Defining the role of respiratory gland patterning in rhinosinusitis

项目摘要/摘要 鼻窦炎(RS)是最常见的呼吸道疾病之一，影响美国约15%的人口 人口。有鼻腔粘液分泌增多、鼻塞、面部剧烈疼痛、呼吸困难等症状 困难，RS对生活质量和社会经济负担都有显著影响。尽管有这些可怕的结果， RS的病因完全未知，严重阻碍了预防性或治愈性的发展 治疗。 这项建议调查了提供大部分粘液的器官中的异常模式是如何 鼻黏膜下腺(SMGs)可能是慢性RS(CRS，&GT；12周)的病因。基于高 囊性纤维化跨膜电导调节因子突变患者CRS的外显性 基因(囊性纤维化)和已发表的显示SMG形态和功能异常的初步研究 都是这种疾病常见的，这一建议检验了CFTR功能障碍导致SMG异常的假设 图案化，因此，CRS。这一假设将通过三个具体目标进行检验。(1)定义小区身份和 SMG发育过程中的谱系动态。畸形腺的分子和细胞机制研究进展 架构可以理解，欣赏正常的SMG开发是必不可少的。在这个目标上，转录 将使用形态变化的技术和定量测量来揭示过程 管理人类SMG的发育，然后可以用来描述SMG的疾病机制 图案化。(2)阐明SMG的CFTR功能障碍是CRS的潜在原因。这一目标将结合 使用动物模型和体外人类SMG操作来验证CFTR中存在错误调控的假设 是组织重塑和CRS的原因之一。(3)鉴定SMG重塑的分子和细胞特征 在成人CRS中。这一最终目标将检验常见的形态和转录腺表型。 给健康的、非CFCRS和CFCRS患者，提供对腺体结构和功能变化的洞察， 从而对CRS做出贡献。 为确保实验完成，将在K99阶段进行新技术培训，包括3D 成像、RNA测序和类器官培养。与协作者和咨询成员的互动 委员会以及参加讲习班和研讨会也将支持项目的完成和职业生涯 发展。如果成功，拟议的研究不仅将扩大我们对SMG发展的了解 和生物学，但也将为在CRS患者身上测试新的治疗方法提供靶点。

PROJECT SUMMARY/ABSTRACT Rhinosinusitis (RS) is one of the most prevalent airway diseases, effecting approximately 15% of the U.S population. With symptoms of sinonasal mucus hypersecretion and plugging, severe facial pain and breathing difficulties, RS significantly affects both quality of life and socioeconomic burden. Despite these dire outcomes, the etiology of RS is completely unknown, severely hampering the development of preventative or curative treatments. This proposal investigates how aberrant patterning in the organs that provide the majority of the mucus, the nasal submucosal glands (SMGs), may be causative for chronic RS (CRS, > 12 weeks). Based on the high penetrance of CRS in patients with mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene (Cystic Fibrosis) and published and preliminary studies showing aberrant SMG morphology and function are common to this disease, this proposal tests the hypothesis that dysfunction in CFTR leads to aberrant SMG patterning and thus, CRS. This hypothesis will be tested via three specific aims. (1) Define cell identities and lineage dynamics during SMG development. Before molecular and cellular mechanisms of aberrant gland architecture can be understood, appreciation of normal SMG development is essential. In this Aim, transcriptomic techniques and quantitative measures of morphological changes will be employed to uncover processes governing human SMG development, which can then be utilized to delineate mechanisms of disease SMG patterning. (2) Elucidate CFTR dysfunction in SMGs as an underlying cause of CRS. This Aim will combine use of animal models and ex vivo human SMG manipulation, to test the hypothesis that mis-regulation in CFTR is a cause of tissue remodeling and CRS. (3) Identify molecular and cellular signatures of SMG remodeling in human adult CRS. This final aim will examine morphological and transcriptomic gland phenotypes common to healthy, non-CF CRS, and CF CRS patients, providing insight into alterations in gland structure and function, and thus contribution to CRS. To ensure experiment completion, training in new techniques will be carried out in the K99 phase, including 3D imaging, RNA sequencing and organoid culture. Interactions with collaborators and members of an advisory committee, and attendance of workshops and seminars, will also support project completion and career development. If successful, the proposed research will not only expand our knowledge on SMG development and biology, but will also provide targets for novel therapeutics to be tested in patients of CRS.