Activation of Early Inflammatory Genes

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DESCRIPTION: (Provided by applicant): The long-term goal of our studies is to understand the role of interferon regulatory factors (IRF') in the early inflammatory response and innate immunity. Over the past several years we have sequentially identified and characterized two novel transcription factors, IRF-3 and IRF-7. Recent advances from many laboratories, including ours, have revealed a critical role of these two factors in virus-mediated signaling and expression of the interferon (IFN) genes in infected cells. In my laboratory we have focused on the role of IRF-7 in the stimulation of IFN genes and, to my knowledge, IRF-7 is the only transcription factor that can reconstitute expression of IFNA genes in non-producing cells. This suggests that regulation of IRF-7 expression plays critical role in innate immunity. The silencing of IRF-7 expression by hypermethylation observed in immortalized cancer cell lines suggests the IIRF-7 function may extend beyond infected cell. The key objective of this application is to extend our hypothesis that IRF-7 has a key role in the expression of IFNA genes and that its interaction with other members of IRF family affects chromatin structure around the. FNA locus and transcription activation of IFNA genes. Thus, the regulation of IRF-7 expression plays a critical role in innate immunity. The proposed study should not only contribute to basic understanding how the virus activates expression of cellular genes but also offer new strategy for the treatment of inflammatory disease by specific modulation of transcription control. The study has three Aims: Aim #1. Investigate DNA binding specificity of IRF-7 in vivo, its interaction with other members of IRF family and how the interaction between IRF-7 and other IRFs affects the levels and specificity IFNA genes expression. Aim #2. Investigate how the virus-induced remodeling of chromatin structure around IFNA loci relates to IFNA gene expression. Aim #3. Examine the mechanism by which the activity of IRF-7 promoter is regulated.