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

摘要 纤维化作为许多发声障碍的潜在病因的普遍性源于对损伤的失调的修复反应。关键的生化开关最终导致减少失调和更具再生性的愈合结果，是干预的理想目标。我们假设糖皮质激素(GC)是一种理想的治疗方法，因为它们针对损伤后的多种异常过程，包括炎症、新基质沉积、上皮完整性。然而，尽管GC在喉科中普遍使用，但从业者对不同GC的差异特征知之甚少，临床结果也是多种多样的，这可能是由于我们对糖皮质激素生物学的理解存在根本差距。我们试图通过特别强调糖皮质激素受体(GR)的作用来解决这一空白。我们建议研究不同GC的GR磷酸化位点，为临床应用提供理论基础。此外，我们最近在体外发现转化生长因子-β对GR的磷酸化反应；这些数据不仅说明了纤维化的复杂性，而且说明了GR在纤维化背景下的治疗操作的相关性。最后，鉴于异常屏障功能在疾病过程中的影响，我们将研究GCs对VF上皮结构和功能的影响。这项调查是密切相关的；关于一生中嗓音障碍发病率的估计尚不清楚，但假设高于经常引用的人口数字的3%-9%。

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.