WHITE BLOOD CELL OXIDASE - NORMAL AND ABNORMAL
Funded Grant
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Phagocytic cells undergo both metabolic and structural changes when stimulated with either soluble or particulate stimuli. These changes, either spontaneously terminate after a short period of time, or can be made to cease with removal of the stimuli. The overall goal of the proposed investigations for the next five years are to gain a better understanding of the cellular and biochemical aspects, of both reversible and irreversible inactivation of the oxidase system responsible for killing bacteria, and for some of the destructive ability of phagocytic cells. We plan to determine the kinetics of inactivation of both the whole cell superoxide generating system and the particulate fraction - NADPH oxidase - in both the reversible and irreversible manner, and in the presence of various manipulations. These studies will be performed in granulocytes, moncytes and monocyte-derived macrophages. We plan to determine the cellular events that accompany both reversible and irreversible inactivations concentrating on changes in intracellular calcium, membrane potential an intracellular pH together with phosphatidyl inositol metabolism and protein phosphorylation. Finally, we plan to determine the molecular and biochemical events associated with inactivation of the oxidase activated in subcellular particles, the PMA stimulated protein kinase C dependent activity, and the arachidonic acid stimulated soluble factor dependent activity. In these studies we plan to determine the effects of protein kinase C, calmodulin modifiers, and GTP analogs on the inactivation process. By examining cellular and subcellular aspects of inactivation, we hope to gain a better understanding of the control of this important process.
