The long term objective of the proposed study is to obtain an improved understanding of blood coagulation mechanisms and to develop new approaches to anticoagulant and thrombolytic therapy. Functionally important domains in fibrinogen will be identified by determining the structural defects in seven dysfibrinogens. A systematic and general technique, comparative peptide mapping by high-performance liquid chromatography, will be used to locate these structural defects. As each molecular defect is identified,, peptides corresponding to and monoclonal antibodies directed against newly identified functional domains will be used as probes to study the fibrinogen- to-fibrin conversion. In addition, the fibrin(ogen) binding sites of monoclonal antibodies which inhibit coagulation (supplied by consultant B. Kudryk) will be determined. Emphasis will be placed on correlating structure with function. The information derived from these studies will provide a rational basis for (1) design of peptide anticoagulants, (ii) design of targeted thrombolytic agents, and (iii) an improved methodology for determining the structural defects in other dysfibrinogens or mutant proteins.
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