Determining the mechanisms by which a circular RNA regulates the function of Th17 cells

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PROJECT SUMMARY/ABSTRACT There is no cure for autoimmune diseases, which affect more than 23 million Americans. IL-17-producing T helper cells (Th17 cells) play a major role in the pathogenesis of autoimmune diseases. Investigating regulatory mechanisms for Th17 differentiation and function will provide new opportunities for therapeutics. Circular RNAs (circRNAs), whose functions are previously underestimated, have great potential in various cellular activities from different types of cells. However, the role of circRNAs in Th17 cells is poorly understood. Herein, a circRNA produced from the precursor mRNA for Usp3 (circUsp3) was found to be essential for Th17 cell function. Our long-term goal is to develop therapeutically useful Th17 inhibitors for the clinical treatment of human autoimmune diseases. Our overall objectives in this application are to elucidate the molecular mechanisms by which circUsp3 provokes Th17 functions. The central hypothesis is that circUsp3 elevates Th17 differentiation in vitro and promotes Th17-mediated autoimmunity in vivo through forming complex with RORγt. The rationale for this project is that determination of the essential roles of circUsp3 in Th17 function is likely to provide proof- of-concept that circRNA can be targeted to therapeutically treat autoimmune diseases. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the requirement of circUsp3-RORγt complex in Th17 function; and 2) Determine the mechanisms by which circUsp3 activates RORγt-mediated transcription. Upon conclusion, we will understand the role for circUsp3 in Th17 function. These results are expected to have an important positive impact because they will provide a strong evidence base of critical roles of previously unrecognized circRNA-based regulatory mechanisms for Th17 function, ultimately providing opportunities for the development of novel therapies to treat autoimmune diseases. The proposed research is innovative because we investigate the effect of a circular RNA in Th17 function, a heretofore-unexamined process. Since circRNAs are broadly expressed in immune cells, this study will open a new era for exploring regulatory mechanisms of immune responses.