Apoptosis Signaling in Vocal Fold Epithelium in Response to Acute Phonotrauma

 描述(申请人提供)：据估计，美国每年治疗发声障碍的费用在119亿至135亿美元之间。声带创伤是良性声带疾病发展的一个重要因素，如小结、息肉和囊肿。在严重的情况下，良性声带疾病会导致发音困难，总体生活质量下降，沟通功能受损。声带上皮屏障是维持声带完整性的关键。在声音创伤的急性发作中，上皮屏障的结构和功能严重受损。国家耳聋和其他沟通障碍研究所目前的战略计划已经承认，喉部结构和功能的变化以及声音创伤引起的潜在障碍的机制是优先研究的领域。这项拟议的研究的目的是测试一种关于声带上皮屏障如何发生破坏的理论。这一理论认为，声创伤过程中的生物力学应力是细胞凋亡或程序性细胞死亡的信号。我们实验室的初步研究表明，急性声带损伤后，声带上皮细胞表面发生了细胞凋亡信号。这一发现导致了压倒一切的假设，即声带上皮细胞中的细胞凋亡信号随着振动暴露的时间和剂量的增加而增加。如果这一假设得到支持，这项拟议的研究将为声带上皮屏障破坏所涉及的特定信号通路提供经验证据。具体的 本研究的目的是：(1)研究振动暴露的时间剂量和剂量增加对声带上皮细胞凋亡信号的影响。这一目标将使用一些对该领域具有高度创新性的方法来实现，包括末端脱氧核苷酸转移酶dUTP缺口末端标记分析染色、caspase-3染色和透射电子显微镜。如果假设是正确的，研究结果将为维持声带上皮屏障的特定机制提供新的证据。预计这项工作将为一系列计划研究提供坚实的关键知识基础，这些研究集中在开发治疗方法，以调节良性声带疾病患者的细胞凋亡和保护声带上皮屏障的完整性。

 DESCRIPTION (provided by applicant): It is estimated that the annual cost of the treatment for voice disorders in the United States is between $11.9- 13.5 billion. A significant contributor o the development of benign vocal fold disease, such as nodules, polyps, and cysts, is phonotrauma. In severe cases, benign vocal fold disease can result in dysphonia with reduced overall quality of life and compromised communication function. The vocal fold epithelial barrier is critical in maintaining the integrity of the vocal folds. During acute episodes of phonotrauma, the epithelial barrier structure and function are severely compromised. The current strategic plan of the National Institute on Deafness and Other Communication Disorders has acknowledged that laryngeal structure and function changes and mechanisms underlying disorders resulting from phonotrauma are priority areas of research. The objective of the proposed research is to test a theory regarding how vocal fold epithelial barrier disruption occurs. The theory reasons that the biomechanical stresses during phonotrauma signal apoptosis, or programmed cell death. Preliminary studies from our laboratory demonstrate that apoptosis signaling occurs along the apical cell surface of the vocal fold epithelium after acute phonotrauma. This finding has led to the overarching hypothesis that apoptosis signaling in the vocal fold epithelium increases with longer time-doses and larger magnitude-doses of vibration exposure. If this hypothesis is supported, the proposed research will provide empirical evidence for a specific signaling pathway involved in vocal fold epithelial barrier disruption. The specific aim of the proposed research is (1) to measure the effects of increasing time-dose and magnitude-dose of vibration exposure on apoptosis signaling in the vocal fold epithelium. This aim will be addressed using a number of approaches that are highly innovative to this field, including terminal deoxynucleotidyl transferase dUTP nick end labeling assay staining, caspase-3 staining, and transmission electron microscopy. If the hypothesis is correct, findings will provide novel evidence for a specific mechanism that is responsible for the maintenance of the vocal fold epithelial barrier. It is anticipated that this work will provide a solid foundation of critical knowledge for a programmatic line of research focusing on the development of therapeutic approaches to regulate apoptosis and preserve the integrity of the vocal fold epithelial barrier in patients with benign vocal fold disease.