Multiple mechanisms underlying GR-mediated therapies for fibroplasia of the vocal folds

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ABSTRACT The universality of fibrosis as an underlying etiology for many voice disorders stems from a dysregulated reparative response to injury. Key biochemical switches that ultimately lead to decreased dysregulation and a more regenerative healing outcome are ideal targets for intervention. We hypothesize that glucocorticoids (GC) are an ideal treatment as they target multiple aberrant processes following injury including inflammation, neomatrix deposition, epithelial integrity. However, despite the ubiquitous use of GCs in laryngology, practitioners have little insight into the differential characteristics of across GCs and clinical outcomes are variable, likely due to fundamental gaps in our understanding of glucocorticoid biology. We seek to address this void with particular emphasis on the role of the glucocorticoid receptor (GR). We propose to investigate differential GR phosphorylation sites across GCs to provide rationale for clinical utility. Additionally, we recently found GR phosphorylation in response to Transforming Growth Factor (TGF)-β in vitro; these data speak not only to the complexity of fibrosis, but the relevance of therapeutic manipulation of GR in the context of fibrosis. Finally, given that aberrant barrier function is implicated across diseases processes, we will investigate the effects of GCs on VF epithelial structure and function. This investigation is germane; estimates regarding the incidence of voice disorders across the lifespan are not known, but are hypothesized to be higher than the 3-9% of the population figure that is often cited.