Molecular mechanisms underlying optimal glucocorticoid therapy for vocal fold disease

声带疾病最佳糖皮质激素治疗的分子机制

基本信息

批准号：
10647027
负责人：
Ryan Comfort Branski
金额：
$ 25.43万
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：
2023
资助国家：
美国
起止时间：
2023-05-11 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10647027
关键词：
Affect American Anti-Inflammatory Agents Anxiety Asthma Binding Cells ChIP-seq Chromatin Chronic Obstructive Pulmonary Disease Cicatrix Clinical Clinical Management Communication impairment DNA Binding Data Dependence Development Dexamethasone Disease Dose Effectiveness Equilibrium Event Fibroblasts Fibrosis Fostering Foundations Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Genomics Glucocorticoid Receptor Glucocorticoids Goals Half-Life Health Care Costs Heterogeneity Histones Human Impairment In Vitro Income Individual Inflammation Inflammatory Inflammatory Response Injections Injury Investigation Laboratories Laryngeal Diseases Laryngeal Injury Larynx Lesion Mass Spectrum Analysis Mediating Mental Depression Methylprednisolone Molecular Occupational Otolaryngologist Outcome Pathway interactions Patients Pharmaceutical Preparations Population Pre-Clinical Model Procedures Property Proteins Publishing Rattus Reporting Repression Site Small Interfering RNA Steroids Testing Therapeutic Transcription Coactivator Transcriptional Regulation Treatment Protocols Triamcinolone Acetonide Voice Voice Disorders Work cell type chromatin immunoprecipitation chromatin protein clinical investigation clinically relevant cofactor disability experience experimental study gene repression genetic corepressor genome-wide healing iatrogenic injury improved outcome in vivo injured innovation insight pharmacologic pre-clinical preference public health priorities receptor binding recruit regenerative response single-cell RNA sequencing social transcription factor transcriptome sequencing treatment optimization vocal cord wound healing

项目摘要

PROJECT SUMMARY The goal of this proposal is to determine the type of glucocorticoids (GCs) that fosters the appropriate balance of anti-inflammatory and fibrotic gene expression in pre-clinical models of vocal fold injury to improve outcomes of GC therapy. GCs are used by otolaryngologists in office-based procedures to treat vocal fold disease to reduce inflammation and promote effective wound healing, yet the optimal GC treatment regimen isn’t known. Ideal GC therapy for laryngeal disease would not only suppress inflammation but would also induce fibroblasts to promote laryngeal healing without excessive fibrosis that leads to scaring, vocal impairment, and poor outcomes. Our preliminary studies demonstrate that in vocal fold fibroblasts there are significant differences in the GC type and concentration required to activate pro-fibrotic genes and repress pro-inflammatory genes by GR. We hypothesize that such variability in gene expression among the three different clinically used GCs is likely to reflect divergent GR DNA binding capacity and/or interactions with co-regulator molecules (e.g. transcriptional co-activators and co-repressor). We further propose that understanding the type of GC that fosters the correct balance of anti-inflammatory and fibrotic gene expression in pre-clinical models of vocal fold injury will improve outcomes of GC therapy. To test these hypotheses we will determine the effects of three commonly employed GCs on GR-dependent gene expression, GR chromatin occupancy, and GR chromatin-associated proteins in vocal fold fibroblasts, and evaluate the mechanisms underlying GC therapy following iatrogenic injury in vivo. Successful completion of the aims will provide the pre-clinical foundation for optimized GC therapy among clinically common GCs.

项目概要该提案的目标是确定促进适当平衡的糖皮质激素 (GC) 类型声带损伤临床前模型中的抗炎和纤维化基因表达以改善结果 GC 疗法被耳鼻喉科医师用于治疗声带疾病。减少炎症并促进伤口有效愈合，但 GC 治疗方案尚不清楚。理想的 GC 治疗喉疾病不仅可以抑制炎症，还可以诱导成纤维细胞促进喉部愈合，而不会导致过度纤维化，从而导致疤痕、声音障碍和不良症状结果。我们的初步研究表明，在声带成纤维细胞中，GC 存在显着差异类型并需要通过 GR 激活促纤维化基因并抑制促炎基因。表明三种不同临床使用的 GC 之间基因表达的这种变异性可能是反映不同的 GR DNA 结合能力和/或与共调节分子的相互作用（例如转录我们进一步建议了解促进正确的 GC 类型。声带损伤临床前模型中抗炎和纤维化基因表达的平衡将得到改善为了检验这些假设，我们将确定三种常用疗法的效果。 GC 对 GR 依赖性基因表达、GR 染色质占据和 GR 染色质蛋白的影响声带成纤维细胞，并评估体内医源性损伤后 GC 治疗的机制。目标的成功完成将为优化GC治疗提供临床前基础临床上常见的GC。