Defining the role of respiratory gland patterning in rhinosinusitis

定义呼吸腺模式在鼻窦炎中的作用

• 批准号: 10680552
• 负责人: Alison May
• 金额: $ 24.9万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680552
• 关键词: Ablation; Acinus organ component; Adult; Advisory Committees; Affect; Airway Disease; Animal Model; Architecture; Biology; Breathing; Cells; Cellular Morphology; Chronic; Cues; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Development; Dimensions; Disease; Drainage procedure; Duct (organ) structure; Economic Burden; Educational workshop; Ensure; Environmental Risk Factor; Epithelial Cells; Epithelium; Etiology; Exhibits; Expenditure; Facial Pain; Functional disorder; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Diseases; Gland; Goals; Heterogeneity; Histologic; Human; Imaging Techniques; Immune System Diseases; Immunohistochemistry; Impairment; In Situ Hybridization; Integration Host Factors; Knowledge; Location; Lung; Maps; Measures; Medical; Molecular; Morbidity - disease rate; Morphogenesis; Morphology; Mucous Membrane; Mucous body substance; Mus; Mutation; Nose; Operative Surgical Procedures; Organ; Organogenesis; Organoids; Outcome; Outcome Study; Pathogenesis; Pathway interactions; Patients; Pattern; Penetrance; Phase; Phenotype; Polyps; Population; Positioning Attribute; Preventive treatment; Process; Publishing; Quality of life; Regulator Genes; Research; Role; Signal Pathway; Sinus; Structure; Submucosa; Swelling; Symptoms; System; Techniques; Testing; Therapeutic; Three-Dimensional Imaging; Time; Tissues; Training; United States; acute rhinosinusitis; career development; cell behavior; cell type; chronic rhinosinusitis; curative treatments; cystic fibrosis patients; deep sequencing; design; disorder prevention; experimental study; fetal; gland development; insight; loss of function; member; mouse model; mucus hypersecretion; mutant; new therapeutic target; novel; organ repair; particle; pathogen; respiratory; rhinosinusitis; single-cell RNA sequencing; socioeconomics; transcriptome sequencing; transcriptomics

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.

项目总结/摘要 鼻窦炎（RS）是最常见的气道疾病之一，影响美国约15 人口伴随鼻窦粘液分泌过多和堵塞的症状，严重的面部疼痛和呼吸 困难，RS显着影响生活质量和社会经济负担。尽管有这些可怕的结果， RS的病因完全未知，严重阻碍了预防或治疗方法的发展 治疗。 这项提议调查了提供大部分粘液的器官中的异常模式， 鼻粘膜下腺体（SMG）可能是慢性RS（CRS，> 12周）的病因。基于高 囊性纤维化跨膜传导调节因子（CFTR）突变患者的CRS突变率 基因（囊性纤维化）和已发表的初步研究显示SMG形态和功能异常 是常见的这种疾病，这一建议测试的假设，功能障碍，CFTR导致异常SMG 图案化，从而CRS。这一假设将通过三个具体目标进行检验。(1)定义小区标识， SMG发育过程中的谱系动态。在异常腺体的分子和细胞机制 要想了解SMG的架构，必须了解SMG的正常发展。在这个目标中，转录组学 形态变化的技术和定量测量将被用来揭示过程 控制人类SMG发育，然后可用于描述疾病SMG的机制 模式化(2)阐明SMG中的CFTR功能障碍是CRS的根本原因。本Aim将联合收割机 使用动物模型和离体人SMG操作，以检验CFTR中的误调节 是组织重塑和CRS的原因。(3)识别SMG重塑的分子和细胞特征 在成人CRS中。这最后的目的将检查形态和转录腺体表型常见 健康的非CF CRS和CF CRS患者，提供对腺体结构和功能改变的洞察， 从而对CRS做出贡献。 为确保实验完成，K99阶段将进行新技术培训，包括3D 成像、RNA测序和类器官培养。与合作者和咨询机构成员的互动 委员会，并出席讲习班和研讨会，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，而且还将为在CRS患者中测试的新疗法提供靶点。