Challenges to Vocal Fold Epithelia: Functional and Structural Consequences

描述(申请人提供)：这项建议的目标是研究调节声带上皮功能的机制，并研究声带上皮在维持声带结缔组织和肌肉的生物和机械特性中的作用。上皮位于环境和结缔组织之间的交界处。作为声带的最外层，声带上皮经常暴露在有害的、吸入的和全身的挑战中。这些挑战对上皮功能的不利影响程度，以及上皮功能障碍对潜在结缔组织和肌肉的生物和机械特性的影响尚未得到研究。这些都是关键的问题，因为结缔组织和肌肉的特性受损会导致发音困难，而全身和吸入性挑战被认为增加了语音障碍的易感性。这项提议将通过将声带上皮暴露在挑战中并研究上皮功能障碍对结缔组织和肌肉的影响来量化上皮在保护底层组织中的作用。反流和污染物将是具有代表性的挑战，因为声带上皮在日常活动中暴露在胃反流和污染中。这项拟议的研究对嗓音障碍领域具有重要意义，因为它系统地检查了相关剂量的挑战对整个声带(上皮、结缔组织和肌肉)的不良后果。该提案的三个重点是：表征调控上皮屏障功能和上皮离子转运功能的机制；确定相关剂量的现实挑战暴露是否扰乱上皮功能；以及调查上皮功能障碍对结缔组织和肌肉的后果。这里提出的前瞻性、盲目实验将结合电生理、分子、组织学和生物力学方法来产生出于几个原因而重要的数据。首先，数据将展示共同挑战对发音系统的不利影响。其次，数据将展示上皮对底层结缔组织和肌肉的保护程度。第三，数据将突出上皮-结缔组织相互作用的一条途径。总之，这些发现将阐明声带上皮在具有挑战性的环境中维持底层动态平衡的作用。此外，这些发现将为药物治疗和组织再生策略奠定基础，以加强和恢复上皮功能，保护潜在的结缔组织和肌肉，并防止发音困难。 公共卫生相关性：声带上皮暴露在来自环境的有害挑战中。这项应用将研究上皮在保护结缔组织和肌肉免受这些挑战中的作用。长期目标是了解暴露在这些挑战中导致的负面声音变化的潜在机制，并开发恢复声带结构和功能的治疗方法。

DESCRIPTION (provided by applicant): The goals of this proposal are to investigate the mechanisms that regulate vocal fold epithelial functions, and to examine the role of the epithelium in maintaining the biological and mechanical properties of vocal fold connective tissue and muscle. The epithelium lies at the interface between the environment and connective tissue. As the outermost layer of the vocal folds, the epithelium is routinely exposed to noxious, inhaled and systemic challenges. The extent to which these challenges adversely affect epithelial functions, and the consequences of epithelial dysfunction on compromising the biological and mechanical properties of underlying connective tissue and muscle have not been investigated. These are critical questions because compromised properties of connective tissue and muscle result in dysphonia, and systemic and inhaled challenges are thought to increase the vulnerability to voice disorders. This proposal will quantify the role of the epithelium in protecting underlying tissue, by exposing vocal fold epithelia to challenges and investigating the ramifications of epithelial dysfunction on connective tissue and muscle. Reflux and pollutants will serve as representative challenges, because vocal fold epithelia are exposed to gastric reflux and pollution during daily activities. The proposed research is significant to the area of voice disorders because it systematically examines the adverse consequences of challenges at relevant dosages, on the entire vocal fold (epithelium, connective tissue, and muscle). The three foci of the proposal are: to characterize the mechanisms that regulate epithelial barrier function and epithelial ion transport function; to determine whether realistic challenge exposures at relevant dosages disrupt epithelial functions; and to investigate the consequences of epithelial dysfunction on connective tissue and muscle. The prospective, blinded experiments proposed here will combine electrophysiological, molecular, histological, and biomechanical approaches to yield data that are important for several reasons. First, data will demonstrate the adverse effects of common challenges on the phonatory system. Second, data will demonstrate the extent to which the epithelium protects underlying connective tissue and muscle. Third, data will highlight one pathway for epithelial-connective tissue interaction. Altogether, the findings will shed light on the role of vocal fold epithelium in maintaining the homeostasis of underlying layers in a challenging environment. Additionally, the findings will lay the groundwork for pharmacological treatments and tissue regenerative strategies to focus on strengthening and restoring epithelial function, to protect underlying connective tissue and muscle, and prevent dysphonia. PUBLIC HEALTH RELEVANCE: The vocal fold epithelium is exposed to noxious challenges from the environment. This application will investigate the role of the epithelium in protecting connective tissue and muscle from these challenges. The long-term goal is to understand the underlying mechanisms for negative voice changes resulting from exposure to these challenges, and to develop treatments that restore vocal fold structure and function.