Analytical, scanning, and transmission electron microscopy, freeze-etching, cyto-chemistry and immunocytochemistry (all basic techniques of structural physiology) will be combined with advanced biochemical methods and physiological approaches to develop new knowledge essential for understanding the role of platelets in hemostasis, in the pathogenesis of bleeding disorders due to defective platelets or reduced numbers of cells, in the development of vessel wall injury, thrombosis and atherosclerosis, and in host-defense. The multidisciplinary proposal is separated into seven closely linked project areas. Application of the principles of structural physiology developed in this laboratory will reveal basic relationships between normal platelet structure and function and defects in similar associations in abnormal platelets. Prostaglandin and cyclic nucleotide synthesis, adenine nucleotide and serotonin metabolism, calcium flux and contractile physiology will be studied in normal and abnormal platelets in vitro and in vivo to develop basic knowledge of regulatory mechanisms modulating platelet activation. The influence of platelets and products of platelet prostaglandin biosynthesis on the integrity of endothelial cells and subendothelial structures will be examined in vivo in several animal models. The role of platelets in host defense through their influence on functions of phagocytic cells will be evaluated in a new thrombocytopenic dog model and in vitro. Results of these studies will provide information essential for preventing and controlling hemorrhagic, thrombotic and vascular disease.