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

基本信息

批准号：
10412081
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
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2024-05-31
项目状态：
已结题

项目摘要

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/摘要大规模的生化蛋白质组学和代谢组学方法的发展导致了更多对涉及神经肌肉可塑性涉及的途径和生物标志物的软化理解在肢体肌肉组织中使用，消除和衰老。但是，喉肌蛋白质组和代谢组仍然相对出乎意料。没有直接研究喉部肌肉，诊断和治疗喉咙肌肉功能障碍引起的沟通障碍方法仍然存在理论上投机。我们的长期目标是了解喉神经肌肉对语音使用增加，例如声带训练和语音疗法以及语音使用增加，例如语音休息和敏感。该提案的总体目的是确定蛋白质组和代谢组如何甲状腺素肌肉对发声训练和衰老有反应。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传导途径并且衰老将在甲状腺素肌肉中具有独特的蛋白质组学和代谢组作用肢体肌肉。这项工作将通过两个目标来完成。在雄性和雌性大鼠中，我们将描述并确定甲状腺类肌肉中的特定生物标志物和生化途径在以下两个条件下的神经肌肉适应：（1）发声训练和（2）感应（衰老）。特别是，我们将广泛地表征肌肉收缩特性，生物能和氧化还原应激甲状腺类肌肉肌肉组织的蛋白质和代谢产物内的反应。这项工作将建立在先前建立的行为动物模型的基础上，涉及训练大鼠以增加其生产超声波发声。另外，使用相同的蛋白质组学和代谢组方法，我们将阐明与年龄相关的变化在整个寿命中如何通过检查甲状腺素肌肉年轻的成年人，老年人和感觉雄性和女性大鼠，并将这种肌肉中的生物标志物与胃内象后肢的生物标志物。这项研究在使用行为动物模型方面具有创新性研究喉肌的使用和感应对神经肌肉机制的影响实施新型的高通量蛋白质组学和代谢组方法检查喉的方法神经肌肉结构和功能。这些多词的方法将完成以前的研究在我们的实验室关于正常和衰老啮齿动物模型中的神经肌肉连接和肌肉纤维可塑性的实验室中，从而为理解与正常和衰老的内在喉部肌肉结构和功能。这项翻译工作将提供证据对于未来的治疗靶标，例如长老会和高功能性语音疾病等临床人群。这项工作与NIDCD的早期职业研究奖一致，我们提出了在开发新型的研究方法和技术的同时，高度翻译的研究。