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.

项目概要/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途径和生物标志物的深入了解然而，肢体肌肉组织的使用、废弃和老化。在没有对喉部肌肉、诊断和治疗的直接研究的情况下，这一问题仍然相对未经探索。由推测的喉部肌肉功能障碍引起的沟通障碍的方法仍然存在我们的长期目标是了解喉部神经肌肉的反应。增加发声使用，例如发声训练和发声治疗，以及减少发声使用，例如发声休息该提案的总体目标是确定蛋白质组和代谢组如何影响衰老。甲杓肌对发声训练和衰老有反应。发声训练将增加线粒体功能和氧化应激反应的信号通路并且衰老将对甲杓肌产生独特的蛋白质组学和代谢组学影响。我们将通过雄性和雌性大鼠的肢体肌肉来完成这项工作。并确定甲杓肌指标中的特定生物标志物和生化途径以下两种情况下的神经肌肉适应：（1）发声训练和（2）衰老具体来说，我们将广泛地描述肌肉收缩特性、生物能学和氧化还原应激。这项工作将研究甲杓肌的蛋白质和代谢物内的反应。建立在先前建立的行为动物模型的基础上，包括训练老鼠增加其生产此外，我们将使用相同的蛋白质组学和代谢组学方法。通过检查甲杓肌来阐明与年龄相关的变化如何在整个生命周期中表现出来年轻的成年大鼠、老年大鼠以及衰老的雄性和雌性大鼠，并将该肌肉中的生物标志物与该研究的创新之处在于使用行为动物模型来研究腓肠肌后肢的生物标志物。研究喉部肌肉的使用和衰老对神经肌肉机制及其影响实施新型高通量蛋白质组学和代谢组学方法来检查喉部这些多组学方法将补充以前的研究。我们的实验室对正常和衰老啮齿动物模型的神经肌肉接头和肌纤维可塑性进行了研究，从而为理解参与的细胞和分子神经肌肉通路奠定了基础这项转化工作将为正常和老化的喉部肌肉结构和功能提供证据。为临床人群未来的治疗目标，如老花音和功能亢进的声音障碍。这项工作与 NIDCD 早期职业研究奖的使命是一致的，因为我们建议高度转化研究，同时开发新颖的研究方法和技术。