Mechanistic studies of a long noncoding RNA in macrophage-mediated inflammatory responses

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PROJECT SUMMARY The goal of this study is to understand how a pseudogene-derived long noncoding RNA named Bambi-ps1 regulates macrophage-mediated inflammatory responses. Macrophages, a vital type of innate immune cell, play critical roles in detecting danger signals and mounting proper inflammatory responses. Many gene products from these immune responses, such as TNF, however, are also toxic to healthy tissues. Thus, multiple regulatory circuits precisely control the expression of these inflammatory genes to maintain a delicate balance between managing infection/injury and damaging healthy tissues. Critically, malfunction of these regulatory events can result in many acute and chronic diseases, such as sepsis and autoimmune disorders (e.g., rheumatoid arthritis), etc. Thus, characterizing regulatory programs in macrophage-mediated inflammatory responses will both reveal fundamental mechanisms of gene expression and provide insights into the pathogenesis of many immunological disorders. Recent studies revealed a novel layer of regulation of inflammatory responses mediated by long noncoding RNAs, which are longer than 200 nucleotides and do not have functional protein-coding capacity. These RNAs can regulate gene expression via diverse mechanisms. We identified a bona fide lncRNA, Bambi-ps1, which is abundantly and specifically expressed in activated macrophages during inflammatory responses. Moreover, our preliminary data indicated that Bambi-ps1 is required for proper inflammatory responses both in vivo and in vitro. In this explorative study, we plan to decipher the molecular mechanisms of Bambi-ps1-mediated regulation of gene expression in macrophages. The results will not only reveal novel regulatory mechanisms of gene expression in macrophage-mediated inflammatory responses but also may potentially result in new therapeutic targets for innate immune disorders, such as sepsis.