Molecular Pathophysiology of Acute Phonotrauma

描述（由申请人提供）：声音障碍影响美国约750万人。这些疾病使人衰弱，并可能导致社会退缩，收入损失，长期残疾和严重的社会情绪后果。一般认为，这些疾病可以通过有效地利用发声机制来预防，并且声创伤是声带病变的主要原因。虽然组织学和生理学上的比较经常在声带和身体中的其他移动的组织之间进行，但对继发于发声的创伤和炎症的重复循环的细胞反应是这种专门的结缔组织所特有的。不幸的是，存在着严重短缺的信息的细胞和分子事件的基础上急性phonotrauma，一个领域已被公认为一个迫切的公共卫生需要的国家研究所耳聋和其他沟通障碍。提高对这些事件的理解是至关重要的药物制剂，行为策略和治疗的发展和测试，以康复和预防人类嗓音障碍。识别参与保护声带的机制具有重要的治疗意义，并将允许直接测试一些最广泛接受的假设，目前有非常有限的经验数据来支持。为了解决这一重大需求，我们的实验室开发了一种新的在体兔发声模型，以研究急性声创伤的细胞和分子机制。本申请书中提议的工作以一系列有计划的调查为基础，这些调查提供了必要的试点数据，并提出了几个关键假设，供本申请书检验。我们的初步研究揭示了提高发声强度后声带中炎症信号的改变。这些转录水平的变化与上皮表面形态的变化、微孔形成的证据和上皮紧密连接的扩张有关。这些研究导致了一个总体假设，即紧密连接蛋白的下调、细胞旁途径的改变和细胞旁通透性的增加，损害了上皮屏障功能，并使下层固有层暴露于炎症和进一步损伤。如果我们的总体假设得到支持，它将涉及屏障功能障碍作为粘膜炎症的早期事件，并提供支持的上皮屏障完整性的维护作为一种方法，以防止发声相关的损伤。我们预计，这一系列的程序化调查将最终转化为一个研究计划，重点是设计和测试的药理学药物，以改善上皮屏障功能，在未来的人体试验。

DESCRIPTION (provided by applicant): Voice disorders affect approximately 7.5 million people in the United States 1. These disorders are debilitating and can lead to social withdrawal, loss of income, long-term disability, and significant socioemotional consequences. It is generally believed that these disorders can be prevented through efficient use of the vocal mechanism, and that phonotrauma is a major cause of vocal fold lesions. Although histological and physiological comparisons are often made between the vocal folds and other mobile tissues in the body, the cellular response to repeated cycles of trauma and inflammation secondary to phonation are unique to this specialized connective tissue. Unfortunately, there exists a critical shortage of information on the cellular and molecular events underlying acute phonotrauma, an area which has been acknowledged as a compelling public health need by the National Institute on Deafness and other Communication Disorders. Improved understanding of these events is critical to the development and testing of pharmacologic agents, behavioral strategies, and treatments for rehabilitation and prevention of human voice disorders. The identification of mechanisms involved in protection of the vocal fold has important therapeutic implications and will allow for the direct testing of some of the most widely accepted hypotheses for which there are currently very limited empirical data to support. To address this significant need, our laboratory has developed a novel in-vivo rabbit phonation model to investigate the cellular and molecular mechanisms underlying acute phonotrauma. The work proposed in this application builds on a programmatic series of investigations, which provided the necessary pilot data and the development of several key hypotheses to be tested in the current proposal. Our preliminary studies have revealed alterations in inflammatory signaling in the vocal folds following raised intensity phonation. These transcript level changes are associated with changes to epithelial surface morphology, evidence of microhole formation, and dilatation of epithelial tight junctions. These investigations have led to an overarching hypothesis that the downregulation of tight junction proteins, alteration of the paracellular pathway, and increased paracellular permeability, compromises epithelial barrier function and exposes the underlying lamina propria to inflammation and further injury. If our overarching hypothesis is supported it will implicate barrier dysfunction as an early event in mucosal inflammation, and provide support for the maintenance of epithelial barrier integrity as an approach for protection against phonation related injury. We anticipate that this line of programmatic inquiry will ultimately translate into a research program focusing on the design and testing of pharmacologic agents for improving epithelial barrier function in future human trials.