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

摘要 纤维化作为许多嗓音疾病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再生愈合的结果是理想的干预目标。我们假设糖皮质激素（GC）是一种理想的治疗方法，因为它们靶向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在喉科中的普遍使用，从业者对GC的差异特征几乎没有深入了解，临床结果也是可变的，这可能是由于我们对糖皮质激素生物学的理解存在根本性的差距。我们试图解决这个空白，特别强调糖皮质激素受体（GR）的作用。我们建议研究不同的GR磷酸化位点在GC提供的临床实用性的理由。此外，我们最近在体外发现了对转化生长因子（TGF）-β的响应的GR磷酸化;这些数据不仅说明了纤维化的复杂性，而且还说明了在纤维化背景下GR治疗操作的相关性。最后，考虑到异常屏障功能涉及疾病过程，我们将研究GC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的发生率的估计尚不清楚，但据推测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.