This application proposes to examine the cellular biology of thrombospondin (TSP), a platelet alpha granule protein with lectin-like properties. Several approaches will be employed to study the role of this molecule in platelet aggregation, atherosclerosis, and organogenesis. The topographical relationships of TSP with other proteins critical to platelet aggregation will be studied using immunoelectronmicroscopy. The distribution of TSP, fibrinogen, von Willebrand factor (vWF), fibronectin, and platelet membrane glycoproteins IIb/IIIa and Ib will be followed in resting and in stimulated human platelets. The functional roles of TSP in platelet aggregation, particularly with respect to the other alpha granule constituents, will be further explored in aggregation studies using antibodies to these proteins in an effort to dissect out important interactions. The recently described TSP-plasminogen-histidine rich glycoprotein interactions will be studied in radiolabeled ligand binding studies and immunoelectronmicroscopy on platelets. The roles of TSP and its interacting ligands in the pathogenesis of atherosclerosis will be characterized in animal as well as cell culture models. Thrombospondin's potentially broader role as a cell adhesion molecule of importance in development will be studied in animal models and in tissue culture. The knowledge gained from these studies will provide important insights into the cellular biology of thrombospondin, the molecular mechanisms of normal hemostasis, the roles of platelet aggregation, platelet-endothelial cell and platelet-smooth muscle cell interactions in the pathogenesis of atherosclerosis as well as a greater understanding of cell adhesion as it relates to organogenesis in development.
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