SUMMARY
The goal of our studies is to understand RORa’s role in the transcriptional regulation of TH17 cell
pathogenicity and chronic inflammation. RORa is a member of the ligand-regulated nuclear receptor
(NR) superfamily of transcription factors. Significantly less is known about RORa in the transcriptional
regulation of TH17-mediated immunity. We and others recently published RORa is required for full
TH17-cell development, particularly in mouse models of chronic inflammation. Despite this evidence,
RORa is considered functionally redundant to ROR¿t, the lineage defining transcription factor of TH17
cells. As ligand-regulated transcription factors, NRs evolved to respond to endogenous small
molecules, translating these signals into changes in gene expression. Synthetic small molecules can
also be utilized to understand receptor function. Our data suggests that RORa/ligand-regulation may
protect from chronic inflammation, including colitis. Given the evidence that both intra- and extra-
cellular ligands regulate NR activity in TH17 cells, defining RORa and ligand mechanisms of action is
key to understanding signaling pathways underlying homeostasis vs. pathogenesis. Therefore,
understanding these processes may be essential to understand how RORa contributes to TH17 cells
and disease. Our overarching goals are to elucidate the mechanisms that regulate RORa’s
transcriptional activity and interacting partners, thus driving functionality in TH17 cells during
inflammatory processes. Understanding RORa’s transcriptional role in TH17 cells may reveal a novel
therapeutic option for the treatment of TH17-mediated chronic inflammatory disorders. We will achieve
our goals by: 1) establishing how RORa transcriptionally promotes and maintains pathogenic TH17-
mediated inflammation and 2) using pharmacological approaches to understand how ligands affect the
transcriptional activity of RORa in TH17 cells. Collectively, our studies will uncover important
transcriptional roles for RORa in TH17 cell biology and reveal whether targeting RORa may be
advantageous for the treatment of TH17-mediated chronic inflammation.
