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.

项目摘要该建议的目的是确定促进适当平衡的糖皮质激素（GC）的类型在声带损伤的临床前模型中的抗炎和纤维化基因表达以改善预后 GC疗法。 Otryngologists使用GC在基于办公室的程序中使用，以治疗声带疾病减少炎症并促进有效的伤口愈合，但最佳的GC治疗方案尚不清楚。理想的喉病治疗不仅会抑制注射，还会诱导成纤维细胞促进喉部愈合而不过多的纤维化，从而导致恐惧，人声障碍和差结果。我们的初步研究表明，在声带褶皱成纤维细胞中，GC存在显着差异激活促纤维化基因并通过GR反映促炎基因所需的类型和浓度。我们假设三种不同临床使用的GC中基因表达的这种变异性可能很可能反映发散的GR DNA结合能力和/或与共同调节分子的相互作用（例如转录联合激活剂和共抑制剂）。我们进一步建议理解促进正确的GC的类型抗炎和纤维化基因表达在声带损伤的临床前模型中的平衡将改善 GC疗法的结果。为了检验这些假设，我们将确定三个常用的影响 GC在GR依赖性基因表达，GR染色质占用和与GR染色质相关蛋白中声带褶皱成纤维细胞，并评估体内医源性损伤后GC治疗的机制。成功完成目标将为临床前的基础提供优化的GC治疗临床上常见的GC。