Quantitative analysis of mucociliary clearance in airway ciliopathies

气道纤毛病中粘液纤毛清除的定量分析

• 批准号: 10397129
• 负责人: Eva Kanso
• 金额: $ 43.14万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-23 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10397129
• 关键词: Address; Affect; Asthma; Biomechanics; Cells; Characteristics; Chronic Bronchitis; Chronic lung disease; Cilia; Clinical; Complex; Cystic Fibrosis; Defect; Defense Mechanisms; Disease; Disease Progression; Epithelium; Functional disorder; Genes; Genetic Diseases; Genotype; Goals; Human; Impairment; In Vitro; Infection; Inherited; Knowledge; Link; Lung; Lung diseases; Maps; Measures; Mechanics; Mediating; Modeling; Mucociliary Clearance; Mucous body substance; Mutation; Patients; Phenotype; Physics; Primary Ciliary Dyskinesias; Property; Research; Respiratory Disease; Respiratory System; Secretory Cell; Structure; Structure of parenchyma of lung; Structure-Activity Relationship; Tissues; Tracheobronchial; Treatment Protocols; Variant; airway epithelium; cell type; ciliopathy; cilium motility; design; fluid flow; in silico; in vitro Model; in vivo; novel therapeutic intervention; pathogen; pre-clinical; precision medicine; programs; respiratory; small molecule; therapeutic genome editing; tool

PROJECT SUMMARY Mucociliary clearance (MCC) is a critical mechanical defense mechanism of the human respiratory system. Poor MCC is a fundamental feature of many inherited and acquired respiratory diseases including primary ciliary dyskinesia (PCD), asthma, chronic bronchitis, and cystic fibrosis (CF). Due to the complex organization of the lung, it is largely unknown how defects of the ciliary machinery change functional MCC and how regional variability of airway epithelial structure, including cell type proportions and ciliary beat parameters, affect local MCC pathophysiology. These knowledge gaps dramatically impair our ability to predict the degree of pulmonary dysfunction imparted by specific ciliary defects, and to understand the airway region-specific onset observed in many lung diseases. While impaired MCC is a pre-determined functional consequence of PCD and other chronic lung diseases, to date, there is no established in vitro model that is able to accurately predict the relationship between genotype, cilia motility, MCC, and respiratory phenotype and, therefore, many genotype-phenotype relationships remain unexplained. Our transdisciplinary research program is designed to address an unmet need to understand how a) region-specific airway organization and b) ciliopathy- causing genotypes, impact MCC. To achieve this we will complete specific aims designed to: 1) use ex vivo lung tissues, that retain their in vivo epithelial organization, as models of ciliated airway epithelia to comprehensively evaluate biomechanical structure-function relationships in large and small airways (Aim 1); 2) use established in vitro models of the human tracheo-bronchial (large) airways to determine a minimal set of structural and functional parameters that are conserved between in vitro and ex vivo ciliated tissues (Aim 2); 3) apply state-of-the-art physics-based computational approaches to develop an in silico model that will be able to predict structure-function relationships of ciliated tissues (Aim 3) and 4) use the minimal set of parameters that define functional MCC in both in vitro and ex vivo models as input into the in silico model to predict regional- specific changes in MCC due to ciliary defects in both large and small airways (All Aims). Our specific objectives build to our long-term goal of combining in vitro and in silico models as a preclinical, precision medicine tool for evaluating small molecule or gene-editing therapeutics toward more targeted and efficient treatment regimens of pulmonary diseases characterized by poor mucociliary clearance.

项目概要 粘膜纤毛清除（MCC）是人体呼吸系统的重要机械防御机制。 不良 MCC 是许多遗传性和获得性呼吸道疾病（包括原发性呼吸道疾病）的基本特征 纤毛运动障碍（PCD）、哮喘、慢性支气管炎和囊性纤维化（CF）。由于组织复杂 对于肺部，目前尚不清楚纤毛机制的缺陷如何改变功能性 MCC 以及区域性 MCC 气道上皮结构的变异性，包括细胞类型比例和纤毛跳动参数，影响局部 MCC 病理生理学。这些知识差距极大地削弱了我们预测肺部疾病程度的能力 特定纤毛缺陷所造成的功能障碍，并了解在 许多肺部疾病。虽然 MCC 受损是 PCD 和其他疾病的预定功能后果 迄今为止，还没有建立能够准确预测慢性肺部疾病的体外模型 基因型、纤毛运动、MCC 和呼吸表型之间的关系，因此，许多 基因型与表型的关系仍然无法解释。我们的跨学科研究计划的设计 解决未满足的需求，了解 a) 区域特定的气道组织和 b) 纤毛病- 引起基因型，影响 MCC。为了实现这一目标，我们将完成旨在以下方面的具体目标：1）使用离体 肺组织，保留其体内上皮组织，作为纤毛气道上皮的模型 全面评估大小气道的生物力学结构-功能关系（目标1）； 2） 使用已建立的人类气管支气管（大）气道的体外模型来确定最小的一组 体外和离体纤毛组织之间保守的结构和功能参数（目标 2）； 3） 应用最先进的基于物理的计算方法来开发一个计算机模型，该模型将能够 使用最小参数集来预测纤毛组织的结构功能关系（目标 3）和 4） 将体外和离体模型中的功能性 MCC 定义为计算机模型的输入，以预测区域性 由于大气道和小气道纤毛缺陷导致的 MCC 的特定变化（所有目标）。我们的具体目标 实现我们将体外和计算机模型相结合作为临床前精准医学的长期目标 用于评估小分子或基因编辑疗法以实现更有针对性和更有效的工具 以粘膜纤毛清除不良为特征的肺部疾病的治疗方案。