Molecular Pathophysiology of Acute Phonotrauma

急性声损伤的分子病理生理学

• 批准号: 8773588
• 负责人: Bernard Rousseau
• 金额: $ 37.08万
• 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/8773588
• 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; Health; 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; response; social; stem; treatment strategy; vibration; vocal cord; working group; 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; Health; 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; 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）：语音障碍影响美国约750万人1。这些疾病令人衰弱，可能导致社会退出，收入损失，长期残疾和重大的社会情感后果。通常认为，可以通过有效利用声乐机制来预防这些疾病，并且Phonotrauma是声带病变的主要原因。尽管通常在人体中的声带和其他移动组织之间进行组织学和生理比较，但对重复的创伤和发作炎症的反复反应是这种专业结缔组织的独特之处。不幸的是，关于急性Phonotrauma的细胞和分子事件的严重信息存在严重的信息，该领域已被美国国家耳聋和其他沟通障碍研究所承认为令人信服的公共卫生需求。对这些事件的理解的提高对于制定和测试的药理剂，行为策略以及治疗人类语音疾病的治疗至关重要。识别涉及人声折叠的机制具有重要的治疗意义，并将允许直接测试某些最广泛接受的假设，目前有非常有限的经验数据可以支持。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发音模型，以研究急性急性Phonotrauma的细胞和分子机制。本申请中提出的工作基于一系列调查，该调查提供了必要的试点数据，并开发了当前建议中要测试的几个关键假设。我们的初步研究揭示了强度发音后声带中炎症信号传导的改变。这些转录水平的变化与上皮表面形态的变化有关，微孔形成的证据以及上皮紧密连接的扩张。这些研究导致了一个总体假设，即紧密连接蛋白的下调，细胞细胞途径的改变并增加了细胞细胞通透性，损害了上皮屏障功能，并暴露了基础的层层次，炎症和进一步的伤害。如果支持我们的总体假设，它将暗示屏障功能障碍是粘膜炎症中的早期事件，并为维持上皮屏障完整性的维持提供支持，作为保护相关损伤的方法。我们预计，这种程序化询问最终将转化为一项研究计划，重点是在未来人类试验中改善上皮屏障功能的药理学剂的设计和测试。