In the coming year, the Program focuses upon selected biochemical and cellular aspects of the hemostatic mechanism that are critically involved in initiating, or protecting against, thrombosis and atherosclerosis. Regulatory processes that result in the production of anticoagulantly active heparin like molecules by the endothelium as well as those governing the inhibition of Smooth Muscle Cell proliferation by antiproliferative heparin molecules synthesized by SMC's will be analyzed. The interaction between thrombin as well as prethrombin 2 with fibrinogen and fibrin monomer will be investigated. The regulation of platelet function will be studied with particular emphasis on the intercellular reactions between these elements with cytoplasmic ionized calcium, cyclic AMP, and products of arachidonic acid metabolism as well as that of other lipids. The interaction of platelets with fibrinogen and von Willebrand's factor will be investigated by analyzing structure-function relationships of the fibrinogen gamma/alpha chains as well as the platelet receptors for vWF. A full length cDNA clone of vWF has been obtained and the entire predicted amino acid sequence for vWF precursor and mature protein. During the coming year recombinant vWF will be expressed in eukaryotic and prokaryotic cells. In addition, the GpIb and collagen binding sites will be localized. The structure of thrombospondin will be analyzed at both the biological and biochemical levels with emphasis on peptide mapping, use of monoclonal antibodies, and macromolecular microscopy. Investigations of the hypercoagulable state in patients with congenital disorders such as antithrombin or protein C deficiency will be continued. The efficacy of predicting the occurence of thrombosis in patients with acquired disorders such as deep vain thrombosis will be initiated. A plethora of collaborative efforts will be undertaken by investigators on the program. Among these, are studies of the structure function relationships of vWF, interactions of hemostatic system proteins with fibrinogen/fibrin, binding of fibrinogen and vWF to platelet membrane receptors as well as to GpIb/GpIIIa heterodimers, the precise localization of heparin-like molecules on the surface of the microvasculature, etc.
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