Effect of vocal fold injury on laryngeal muscle dysfunction

声带损伤对喉肌功能障碍的影响

• 批准号: 10736684
• 负责人: Aaron Matthew Johnson
• 金额: $ 65.66万
• 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: 2023-07-10 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736684
• 关键词: Acoustics; Acute; Affect; American; Autocrine Communication; Benign; Big Data; Cells; Chronic; Chronic Laryngitis; Cicatrix; Classification; Clinical; Clinical Research; Coculture Techniques; Communication impairment; Complex; Data; Development; Diagnosis; Dysphonia; Etiology; Event; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Female; Fibroblasts; Foundations; Functional disorder; Future; Genes; Goals; Health; Histology; Homeostasis; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Injury; Intervention; Investigation; Laboratories; Lamina Propria; Laryngeal Mucosa; Laryngeal muscle structure; Larynx; Lead; Lesion; Life; Literature; Longevity; Macrophage; Methodology; Mission; Motivation; Motor; Mucous Membrane; Muscle; Muscle Tension; Muscle function; Myoblasts; Myosin Heavy Chains; National Institute on Deafness and Other Communication Disorders; Paracrine Communication; Pathology; Patient observation; Patients; Performance; Phenotype; Population; Process; Proteins; Proteomics; Public Health; Rattus; Reporting; Research; Rodent; Rodent Model; Signal Transduction; Skeletal Muscle; Structure; Therapeutic; Thinking; Thyroarytenoid Muscle; Time; Tissues; Trauma; Ultrasonics; United States National Institutes of Health; Up-Regulation; Voice; Voice Disorders; Wages; Work; cell type; cost; disability; economic cost; efficacious treatment; experience; experimental study; healing; improved; in vivo; injured; innovation; insight; male; medical specialties; neuromuscular; novel; pharmacologic; repaired; response; response to injury; screening; targeted treatment; treatment optimization; vocal cord; vocalization

ABSTRACT Voice disorders affect millions of Americans at substantive economic cost. Decisions regarding treatment are often primarily based on dichotomous thinking: mucosal injury versus muscle dysfunction. However, laryngeal muscle dysfunction often accompanies laryngeal mucosal pathologies and may be both causative and reactive. This proposal is an innovative combination of in vivo and in vitro methodologies to investigate the effect of both transient and persistent vocal fold mucosal injury on the underlying function, structure, and mechanistic response of the thyroarytenoid muscle, the primary muscle of the vocal fold. The long-term goal of this research is to provide mechanistic insight regarding the complex interactions between the mucosal and muscular vocal fold layers, thereby contributing to a shift in clinical schema and classification of voice disorders, but more importantly, lead to the development of novel, targeted therapeutic strategies for the millions of patients with voice-related disability. The central hypothesis of this work is injury to the vocal folds elicits complex interactions between the vocal fold mucosa and underlying muscle, which consequently results in altered laryngeal muscle structure and function. The proposed research has two specific aims. Aim 1 is to determine functional, structural, and mechanistic laryngeal muscle responses to vocal fold injury in an established in vivo rodent model. Two depths of vocal fold injuries, shallow injury of the mucosa only or deep injury of the mucosa and underlying muscle, will be created in male and female rats to determine the time course of vocal fold injury on a) muscle function via analysis of ultrasonic vocalization acoustic complexity, b) mechanistic response of the muscle via proteomic analysis, and c) changes in specific protein levels identified in the big-data proteomic interrogation. Injury depths will be confirmed via muscle histology. Aim 2 is to characterize and quantify signaling between fibroblasts and myoblasts as well as inflammatory cells from the vocal folds in vitro under basal and stimulated (e.g., injured) conditions. In vitro experimentation will examine the effects of fibrotic and inflammatory mediators on fibroblasts from the vocal fold lamina propria and myoblasts from intrinsic laryngeal muscle to interrogate unique interactions between the two cell types via co-culture and conditioned media experiments. These data will provide critical mechanistic and translational insight regarding the cycle of dysphonia and provide potential targets for pharmacological interventions. The proposed research is significant because this foundational mechanistic insight will optimize treatments for millions of patients with voice-related disability. The proposal is conceptually innovative, proposes novel, cutting-edge methodologies, and coalesces expertise across multiple laboratories and specialties.

抽象的 语音障碍以实质性的经济成本影响数百万美国人。关于 治疗通常主要基于二分法：粘膜损伤与肌肉功能障碍。 但是，喉肌功能障碍通常伴有喉粘膜病理，可能是 病因和反应性。该建议是体内和体外方法的创新组合 研究瞬态和持续性声褶皱粘膜损伤对基础功能的影响， 甲状腺素肌肉的结构和机械反应，这是声带的主要肌肉。这 这项研究的长期目标是提供有关复杂相互作用的机械洞察力 粘膜和肌肉发音层，从而导致临床模式和分类的变化 语音障碍，但更重要的是，导致了新颖的，有针对性的治疗策略的发展 数百万与语音相关的残疾患者。这项工作的核心假设是人声的伤害 折叠会引起声褶粘膜和基础肌肉之间的复杂相互作用，因此 导致喉部肌肉结构和功能改变。 拟议的研究有两个具体的目标。目标1是确定功能，结构和 在体内啮齿动物模型中，机械性喉肌对声带损伤的反应。两个深度 声带损伤，仅粘膜浅损伤或粘膜的深损伤和下面的肌肉， 将在雄性和雌性大鼠中创建，以确定a）肌肉功能的声带损伤的时间过程 通过分析超声声音的声学复杂性，b）肌肉通过 蛋白质组学分析和c）在大数据蛋白质组学询问中鉴定出的特定蛋白质水平的变化。 损伤深度将通过肌肉组织学确认。目标2是表征和量化信号 成纤维细胞和成肌细胞以及从基础下的人声褶皱和刺激的炎症细胞 （例如，受伤的）条件。体外实验将检查纤维化和炎症的影响 来自人声折叠椎板的介体和固有喉肌的成肌细胞到成纤维细胞的介体 通过共培养和条件培养基实验询问两种细胞类型之间的独特相互作用。 这些数据将提供有关吞咽困难周期和的关键机理和转化见解 为药理学干预提供潜在目标。 拟议的研究很重要，因为这种基本机械洞察力将优化 数百万与语音残疾患者的治疗。该提议在概念上是创新的， 提出了新颖的，尖端的方法论，并融合了多个实验室的专业知识， 专业。