REGULATION OF CHANGES IN GENE EXPRESSION WITH ACTIVATION OF PMNS

一项对人类中性粒细胞mRNA表达的广泛研究揭示了在细胞暴露于非致病菌后的最初几个小时内mRNA水平的复杂和非同步变化模式。这种模式部分由许多细胞类型的激活所共有的变化组成，部分由其他细胞和/或中性粒细胞激活所特有的变化组成。用LPS或几种细胞因子中的任何一种处理细胞都不能复制。在目前的应用中，我们建议完成小鼠中性粒细胞成熟和激活过程中mRNA模式变化的表征，以及这些事件的体外细胞模型。对中性粒细胞发育或激活过程中数百种mRNA表达水平变化的时间过程的分析，使我们关注介导钙信号的酶的发育变化，某些mRNA的选择性不稳定机制，以及两种转录因子和激酶的表达增加。mRNA表达变化的时间过程、幅度和变化的特异性使这些过程成为介导激活过程特异性的良好候选者。然后，我们建议详细探讨这些过程的机制和生理后果。

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.