My interest is in oxygen-dependent and independent mechanisms participating in phagocytosis. Appropriately stimulated phagocytes release oxygen radicals and antimicrobial agents to combat invading microorganisms. Different transduction pathways propagate signals arriving at the cell membrane to mediate assembly of the superoxide-generating NADPH oxidase and secretion of phagocyte granules constituents. The active NADPH oxidase consists of the heterodimeric, membrane-bound cytochrome b558 and of three cytosolic subunits: p67-phox, p47-phox and a small G protein, Rac2. Radicals generated by the enzymatic complex as well as components of the cytoplasmic granules are vital for the host defense, but may inflict serious injury on body tissues. This dual action of the activated phagocyte explains the necessity for a careful regulation of its activation. Our laboratory engages in several aspects of the process:
- Signal transduction elements involved in activation/assembly of the NADPH oxidase: The participation of calcium ions, protein kinases, phospholipases as well as modulation of the process by exogenous synthetic peptides or analogs are being investigated.
- Regulation of activity/activation by endogenous proteins: Proteinase 3 is a serine protease localized to cytoplasmic granules of neutrophils. It is the main autoantigen in the autoimmune disorder Wegener Granulomatosis . The enzyme has been identified on membranes of neutrophils . In patiens of Wegener Granulomatosis PR3 has been implicated in overproduction of oxygen radicals. We are studying the effects of Proteinase 3 on the NADPH oxidase activity in cells of healthy individuals.