Our long term objective is to conduct both clinical and basic research on the pathophysiology of a variety of hemostatic and thrombotic disorders with emphasis on the thrombotic microangiopathy (TMA), such as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. We have identified and isolated two platelet agglutinating/aggregation proteins p37 (PAP p37) and p58 (PAP p58) out of the plasmas from two different patients with TTP, which are thought to cause the thrombotic lesions in the small vessels in some TTP patients.
The specific aims of this proposal include: 1) Further elucidation of the physicochemical properties of PAP p37 and p58 including the molecular weight, Stokes Radius, frictional ratio, sedimentation coefficient, isoelectric point, amino acid composition, carbohydrate, and lipid contents, N- terminal amino acid sequence of PAP p37 and p58 and the effect of proteases, glycosidases, and phospholidases on PAP p37 and p58; 2) Elucidation of the mechanism of platelet agglutination induced by PAP p37 and p58 including the effect of platelet inhibitors on PAP p37- or PAP p58-induced agglutination/aggregation, the binding properties of PAP p37 or p58 to platelets, the nature of platelet receptor for PAP p37 or p58, possible release reaction, phosphorylation and thromhoxane A2 synthesis associated with PAP p37 or p58 binding; 3) Study of the structure and function relationships of PAP p37 and p58 using monoclonal antibodies; 4) identification of the source of PAP p37 and p58; 5) Determination of the incidence of PAP p37 and p58 antigen in the TMA plasmas and the frequency of the general population possessing antibodies against PAP p37 and p58; and 6) purification and characterization of other platelet agglutinating/aggregating factors from TMA plasma if time permits. Through these studies, we shall be able to understand better the pathogenetic mechanism of thrombotic microangiopathy and other microcirculation disorders, to enhance our laboratory diagnostic skills, and hopefully, to improve our therapeutic maneuvers against this highly lethal disease and other thrombotic disorders.
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