REGULATION OF CHANGES IN GENE EXPRESSION WITH ACTIVATION OF PMNS

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An extensive study of mRNA expression in human neutrophils has revealed a complex and non-synchronous pattern of changes in mRNA levels over the first few hours following exposure of the cells to non-pathogenic bacteria. This pattern consists partly of changes common to activation in a number of cell types and partly of changes not previously noted in other cells and/or specific to neutrophil activation. It is not reproduced by treatment of the cells with LPS ro any of several cytokines. In the present application we propose to complete characterization of changes in mRNA patterns during maturation and activation of murine neutrophils, and of in- vitro cellular models for these events. Analysis of the time course of expression of hundreds of mRNA whose level change during neutrophil development or activation has led us to focus on developmental changes in enzymes mediating calcium signaling, mechanisms for selective destabilization of certain mRNAs, and increased expression of two transcription factors and nuclear kinase. The time course, magnitude of changes in mRNA expression, and specific nature of the changes make these good candidates for processes that mediate the specificity of the activation process. We then propose to explore in detail the mechanisms and physiologic consequences of these processes.