Molecular mechanisms underlying optimal glucocorticoid therapy for vocal fold disease

点击翻译按钮获取中文摘要

PROJECT SUMMARY The goal of this proposal is to determine the type of glucocorticoids (GCs) that fosters the appropriate balance of anti-inflammatory and fibrotic gene expression in pre-clinical models of vocal fold injury to improve outcomes of GC therapy. GCs are used by otolaryngologists in office-based procedures to treat vocal fold disease to reduce inflammation and promote effective wound healing, yet the optimal GC treatment regimen isn’t known. Ideal GC therapy for laryngeal disease would not only suppress inflammation but would also induce fibroblasts to promote laryngeal healing without excessive fibrosis that leads to scaring, vocal impairment, and poor outcomes. Our preliminary studies demonstrate that in vocal fold fibroblasts there are significant differences in the GC type and concentration required to activate pro-fibrotic genes and repress pro-inflammatory genes by GR. We hypothesize that such variability in gene expression among the three different clinically used GCs is likely to reflect divergent GR DNA binding capacity and/or interactions with co-regulator molecules (e.g. transcriptional co-activators and co-repressor). We further propose that understanding the type of GC that fosters the correct balance of anti-inflammatory and fibrotic gene expression in pre-clinical models of vocal fold injury will improve outcomes of GC therapy. To test these hypotheses we will determine the effects of three commonly employed GCs on GR-dependent gene expression, GR chromatin occupancy, and GR chromatin-associated proteins in vocal fold fibroblasts, and evaluate the mechanisms underlying GC therapy following iatrogenic injury in vivo. Successful completion of the aims will provide the pre-clinical foundation for optimized GC therapy among clinically common GCs.