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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

基本信息

批准号：
8304539
负责人：
COLLEEN A MCMULLEN
金额：
$ 17.97万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-13 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8304539
关键词：
Address Age Aging Basic Science Biochemical Brain Brain-Derived Neurotrophic Factor Clinical Clinical Treatment Complex Data Deglutition Disorders Denervation Elderly Experimental Designs Functional disorder Gastrointestinal tract structure Growth Factor Health Health Care Costs Human Hybrids Individual Infiltration Institutionalization Intervention Language Laryngeal muscle structure Larynx Lead Maintenance Messenger RNA Modality Modeling Molecular Morbidity - disease rate Morphology Motor Muscle Muscle Weakness Muscle denervation procedure Muscle function National Institute on Deafness and Other Communication Disorders Nerve Nerve Growth Factors Nerve Regeneration Neuromuscular Diseases Neuromuscular Junction Norway Outcome Study Pathologist Performance Phenotype Phonation Physiological Proteins Quality of life Rattus Rattus norvegicus Recovery Reflex action Research Personnel Research Project Grants Risk Rodent Route Scientist Signal Transduction Source Specialist Speech Staging Structure System Testing Translating Translations Voice Disorders Voice Quality age effect age related base density design disability effective therapy efficacy testing experience improved mortality nerve supply neuromuscular neuronal growth neurotrophic factor neurotrophin 4 novel prevent public health relevance reinnervation research clinical testing research study response tool vocal cord

项目摘要

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研究资助（R21）（PAR-08-018）的回应。随着个人年龄的增长，肌肉无力和神经肌肉疾病有可能降低生活质量，增加医疗保健费用，并导致制度化。喉是一个复杂的运动系统的一部分，作为发声的振动源和作为分离和保护气道与消化道的调节器。在老年人中，与年龄相关的喉部固有肌肉的变化可能会损害语音质量，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，这些因素会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，显着改变年龄。更具体地说，在衰老的大鼠喉部肌肉中，神经肌肉连接（NMJs）变得更小、更少，并且有证据表明功能失神经支配。因此，本项目有两个主要目标：(1)测试外源性神经营养素作为治疗逆转衰老喉内肌去神经支配的疗效；(2)为将这些发现扩展到临床治疗提供了背景。这些研究将检验中心假设，即外源性神经元生长因子治疗可以纠正与年龄相关的喉肌失神经支配。使用Fisher 344-Brown Norway F1杂交衰老大鼠模型，研究将检验神经营养物质在多大程度上纠正环鼻腱后肌（PCA，声带外展肌）和甲状腺腱样肌（TA，声带内收肌）的NMJ紊乱。我将研究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）的全身给药是否会改变老化PCA和TA中NMJ组装的决定因素。特异性目的2将测试两种生长因子的局部浸润是否会影响老化的PCA和TA肌肉中NMJ的结构和丰度。这将是旨在逆转喉部肌肉中与年龄相关的神经肌肉功能障碍的药理学干预的第一次试验。该项目将产生新的数据，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，这是在临床环境中测试其功效的第一步。