Molecular Pathophysiology of Acute Phonotrauma

描述（由申请人提供）：在美国，声音障碍影响了大约750万人。这些疾病使人衰弱，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利用发声机制来预防，并且声腔创伤是声带病变的主要原因。虽然经常将声带与身体其他可移动组织进行组织学和生理学比较，但这种特殊结缔组织对重复循环的创伤和继发发声炎症的细胞反应是独特的。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缺乏，而国家耳聋和其他交流障碍研究所认为这是一个迫切的公共卫生需求。提高对这些事件的理解对于开发和测试药物、行为策略以及康复和预防人类声音障碍的治疗至关重要。识别涉及声带保护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，这些假设目前有非常有限的经验数据支持。为了满足这一重大需求，我们的实验室开发了一种新的兔体内发声模型来研究急性声音损伤的细胞和分子机制。本申请中提出的工作建立在一系列程序化的调查基础上，这些调查提供了必要的试点数据，并发展了几个关键假设，以在当前提案中进行测试。我们的初步研究已经揭示了声部炎症信号的改变随着声音强度的提高。这些转录物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、细胞旁通路的改变和细胞旁通透性的增加，损害了上皮屏障功能，使底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，它将暗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作为防止发音相关损伤的一种方法提供支持。我们预计，这条程序性研究路线最终将转化为一个研究项目，重点是在未来的人体试验中设计和测试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.