The long-term objectives are to understand the early signal transduction and second messenger systems which control neutrophil responses (e.g., secretion, chemotaxis), with particular emphasis on protein kinase C activating/inhibiting factors and lipid-derived mediators including diacylglycerol (DAG), sphingosine, and alkyl, acylglycerol (EAG). Information and new methodologies deriving from these studies are expected to be widely applicable to a variety of systems, including oncogene-related pathways wherein protein kinase C and associated pathways are perturbed and may participate in cancer development. These studies will also provide important fundamental information relating to altered neutrophil function in AIDS and Localized Juvenile Periodontitis, and pathological roles for neutrophils in such conditions as Reperfusion Injury, as, for example, following a myocardial infarction. Studies investigating neutrophil priming using Granulocyte/Monocyte Colony Stimulating Factor (GM-CSF) are expected to be directly relevant to understanding how this factor corrects the defect in neutrophils from AIDS patients. Studies will focus on the regulation of lipid metabolic pathways which participate in the generation of bioactive lipid mediators, their perturbation in LJP, and their modulation by priming factors and cyclic AMP. Techniques which will be used include analysis of diglyceride molecular species (chemical derivatization and HPLC), analysis of phospholipid headgroup release (mass and radiochemical analyses), protein phosphorylation (autoradiography), lipid mediator analysis (radiochemical methods) and a variety of other biochemical analytical methods.
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