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: 10556904
• 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/10556904
• 关键词: Ablation; Acinus organ component; Address; Adult; Advisory Committees; Affect; Airway Disease; Animal Model; Architecture; Biology; Breathing; Cells; Cellular Morphology; Chronic; Cues; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Development; Disease; Drainage procedure; Duct (organ) structure; Economic Burden; Educational workshop; Ensure; Environmental Risk Factor; Epithelial; Epithelial Cells; Etiology; Exhibits; 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; Regulation; Regulator Genes; Research; Role; Signal Pathway; Sinus; Structure; Swelling; Symptoms; System; Techniques; Testing; Therapeutic; Three-Dimensional Imaging; Time; Tissues; Training; United States; acute rhinosinusitis; base; 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.

项目摘要/摘要 鼻孔炎（RS）是最普遍的气道疾病之一，约15％的美国疾病 人口。鼻窦粘液过度分泌和塞子的症状，严重的面部疼痛和呼吸 困难，RS极大地影响了生活质量和社会经济负担。尽管有这些可怕的结果， RS的病因是完全未知的，严重阻碍了预防或治愈性的发展 治疗。 该提案调查了如何在提供大多数粘液的器官中的异常图案。 鼻粘膜腺（SMG）可能是慢性RS（CRS，> 12周）的原因。基于高 CRS在囊性纤维化跨膜电导调节剂（CFTR）中突变患者的渗透率 基因（囊性纤维化）和发表和初步研究，显示了异常SMG形态和功能 该提案是这种疾病常见的，检验了以下假设：CFTR中的功能障碍导致异常SMG 图案，因此，CRS。该假设将通过三个特定目的进行检验。 （1）定义细胞身份和 SMG开发过程中的谱系动态。在异常腺体的分子和细胞机制之前 可以理解建筑，对正常SMG发展的欣赏至关重要。在这个目标中，转录组 形态变化的技术和定量测量将用于发现过程 管理人类SMG的发展，然后可以用来描述疾病SMG的机制 图案。 （2）阐明SMG中的CFTR功能障碍是CRS的根本原因。这个目标将结合在一起 使用动物模型和实体人类SMG操纵，以检验CFTR中错误调节的假设 是组织重塑和CRS的原因。 （3）确定SMG重塑的分子和细胞特征 在人类成人CR中。这个最终目标将检查形态和转录腺表型常见 对于健康的非CF CRS和CF CRS患者，提供了有关腺体结构和功能改变的见解， 因此对CRS做出了贡献。 为了确保实验完成，将在K99阶段进行新技术的培训，包括3D 成像，RNA测序和器官培养。与合作者和咨询成员的互动 委员会以及研讨会和研讨会的参加，还将支持项目完成和职业 发展。如果成功，拟议的研究不仅将扩大我们对SMG开发的知识 和生物学，但还将为CRS患者进行测试的新型治疗剂提供靶标。