Exogenous growth factors for reversal of age-related laryngeal muscle denervation

外源性生长因子逆转与年龄相关的喉肌去神经支配

• 批准号: 8019657
• 负责人: COLLEEN A MCMULLEN
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-13 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8019657
• 关键词: Exogenous; growth; factors; reversal; age

DESCRIPTION (provided by applicant): This application is in response to the NIDCD Research Grants for Translating Basic Research into Clinical Tools for Human Health (R21) (PAR-08-018). As individuals age, muscle weakness and neuromuscular disorders have the potential to diminish the quality of life, increase healthcare costs, and lead to institutionalization. The larynx is part of a complex motor system that serves as a vibratory source of phonation and as a regulator that separates and protects the airway from the digestive tract. In the elderly, age-related changes in the intrinsic laryngeal muscles may compromise voice quality, thus impair the ability to communicate and diminish the ability to remain socially engaged. Laryngeal muscle dysfunction may also cause dysphagia and increase the risk of aspiration, factors that lead to higher mortality and morbidity. Our preliminary findings indicate that the intrinsic laryngeal muscles have a unique phenotype that is significantly altered by age. More specifically, the neuromuscular junctions (NMJs) become smaller and less abundant in aging rat laryngeal muscles, and there is evidence of functional denervation. Therefore, this project has two major objectives:(1) it will test the efficacy of exogenous neurotrophins as treatment to reverse denervation in the aging intrinsic laryngeal muscles; (2) it will provide the background to extend these findings to clinical treatments. The studies will test the central hypothesis that age related laryngeal muscle denervation is corrected by treatment with exogenous neuronal growth factors. Using the Fisher 344-Brown Norway F1 hybrid rat model of aging, the studies will examine to what extent neurtrophins correct NMJ disorganization in the posterior cricoarytenoid (PCA, vocal fold abductor) and thyoarytenoid (TA, vocal fold adductor) muscles. Specific Aim I will examine whether systemic administration of the exogenous neurotrophins brain-derived nerve growth factor (BDNF) and neurotrophin-4 (NT-4) changes determinants of NMJ assembly in the aging PCA and TA. Specific Aim 2 will test whether local infiltration with the two growth factors influences NMJ structure and abundance in the aging PCA and TA muscles. This will be a first test of pharmacological interventions intended to reverse age-related neuromuscular dysfunction in the laryngeal muscles. This project will generate novel data on interventions aimed at preventing or reversing age-related neuromuscular dysfunction in these small muscles, a first step to testing their efficacy in the clinical setting. PUBLIC HEALTH RELEVANCE: Laryngeal dysfunction in the elderly is a major cause of disability, from voice disorders to dysphagia and loss of airway protective reflexes. Few, if any, therapies exist that target age-related laryngeal muscle dysfunction. This project will test the efficacy of exogenous growth factors as treatment for functional denervation of laryngeal muscles in aging subjects.

描述（由申请人提供）：本申请是对NIDCD将基础研究转化为人类健康临床工具的研究赠款（R21）（PAR-08-018）的回应。随着年龄的增长，肌肉无力和神经肌肉疾病有可能降低生活质量，增加医疗费用，并导致机构化。喉是一个复杂的运动系统的一部分，作为发声的振动源，并作为一个调节器，分离和保护呼吸道从消化道。在老年人中，与年龄相关的喉内肌变化可能会损害声音质量，从而损害沟通能力并降低保持社交参与的能力。喉肌功能障碍也可能导致吞咽困难和增加误吸的风险，这些因素导致更高的死亡率和发病率。我们的初步研究结果表明，喉内肌有一个独特的表型，是显着改变的年龄。更具体地说，神经肌肉接头（NMJs）变得更小，更丰富的老化大鼠喉肌，有证据表明功能性去神经支配。因此，本项目有两个主要目标：（1）它将测试外源性神经营养因子作为治疗的有效性，以逆转老化的喉内肌的去神经支配;（2）它将提供背景，以将这些发现扩展到临床治疗。这些研究将检验中心假设，即年龄相关的喉肌去神经支配通过外源性神经元生长因子治疗得到纠正。使用Fisher 344-Brown Norway F1杂交大鼠衰老模型，研究将检查神经营养因子在多大程度上纠正环杓后肌（PCA，声带外展肌）和甲杓肌（TA，声带内收肌）中的NMJ紊乱。具体目的我将检查是否系统管理的外源性神经营养因子脑源性神经生长因子（BDNF）和神经营养因子-4（NT-4）的变化的决定因素NMJ组装在老化PCA和TA。具体目标2将测试两种生长因子的局部浸润是否影响老化PCA和TA肌肉中的NMJ结构和丰度。这将是旨在逆转喉肌中与年龄相关的神经肌肉功能障碍的药物干预的第一次测试。该项目将产生旨在预防或逆转这些小肌肉中与年龄相关的神经肌肉功能障碍的干预措施的新数据，这是在临床环境中测试其疗效的第一步。 公共卫生相关性：老年人的喉功能障碍是残疾的主要原因，从语音障碍到吞咽困难和气道保护反射的丧失。针对与年龄相关的喉肌功能障碍的治疗方法很少（如果有的话）。本项目将测试外源性生长因子作为治疗老年受试者喉肌功能性去神经支配的有效性。