The transcriptional control of genes involved in inflammation plays a critical role in host defense against pathogens, as well as in development of inflammatory diseases. At the chromatin level, the gene activity is governed largely by post-translational nuclear protein modifications, including the protein lysine acetylation. The lysine acetylation of histones or non-histone proteins controls transcription by assembly of structurally and functionally distinct transcription complexes. The complex assembly relies on acetyl lysine interaction with the specialized bromodomain (BRD) that are present in numerous nuclear proteins. The BRD containing proteins (BCP) have recently emerged as promising targets for the development of specific interaction inhibitors, enabling a novel exiting strategy for the development of new therapies, including treatment of inflammation. This proposal addresses previously unknown role the BCP involvement in negative regulation of inflammation. We have identified a subfamily of anti-inflammatory BCP (aiBCP) that suppresses inflammatory gene expression in macrophages. In this proposal, we will address the mechanism of the aiBCP involvement in inflammatory gene regulation and aiBCP contribution to modulation of inflammatory processes in vivo. Our studies of the role of BRD in aiBCP function will facilitate development of novel immunomodulatory approaches that will target selectively BRD.
We propose to address the mechanism and physiological significance of the novel negative regulators of the inflammatory gene expression. We found that members of the structurally-related subfamily of the bromodomain containing proteins (BCP) suppress inflammatory gene expression in activated macrophages. Using in vitro and in vivo genetic approaches, as well as the chromatin and transcriptional analysis, we will identify the mechanism of the anti-inflammatory BCP (aiBCP) function and will address the significance of these proteins in inflammation in vivo. The proposed program will provide a fundamentally novel insight into transcriptional control of inflammation and will suggest novel approaches for the pharmacological control of inflammation by targeting the aiBCP.
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