Broad Objectives: Determination of structure-function relationships in human fibrinogen using genetically determined variants as probes.
Specific aims : Identification of the mutations within the primary structures of the variants of human fibrinogen. Evaluation of the influence of the structural abnormalities on the properties of fibrinogen. Prediction of the localization of functional sites in fibrinogen. Experimental Design and Methods: A large number of families with dysfunctional fibrinogen have detected all over the world, and many of their blood samples are available to me for analysis. Fibrinogens will be isolated and the structural abnormalities will be identified by high-performance liquid chromatography-based fingerprinting followed by amino acid sequence analysis of relevant fragments. The influence on the functional properties will be tested by comparing abnormal and normal fibrinogen as regards fibrinopeptide release, coagulation, crosslinking, plasmic degradability, thrombin binding, plasminogen binding, plasminogen activator binding, support of plasminogen activation, platelet binding, support of platelet aggregation, fibroblast interaction and endothelial cell interaction. All methods needed are in principle already available. Health Relatedness: Fibrinogen is a central protein in the blood coagulation system, and the present work is directed towards an understanding of the role of fibrinogen in thrombotic cardiovascular disease and bleeding disorders. The correlation between the structural-functional properties of the isolated abnormal fibrinogen variants and clinical observations in the respective families will be analyzed.
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