The major aim of this proposal is to elucidate the origin, composition and the enzymatic mechanisms involved in the generation of fibrinogen complexes. Covalent multimerization products of fibrin(ogen) are present in the circulating plasma, and in the vessel wall of patients with atherosclerosis and possibly with other vascular disorders. One of the major objectives of the proposal is to characterize these fibrinogen complexes which are formed by the cross-linking of the alpha and gamma chains, a reaction which is catalyzed by two different transglutaminases: Factor XIIIa or tissue transglutaminase. Identification of the sub-unit composition of these complexes will be done by separation of the materials, using an original electrophoretic system devised by the applicant, followed by immunostaining with antibodies specific for the alpha and gamma chains of fibrinogen. In some instances, the cross-linked products will be further analyzed using monoclonal antibodies against specific crosslinked regions and by amino acid sequencing.
A second aim of the proposal, consists in the characterization of the mechanisms involved in the removal of fibrin from the circulation. The applicant is proposing to characterize, biochemically and functionally, a fibrin receptor present in macrophages which seem to exhibit some of the biochemical properties of integrins.Isolation of the receptor will be done by affinity chromatography using fibrin or NDSK-fibrin. After isolation, the receptor will be characterized by amino acid sequencing, and with monoclonal antibodies.
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