecule that plays an important role in inflammation, angiogenesis, wound healing, atherogenesis and tumorigenesis. Despite numerous studies, several basic problems important for a comprehensive understanding of its biological functions are still unresolved. This application deals with three such problems: (1) a high resolution structure, (2) the molecular mechanisms of conversions of fibrinogen to fibrin, and (3) the mechanisms of interactions of fabrin(ogen) with different cell types.
The first aim i s to establish the high resolution structure of the central E regions of fibrinogen and its alpha-C domains.
The second aim i s to elucidate the mechanisms of fibrinogen to fabrin conversions which is hypothesized to involve a switch from intra- to intermolecular binding between alpha-C domains as well as conformation changes in the D region that modulate activity of the secondary polymerization sites and expression of new interaction sites.
The third aim focuses on establishing the mechanisms of interaction of endothelial cells and leukocytes with fibrinogen and fibrin and identification of critical amino acid residues involved.
These aims will be accomplished by preparation of various fibrinogen domains and combinations there of 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 different fibrinogen-dependent processes. They will also have an important practical health-related application to the development of improved bioadhesives (fibrin glue) by the de novo design of fibrinogen with selected functions.
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