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

GR 介导的声带纤维增生治疗的多种机制

• 批准号: 9763596
• 负责人: Ryan Comfort Branski
• 金额: $ 56.76万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-14 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763596
• 关键词: Acute; Address; Aerodigestive Tract; American; Anti-inflammatory; Benign; Binding; Biochemical; Biochemical Process; Biological Assay; Biology; Biomechanics; CRISPR/Cas technology; Cell Line; Cells; Characteristics; Chronic; Cicatrix; Clinical; Clinical Practice Patterns; Clinical Trials; Communication impairment; Complex; Consensus; Data; Deposition; Disease; Drug Kinetics; Dysphonia; Epithelial; Etiology; Expression Profiling; Fibroblasts; Fibrosis; Foundations; Gene Expression; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Health; Human; Iatrogenesis; Immune; Immune System Diseases; In Vitro; Incidence; Inflammation; Inflammatory; Injury; Innovative Therapy; Intervention; Investigation; Isotonic Exercise; Knock-in; Laboratories; Lead; Lesion; Literature; Location; Longevity; Mediating; Medicine; Modeling; Morphology; Mucous Membrane; Outcome; Pathology; Patients; Phenotype; Phosphorylation; Phosphorylation Site; Physiological; Population; Pre-Clinical Model; Process; Promoter Regions; Property; Proteins; Reporting; Resistance; Response Elements; Role; Serine; Signal Pathway; Signal Transduction; Signaling Protein; Site; Structure; Surface; Therapeutic; Tight Junctions; Tissues; Transforming Growth Factors; Treatment Efficacy; Voice Disorders; Wages; Wound Healing; base; cigarette smoke; clinical decision-making; cost; glucocorticoid receptor alpha; healing; immunoregulation; improved; in vivo; injured; injury and repair; innovation; insight; receptor function; regenerative; response; response to injury; stem; tissue repair; treatment duration; vocal cord

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.

抽象的 纤维化作为许多声音障碍的潜在病因的普遍性源于对损伤的修复反应失调。最终导致减少失调和更具再生性的愈合结果的关键生化开关是干预的理想目标。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，临床结果也各不相同，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。我们寻求解决这一空白，特别强调糖皮质激素受体（GR）的作用。我们建议研究 GC 中不同的 GR 磷酸化位点，为临床应用提供理论依据。此外，我们最近在体外发现了 GR 磷酸化对转化生长因子 (TGF)-β 的反应；这些数据不仅说明了纤维化的复杂性，还说明了 GR 在纤维化背景下的治疗操作的相关性。最后，鉴于屏障功能异常与疾病进程有关，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；关于整个生命周期中嗓音障碍发生率的估计尚不清楚，但推测该数字高于经常引用的人口数字 3-9%。