The overall goal of this project is to learn more about the biosynthesis, pharmacology, mechanism of action and degradation of allergic mediators. Particular attention will be given to the 5-lipoxygenase products, leukotrienes, B, C, D and E, and 5-HETE because of their already demonstrated potency as spasmogenic agents or modulators of leukocyte function. Considerable emphasis will be given to the continuation of ongoing studies with the initial enzyme in leukotriene synthesis, the 5-lipoxygenase. The 5-lipoxygenases in RBL-1 cells, normal leukocytes and mast cells will be characterized in regard to their molecular structures, mechanism of activation, biosynthesis and degradation, subcellular distribution, immunochemical reactivity, susceptibility to pharmacologic inhibition, substrate specificity and mechanism of triggering in intact cells. Eventually we hope to determine whether there are abnormalities of this enzyme that contribute to human disease. Studies will also be directed toward an improved understanding of the mechanism of action of the leukotrienes both by defining the specific receptors through which they affect cellular function and by attempting to determine their biochemical mechanism of action. Similar studies are planned with the monohydroxyeicosatetraenoates. Other efforts will be directed toward improved methods for quantitation of the leukotrienes and their metabolites which may permit comparative studies of their production in allergic and non allergic individuals. Other active areas of research in our laboratory are concerned with IgE receptors and control of lymphocyte responsiveness through newly acquired cell surface proteins and soluble mediators such as T cell growth factor.
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