REGULATION OF TRYPTASE EXPRESSION IN MAST CELLS

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Mouse mast cells (MC) express three homologous tryptases (designated mMCP-6, mMCP-7, and mMCP-11), whose genes are clustered on chromosome 17. mMCP-6 and mMCP-7 work in concert to differentially regulated the extravasation of neutrophils and eosinophils into inflammatory sites. mMCP also plays an important role in the regulation of clot formation and fibrinogen/integrin-dependent cellular responses in tissue during MC-mediated inflammatory reactions. Because of their importance in innate and adaptive immunity, MC tryptases are regulated at a number of levels. Nevertheless, transcriptional and post-transcriptional mechanisms appear to be the major ways MC control which tryptases they express. The recent identification of cells that contain substantial amounts of tryptase in the blood of patients with allergy and asthma indicates the urgent need contain substantial amounts of tryptase in the blood of patients with allergy and asthma indicates the urgent need to understand how these proteases are regulated in normal and pathologic circumstances. Thus, the long-term objective of Project 1 is to understand the molecular level how MC control the steady-state levels of the transcripts that encode homologous, but functionally distinct, tryptases. The goal of Specific Aim 1 is to elucidate why the tryptase genes are clustered genes are clustered on chromosome 17. In these studies, the role of gene methylation and histone activation in tryptase expression will be evaluated. The goal of Specific Aim 2 is to determine how transcription of the three tryptase genes is differentially regulated. In these studies, the cis-acting elements and trans-acting factors that regulate the transcription of each gene will be identified. Whether or not a locus a control element regulates of the cultured genes will be determined. The goal of Specific Aim 3 is to understand the two very different post-transcription mechanisms the MC uses to control. the steady-state levels of functional and non-functional transcripts in cells. In these studies, the cis-acting elements in the three tryptase transcripts and the trans-acting RNA-binding proteins in the MC that work together to control the stability of each tryptase transcript will be identified.