Corticosteroids or glucocorticoids (GCs) are widely used to treat inflammatory airway diseases such as asthma. Despite their widespread use in the clinic, the molecular mechanisms underlying the therapeutic actions of GCs remain incompletely understood. Glucocorticoids mediate their actions by binding to the glucocorticoid receptor (GR) a nuclear receptor, which then translocates to the nucleus and regulates gene expression. Anti-inflammatory actions of GR have classically been attributed to GR binding to other transcription factors such as NF-KB and repressing their transcriptional activity while activation of gene expression by GR has been implicated in the side effects of GCs. Recent studies, however, have shown that GR can cooperate with NF-kB to activate gene expression. Indeed, our ChIP-Seq studies identified numerous genes that are regulated cooperatively by GR and NF-kB in the airway epithelium. In addition, some of these cooperatively activated genes have known anti-inflammatory actions that are glucocorticoid-independent. Based on this evidence, we hypothesize that GR and NF-kB cooperate to induce anti-inflammatory gene expression that contributes to therapeutic actions of GCs in airway epithelium. We will test our hypothesis by interrogating the mechanism of cooperation between GR and NF-kB to induce SERPINA3 and by elucidating the role of SERPINA3 in allergic airway inflammation.
Our specific aims are 1) Identify and define the role of key DNA sequence elements mediating GR and NF-kB cooperation at a putative SERPINA3 enhancer and 2) Determine if SERPINA3 suppresses allergic airway inflammation in vivo. Through these aims we expect to demonstrate that GR and NFkB cooperation represents a novel pathway underpinning the therapeutic actions of GCs in inflammatory airway diseases.
Corticosteroids or glucocorticoids (GCs) are widely used in the treatment of inflammatory airway diseases including asthma and COPD. Despite their widespread use in the clinic, the mechanisms by which GCs function as anti-inflammatory drugs are incompletely understood. It is essential to understand these mechanisms in order to reduce the deleterious side effects, improve the therapeutic efficacy and ultimately personalize the use of GCs in the treatment of various diseases. This work will shed light into the molecular mechanisms of GC function and potentially identify a novel drug target that could ultimately help the millions of Americans suffering from asthma and COPD.