Development of a behavioral rat model to assess proteomic and metabolomic adaptations of laryngeal muscles in response to vocal exercise

开发行为大鼠模型来评估喉部肌肉对发声运动的蛋白质组学和代谢组学适应性

• 批准号: 10163837
• 负责人: Aaron Matthew Johnson
• 金额: $ 16.95万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163837
• 关键词: Adult; Age; Aging; Animal Model; Area; Automobile Driving; Award; Behavioral; Biochemical; Biochemical Pathway; Bioenergetics; Biological; Biological Assay; Biological Markers; Cell physiology; Clinical; Communication impairment; Complement; Complex; Computers; Data; Data Set; Development; Diagnostic; Dose; Dysphonia; Elderly; Exercise; Female; Fiber; Foundations; Functional disorder; Future; Gastrocnemius Muscle; Goals; Hindlimb; Knowledge; Laboratories; Laryngeal muscle structure; Larynx; Limb structure; Longevity; Metabolic; Methodology; Mission; Mitochondria; Modeling; Molecular; Morphology; Muscle; Muscle Fibers; Muscle Proteins; Muscle Tension; Muscle function; National Institute on Deafness and Other Communication Disorders; Neuromuscular Junction; Operant Conditioning; Outcome; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Physiological; Population; Production; Property; Proteins; Proteome; Proteomics; Public Health; Rattus; Research; Research Methodology; Rest; Rodent Model; Signal Pathway; Social isolation; Structure; System; Techniques; Technology; Testing; Therapeutic; Thyroarytenoid Muscle; Training; Translational Research; Ultrasonics; Voice; Voice Disorders; Voice Training; Work; age related; base; biological adaptation to stress; career; experimental study; improved; innovation; male; metabolome; metabolomics; multiple omics; muscle metabolism; neuromuscular; neuromuscular plasticity; normal aging; novel; protein expression; protein metabolite; response; senescence; sex; specific biomarkers; targeted biomarker; theories; therapeutic target; vocalization; voice therapy; young adult

Project Summary/Abstract The development of large-scale, biochemical proteomics and metabolomics approaches has led to a more sophisticated understanding of the pathways and biomarkers involved in neuromuscular plasticity in response to use, disuse, and aging in the limb musculature. The laryngeal muscle proteome and metabolome, however, remain relatively unexplored. Without direct study of the laryngeal muscles, diagnostic and therapeutic approaches for communication disorders caused by presumed laryngeal muscle dysfunction remain theoretically speculative. Our long-term goal is to understand the laryngeal neuromuscular response to increased voice use, such as vocal training and voice therapy, and decreased voice use, such as voice rest and senescence. The overall objective of this proposal is to determine how the proteome and metabolome of the thyroarytenoid muscle respond to vocalization training and aging. Our central hypothesis is that vocalization training will increase signaling pathways for mitochondrial function and oxidative stress responses and that aging will have unique proteomic and metabolomic effects in the thyroarytenoid muscle relative to the limb muscles. This work will be accomplished through two aims. In male and female rats we will characterize and identify specific biomarkers and biochemical pathways in the thyroarytenoid muscle indicative of neuromuscular adaptations under the following two conditions: (1) vocalization training and (2) senescence (aging). Specifically, we will broadly characterize muscle contractile properties, bioenergetics, and redox stress responses within the proteins and metabolites of muscle tissue of the thyroarytenoid muscle. This work will build on a previously established behavioral animal model involving training rats to increase their production of ultrasonic vocalizations. Additionally, using the same proteomic and metabolomic approaches, we will elucidate how age-related changes manifest across the lifespan by examining the thyroarytenoid muscle of young adult, older adult, and senescent male and female rats, and comparing biomarkers in this muscle to biomarkers in the gastrocnemius hindlimb. The study is innovative in its use of a behavioral animal model to investigate the effects of laryngeal muscle use and senescence on neuromuscular mechanisms and in its implementation of novel high-throughput proteomic and metabolomic approaches to examine laryngeal neuromuscular structure and function. These multi-omics approaches will complement previous studies conducted in our lab on neuromuscular junction and muscle fiber plasticity in normal and aging rodent models, thereby laying the foundation for understanding the cellular and molecular neuromuscular pathways involved in normal and aging intrinsic laryngeal muscle structure and function. This translational work will provide evidence for future therapeutic targets for clinical populations such as presbyphonia and hyperfunctional voice disorders. This work is consistent with the NIDCD’s mission for the Early Career Research Award in that we propose highly translational research while developing both novel research methodology and technology.

项目摘要/摘要 大规模、生化蛋白质组学和代谢组学方法的发展导致了更多 对参与神经肌肉可塑性反应的通路和生物标志物有深入的了解 在四肢肌肉系统中使用、废弃和老化。然而，喉肌肉蛋白质组和代谢组， 仍然是相对未开发的。在没有直接研究喉部肌肉的情况下，诊断和治疗 推定喉肌功能障碍引起的沟通障碍的治疗方法仍然存在 理论上是投机性的。我们的长期目标是了解喉部神经肌肉反应 增加发声训练和发声治疗等发声使用，减少发声休息等发声使用 和衰老。这项提案的总体目标是确定蛋白质组和代谢组是如何 甲状旁肌对发声训练和老化有反应。我们的中心假设是 发声训练将增加线粒体功能和氧化应激反应的信号通路 而衰老将对甲状旁肌产生独特的蛋白质组和代谢组学效应。 四肢肌肉。这项工作将通过两个目标来完成。在雄性和雌性大鼠中，我们将描述 并在甲状旁肌中识别特定的生物标记物和生化途径 神经肌肉适应在以下两种情况下：(1)发声训练和(2)衰老 (老龄化)。具体地说，我们将广泛描述肌肉收缩特性、生物能量学和氧化还原应激。 甲状旁肌组织内蛋白质和代谢物的反应。这项工作将 建立在先前建立的行为动物模型的基础上，包括训练大鼠增加它们的产量 超声波发声。此外，使用相同的蛋白质组和代谢组学方法，我们将 通过观察老年人的甲状旁肌，阐明与年龄相关的变化是如何在人的一生中表现出来的 年轻成年、老年和衰老的雄性和雌性大鼠，并将这块肌肉中的生物标记物与 腓肠肌后肢的生物标志物。这项研究的创新之处在于使用了一种行为动物模型来 探讨喉肌的使用和衰老对神经肌肉机制及其功能的影响。 新的高通量蛋白质组和代谢组学方法在喉部检查中的应用 神经肌肉结构和功能。这些多组学方法将补充先前的研究 本实验室对正常和衰老啮齿动物模型的神经肌肉连接和肌纤维可塑性进行了研究， 从而为理解细胞和分子神经肌肉通路奠定了基础 正常和老化的喉部固有肌肉结构和功能。这项翻译工作将提供证据 用于临床人群的未来治疗目标，如老年痴呆症和功能亢进性声音障碍。 这项工作与NIDCD早期职业研究奖的使命是一致的，因为我们建议 高度翻译性研究，同时开发新的研究方法和技术。