Molecular mechanisms of aging in the intrinsic laryngeal muscles

喉内肌衰老的分子机制

• 批准号: 7844245
• 负责人: COLLEEN A MCMULLEN
• 金额: $ 3.34万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7844245
• 关键词: Acetylcholine; Achievement; Affect; Age; Aging; Architecture; Biochemical; Biological; Biology; Calcium Channel; Cell physiology; Cells; Cholinergic Receptors; Complex; Data; Deglutition Disorders; Development; Disease; ERBB2 gene; Elderly; Ensure; Functional disorder; Gastrointestinal tract structure; Glycoproteins; Goals; Grant; Health Care Costs; Hybrids; Individual; Institutionalization; Intervention; L-Type Calcium Channels; Lambert-Eaton Myasthenic Syndrome; Laryngeal muscle structure; Larynx; Lead; Maintenance; Mentorship; Modeling; Molecular; Morbidity - disease rate; Motor; Muscle; Muscle Weakness; Myasthenia Gravis; National Institute on Deafness and Other Communication Disorders; Neuromuscular Diseases; Neuromuscular Junction; Norway; Phenotype; Phonation; Presynaptic Terminals; Principal Investigator; Quality of life; Rattus; Risk; Scientist; Signal Pathway; Signal Transduction; Source; Structure; System; Testing; Translating; Utrophin; Vesicle; Voice Quality; age effect; age related; base; mortality; neuromuscular; neuromuscular transmission; novel; prevent; programs; research study; response; stoichiometry; synaptotagmin; syntaxin; vesicle-associated membrane protein; vocal cord

DESCRIPTION (provided by applicant): As individuals age, muscle weakness and neuromuscular disorders have the potential to diminish the quality of life, increase health care costs, and lead to institutionalization. The larynx is part of a complex motor system that serves dually as the vibratory source of phonation and as a valve 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 dysfunction may also cause dysphagia and increase the risk of aspiration which may translate to higher mortality and morbidity. Our preliminary findings indicate that the intrinsic laryngeal muscles have a unique phenotype that is significantly altered by age; however, the biology of these small muscles remains largely unexplored. This project, in response to the NIDCD Small Grant (R03) Program, will achieve two objectives: (1) it will determine how age alters neuromuscular junction organization and function in the intrinsic laryngeal muscles; (2) it will provide a mechanism to further the professional development of the PI, leading to scientific independence. The studies will test the central hypothesis that aging disrupts the organization and stability of the neuromuscular junction in the intrinsic laryngeal muscles. Using the Fischer 344-Brown Norway F1 hybrid rat model of aging, the studies will examine to what extent aging alters NMJ organization in the posterior cricoarytenoid (PCA, vocal fold abductor) and thyroarytenoid (TA, vocal fold adductor) muscles. Three Specific Aims will be accomplished. Specific Aim 1 will test whether age changes NMJ ultrastructure and the expression of acetylcholine receptor subunits in the intrinsic laryngeal muscles. Specific Aim 2 will evaluate if aging represses cellular signaling pathways that initiate and sustain NMJ organization in the intrinsic laryngeal muscles. Specific Aim 3 will assess to what extent age alters the acetylcholine vesicle release system in the presynaptic terminals of the intrinsic laryngeal NMJs. This project will generate novel data on how age disrupts NMJ organization in the intrinsic laryngeal muscles, and will provide the bases for interventions aimed at preventing or reversing age-related neuromuscular dysfunction in these small muscles. In addition, the anticipated results will be of relevance to diseases not associated with aging but that affect NMJ structure and function such as myasthenia gravis and the Lambert- Eaton myasthenic syndrome.

描述（由申请人提供）：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，增加医疗费用，并导致机构化。喉是一个复杂的运动系统的一部分，它既作为发声的振动源，又作为将气道与消化道分开并保护气道的阀门。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。喉功能障碍也可能导致吞咽困难，并增加误吸的风险，这可能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;然而，这些小肌肉的生物学仍然在很大程度上未被探索。该项目是对NIDCD小额赠款（R 03）计划的响应，将实现两个目标：（1）确定年龄如何改变喉内肌的神经肌肉接头组织和功能;（2）提供一种机制，以进一步促进PI的专业发展，从而实现科学独立性。这些研究将检验中心假设，即老化破坏喉内肌神经肌肉接头的组织和稳定性。使用Fischer 344-Brown Norway F1杂交大鼠衰老模型，研究将检查衰老在多大程度上改变了环杓后肌（PCA，声带外展肌）和甲杓肌（TA，声带内收肌）肌肉中的NMJ组织。将实现三个具体目标。具体目标1将测试年龄是否改变NMJ超微结构和喉内肌中乙酰胆碱受体亚单位的表达。具体目标2将评估衰老是否抑制启动和维持喉内肌NMJ组织的细胞信号传导途径。具体目标3将评估年龄在多大程度上改变了喉内NMJ突触前末梢的乙酰胆碱囊泡释放系统。该项目将产生关于年龄如何破坏喉内肌NMJ组织的新数据，并将为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提供基础。此外，预期结果将与与衰老无关但影响NMJ结构和功能的疾病相关，如重症肌无力和Lambert-Eaton肌无力综合征。