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机械特性中的作用。上皮位于环境和结缔组织之间的界面。作为声带的最外层，上皮通常暴露于有毒的、吸入的和全身性的挑战。这些挑战对上皮功能产生不利影响的程度，以及上皮功能障碍对损害底层结缔组织和肌肉的生物学和机械特性的后果尚未研究。这些都是至关重要的问题，因为结缔组织和肌肉的性质受损会导致发声困难，而全身和吸入性挑战被认为会增加对语音障碍的脆弱性。该提案将量化上皮在保护底层组织中的作用，通过暴露声带上皮细胞的挑战和研究上皮功能障碍对结缔组织和肌肉的影响。反流和污染物将作为代表性的挑战，因为声带上皮细胞在日常活动中暴露于胃反流和污染。拟议的研究对嗓音障碍领域具有重要意义，因为它系统地研究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转运功能的机制;确定相关剂量的现实挑战暴露是否会破坏上皮功能;以及调查上皮功能障碍对结缔组织和肌肉的后果。本文提出的前瞻性盲法实验将结合联合收割机电生理学、分子学、组织学和生物力学方法，以获得重要的数据。首先，数据将证明常见的挑战对发声系统的不利影响。其次，数据将证明上皮保护下层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。总而言之，这些发现将揭示声带上皮在维持具有挑战性的环境中的底层稳态中的作用。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，保护底层结缔组织和肌肉，并预防发音障碍。

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.