This research program focuses on the cell biology of inflammation and the roles of mononuclear leukocytes in inflammatory processes. Studies are proposed in three major areas: 1) Structure and function of macrophage plasma membranes with particular reference to mechanisms of phagocytosis and pinocytosis. We will compare the protein composition of the segment of macrophage membrane in contact with a ligand (IgG, complement or mannose-rich oligosaccharide) coated target vs membrane that is not in contact with such a target. To determine whether ligand binding alters membrane """"""""fluidity"""""""" we will examine the mobility of membrane proteins in these two domains. Studies are planned of the effects of Fc receptor ligation on Fc receptor synthesis and distribution within various intracellular and surface membrane compartments of macrophages. ATP in the extracellular fluid causes membrane depolarization and inhibition of phagocytosis, presumably by affecting the function of the cells' ecto-ATPase. We will study the possibility that this ATPase is an ATP driven ion pump. 2) Mechanisms of tumor immunity. We have found that coinjection of activated macrophages with B16 melanoma cells in syngeneic C57BL/6 mice does not inhibit tumorigenesis if the mice were pretreated with antithymocyte serum. Tumor formation occurs even though this melanoma induces a more profound mononuclear leukocyte response in antithymocyte-serum treated mice than in normal mice. Several lines of evidence suggest that natural killer cell-macrophage cooperation is required to eradicate this tumor. Studies are proposed to test this hypothesis and to identify the specific types of mononuclear leukocytes that are responsible for tumor rejection. The mechanisms by which mononuclear phagocytes recognize and kill tumor cells also will be studied. 3) Structure of the vascular endothelium and the mechanism of leukocyte emigration. We have developed a """"""""model"""""""" vessel wall composed of bovine endothelial cells cultured on human amnion. The endothelial cell layer is """"""""tight"""""""" to macromolecular tracers. We have begun studies of the mechanism by which polymorphonuclear leukocytes open the junctions between these endothelial cells. Studies also are proposed to search for endothelial cell membrane proteins that are specific for different segments of the vasculature (artery vs vein vs capillary) and to identify the proteins that are responsible for intercellular junction formation.
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