Molecular Pathophysiology of Acute Phonotrauma

描述(由申请人提供)：美国约有750万人患有语音障碍1。这些障碍会使人虚弱，并可能导致社交退缩、收入损失、长期残疾和严重的社会情感后果。人们普遍认为，这些疾病可以通过有效地利用发声机制来预防，而声音创伤是声带损伤的主要原因。虽然经常在声带和体内其他活动组织之间进行组织学和生理学比较，但这种特殊的结缔组织对重复的创伤和继发发声的炎症循环的细胞反应是独一无二的。不幸的是，关于急性声音创伤背后的细胞和分子事件的信息严重不足，这一领域已被国家耳聋和其他沟通障碍研究所确认为迫切的公共卫生需求。提高对这些事件的了解对于开发和测试药物、行为策略以及康复和预防人类发声障碍的治疗至关重要。确定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被广泛接受的假说，目前支持这些假说的经验数据非常有限。为了满足这一重大需求，我们的实验室开发了一种新的体内兔子发声模型，以研究急性声音创伤的细胞和分子机制。本申请中提出的工作建立在一系列方案调查的基础上，这些调查提供了必要的试点数据，并制定了若干关键假设，以便在本提案中加以检验。我们的初步研究显示，发声强度提高后，声带中的炎症信号发生了变化。这些转录水平的变化与上皮表面形态的变化、微孔形成的证据以及上皮紧密连接的扩张有关。这些研究导致了一个重要的假说，即紧密连接蛋白的下调，细胞旁途径的改变，以及细胞旁通透性的增加，损害了上皮屏障功能，使固有层潜在的炎症和进一步的损伤。如果我们的总体假说得到支持，它将提示屏障功能障碍是粘膜炎症的早期事件，并为维持上皮屏障完整性提供支持，作为保护发声相关损伤的一种方法。我们预计，这一系列的程序性研究最终将转化为一个研究计划，重点是在未来的人体试验中设计和测试用于改善上皮屏障功能的药理学药物。

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.