Type I interleukin-1 receptor (IL-1R1) is the functional receptor for IL-1. IL-1 mediates numerous activities in the neuroendocrine, nervous, and immune systems. The transcriptional regulation of IL-1R1 is poorly understood. Current work in our lab has identified three promoters that control the transcription of IL-1R1 in mouse. The activities of these IL-1R1 promoters are tissue-specific, cell type-specific and dependent on developmental stages. In addition, these promoters are found to be regulated by exogenous as well as endogenous genetic regulatory elements. In vivo, the activities of the three murine IL-1R1 promoters showed distinct distribution patterns. Further, these IL-1R1 promoters are differentially regulated by signaling molecules, such as glucocorticoids. A species comparison study between murine and human IL-1R1 structures has been conducted. Aligning the resulting human and murine IL-1R1 promoter regions revealed a conserved framework by which IL-1R1 gene in both species are likely to be regulated by conserved regulatory sequences. These preliminary discoveries lead us to define a genetic region termed IL-1R1 promoter complex. The central hypotheses of this application are: 1) the level and type of IL-1R1 mRNAs expressed in a given cell are regulated by the IL-1R1 promoter complex; 2) the transcriptional control mechanisms in the IL-1R1 promoter complex determine the tissue- and cell type-specific expression of IL-1R1; and 3) IL-1R1 promoter complex contributes to the precise response characteristics of IL-1R1-bearing cells when they are stimulated by signaling molecules. We will pursue the following specific aims: 1) Determine the pattern of distribution of the promoter-specific IL-1R1 expression; 2) Elucidate transcriptional control mechanisms of the IL-1R1 promoter complex; and 3) Investigate promoter activity of IL-1R1 gene in selected cell types after the cells are stimulated by different signaling molecules. The results will reveal the transcriptional mechanisms that allow tissue-specific and cell type-specific expression and regulation of IL-1R1 that may be critical for the vast diversity of IL-1R1 function in multiple systems. This study will contribute significantly to IL-1R1 biology and provide a new foundation for our understanding of how IL-1R1 transcription might be involved in pathogenesis. for """"""""IL-1R1 promoter complex in the neuroendocrine, nervous, and immune system"""""""" This study investigates the transcriptional mechanisms that control the expression of the type 1 interleukin-1 receptor. This receptor is important for many functions in the nervous, neuroendocrine, and immune systems. The results will provide a foundation for the understanding of how dysregulation of the expression of type 1 interleukin-1 receptor may be involved in the pathogenesis of diseases in multiple systems. ? ? ?
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