Challenges to Vocal Fold Epithelia: Functional and Structural Consequences

描述（由申请人提供）：本提案的目的是研究调节声带上皮功能的机制，并检查上皮在维持声带结缔组织和肌肉的生物学和力学特性中的作用。上皮位于环境和结缔组织之间的界面。作为声带的最外层，上皮经常暴露于有害的、吸入的和全身的挑战。这些挑战在多大程度上对上皮功能产生不利影响，以及上皮功能障碍对潜在结缔组织和肌肉的生物学和力学特性的影响尚未得到研究。这些都是关键问题，因为结缔组织和肌肉的特性受损会导致发声障碍，而系统性和吸入性挑战被认为会增加对声音障碍的脆弱性。本研究将通过将声带上皮暴露于挑战和研究上皮功能障碍对结缔组织和肌肉的影响，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于胃反流和污染中。拟议的研究对声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：表征调节上皮屏障功能和上皮离子运输功能的机制；确定相关剂量的实际激发暴露是否会破坏上皮功能；并研究上皮功能障碍对结缔组织和肌肉的影响。这里提出的前瞻性盲法实验将结合电生理、分子、组织学和生物力学方法来产生重要的数据，原因有几个。首先，数据将证明常见挑战对语音系统的不利影响。其次，数据将证明上皮保护潜在结缔组织和肌肉的程度。第三，数据将突出上皮-结缔组织相互作用的一个途径。总之，这些发现将阐明在具有挑战性的环境中，声带上皮在维持底层稳态中的作用。此外，这些发现将为药物治疗和组织再生策略奠定基础，重点是加强和恢复上皮功能，保护潜在的结缔组织和肌肉，并防止语音障碍。

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.