Regulation of TH17 cell development and function by the REV-ERBs

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DESCRIPTION (provided by applicant): TH17 cells have been demonstrated to play a significant role in the pathology of several autoimmune diseases. Elegant genetic studies have established that TH17 cell development and function require both the nuclear receptors (NRs) RORα and RORγt. Nevertheless, the mechanisms underlying the generation and maintenance of TH17 cells are still poorly understood, thus making the development of therapeutics targeting TH17 cells challenging. While accumulating evidence suggests complex transcriptional networks dictate TH17 cell development, a more comprehensive understanding is needed to better understand TH17 cell biology and identify novel therapeutic targets for the treatment of TH17-mediated autoimmune diseases. The REV-ERBs (REV-ERBα and REV-ERBß), two other members of the NR superfamily, are often co-expressed in the same tissues as the RORs and bind the same DNA response elements, which suggest mutual cross talk and co- regulation of their target genes. The REV-ERBs regulate a number of physiological processes and are best known for their roles in the circadian rhythm and metabolic processes. While much is known about the roles for ROR regulation of TH17 cell development and function, the biology of the REV-ERBs in this process is completely unexplored. Our preliminary studies indicate that the REV-ERBs have distinct roles in the regulation of TH17 cell development. Overexpression of the REV-ERBs inhibits TH17 cell development and genetic deletion of REV-ERBα increases IL-17A expression. In contrast, REV-ERBß deficiency decreases IL- 17A expression. Using novel REV-ERB-specific synthetic ligands that we have developed, we demonstrate that pharmacological modulation of REV-ERB activity inhibits TH17 cell development and function both in vitro and in vivo. Based on our data, we hypothesize that the REV-ERBS are key regulators of TH17 cell development and function and REV-ERB-specific synthetic ligands may provide novel therapeutics for the treatment of TH17-mediated autoimmune diseases. To test our hypothesis we propose to 1) Identify the unique and specific roles for each REV-ERB in the transcriptional regulation of TH17 cell development in vitro; 2) Demonstrate that the REV-ERBs are critical regulators of TH17 cell development and autoimmune disease progression in vivo; 3) Establish whether select pharmacological modulation of REV-ERB activity affects TH17 cell development and disease course in mouse models of multiple sclerosis. Successful completion of these studies will uncover a critical role for the REV-ERBs in TH17 cell biology and reveal the REV-ERBs as novel targets for the development of therapeutics to treat TH17-mediated autoimmune diseases.