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

基本信息

批准号：
10224822
负责人：
Ryan Comfort Branski
金额：
$ 63.07万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10224822
关键词：
Acute Address Aerodigestive Tract American Anti-Inflammatory Agents 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 System Diseases Immunomodulators 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 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 wound healing

项目摘要

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疾病的潜在病因，其普遍性源于对损伤的修复反应失调，最终导致失调减少和再生性愈合结果的关键生化开关是糖皮质激素（GC）的理想干预目标。这是一种理想的治疗方法，因为它们针对的是损伤后的多种异常过程，包括炎症、新生基质沉积、上皮完整性。然而，尽管 GC 在喉科中普遍使用，但医生仍然认为它是一种理想的治疗方法。我们对糖皮质激素的差异特征知之甚少，临床结果也存在差异，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差距，我们建议特别强调糖皮质激素受体（GR）的作用。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 GR 的复杂性。最后，考虑到异常的屏障功能与疾病过程有关，我们将研究 GC 对 VF 上皮结构和功能的影响。整个生命周期中声音障碍的发生率尚不清楚，但据统计，该数字高于经常引用的人口数字 3-9%。