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

• 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
• 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

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 本提案的目的是确定促进适当平衡的糖皮质激素（GC）类型 在声带损伤的临床前模型中抗炎和纤维化基因表达以改善结果 GC治疗。GC被耳鼻喉科医生用于基于办公室的程序来治疗声带疾病， 减少炎症和促进有效的伤口愈合，但最佳的GC治疗方案尚不清楚。 理想的喉疾病GC治疗不仅能抑制炎症，而且还能诱导成纤维细胞 促进喉部愈合，而不会过度纤维化，导致疤痕，发音障碍， 结果。 我们的初步研究表明，在声带成纤维细胞有显着差异，在GC GR激活促纤维化基因和抑制促炎基因所需的类型和浓度。 假设在三种不同的临床使用的GC中基因表达的这种变异性可能 反映了不同的GR DNA结合能力和/或与共调节分子（例如转录因子）的相互作用 共激活子和共阻遏子）。我们进一步建议，理解GC的类型， 在声带损伤的临床前模型中抗炎和纤维化基因表达的平衡将得到改善 GC治疗的结果。为了检验这些假设，我们将确定三种常用的 GCs对GR依赖性基因表达、GR染色质占有率和GR染色质相关蛋白的影响 声带成纤维细胞，并评估在体内医源性损伤后GC治疗的机制。 这些目标的成功完成将为优化GC治疗提供临床前基础， 临床常见GC