Molecular Pathophysiology of Acute Phonotrauma

急性声损伤的分子病理生理学

• 批准号: 8385565
• 负责人: Bernard Rousseau
• 金额: $ 35.83万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385565
• 关键词: Acute; Address; Affect; Area; Behavioral; Biology; Communication; Computer Simulation; Connective Tissue; Data; Development; Dilatation - action; Disease; Dose; Down-Regulation; Electron Microscopy; Electrophysiology (science); Epithelial; Event; Functional disorder; Future; Gene Expression; Goals; Grant; Human; Income; Inflammation; Inflammatory; Injury; Investigation; Laboratories; Lamina Propria; Lead; Lesion; Maintenance; Mechanical Stress; Modeling; Molecular; Morphology; Mucositis; National Institute on Deafness and Other Communication Disorders; Oryctolagus cuniculus; Pathway interactions; Patients; Permeability; Phonation; Physiological; Polymerase Chain Reaction; Prevention; Proteins; Public Health; Quality of life; Rehabilitation therapy; Research; Science; Secondary to; Series; Signal Transduction; Spatial Distribution; Strategic Planning; Structure; Surface; Testing; Therapeutic; Tight Junctions; Time; Tissues; Transcript; Translating; Trauma; United States; Voice; Voice Disorders; Western Blotting; Withdrawal; Work; design; disability; effective therapy; improved; in vivo; innovation; insight; morphometry; novel; prevent; programs; protein expression; public health relevance; response; social; stem; treatment strategy; vibration; vocal cord; working group

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.

描述（由申请人提供）：在美国，声音障碍影响着大约 750 万人 1。这些障碍会使人衰弱，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，可以通过有效利用发声机制来预防这些疾病，并且声音损伤是声带病变的主要原因。尽管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，但对发声继发的创伤和炎症重复循环的细胞反应是这种特殊结缔组织所独有的。不幸的是，关于急性语音创伤背后的细胞和分子事件的信息严重缺乏，而国家耳聋和其他沟通障碍研究所已将这一领域视为迫切的公共卫生需求。加深对这些事件的了解对于药物制剂、行为策略以及人类声音障碍康复和预防治疗的开发和测试至关重要。识别声带保护所涉及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，而目前支持这些假设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型的体内兔子发声模型，以研究急性发声损伤背后的细胞和分子机制。本申请中提出的工作建立在一系列计划性调查的基础上，这些调查提供了必要的试点数据以及在当前提案中测试的几个关键假设的发展。我们的初步研究揭示了发声强度增加后声带炎症信号的变化。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。这些研究得出了一个总体假设，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，会损害上皮屏障功能，并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，它将表明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预防发声相关损伤的方法提供支持。我们预计，这一规划性探究最终将转化为一个研究计划，重点关注药物制剂的设计和测试，以在未来的人体试验中改善上皮屏障功能。