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: 10212158
• 负责人: Eva Kanso
• 金额: $ 62.44万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212158
• 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; Distal; Epithelial; 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 System; Secretory Cell; Structural Models; Structure; Structure of parenchyma of lung; Structure-Activity Relationship; Tissues; Tracheobronchial; Treatment Protocols; Variant; airway epithelium; base; 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.

项目摘要 粘膜钙清除率（MCC）是人类呼吸系统的关键机械防御机制。 差的MCC是许多遗传和获得的呼吸道疾病（包括主要）的基本特征 睫状运动障碍（PCD），哮喘，慢性支气管炎和囊性纤维化（CF）。由于组织复杂 肺部的缺陷在很大程度上尚不清楚如何改变功能MCC以及区域 气道上皮结构的可变性，包括细胞类型比例和睫状节拍参数，会影响局部 MCC病理生理学。这些知识差距极大地损害了我们预测肺部程度的能力 功能障碍是由特定睫状缺陷所赋予的，并了解在 许多肺部疾病。虽然受损的MCC是PCD和其他的预定功能结果 迄今为止，还没有建立的体外模型能够准确预测 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 - 表型关系仍然无法解释。我们的跨学科研究计划是设计的 为了满足未满足的需求，以了解a）特定区域的气道组织和b）纤毛病 - 引起基因型，影响MCC。为了实现这一目标，我们将完成针对以下特定目标：1）使用离体 保留其体内上皮组织的肺组织是纤毛气道上皮的模型 全面评估大型和小气道中的生物力学结构 - 功能关系（AIM 1）； 2） 使用建立的人类气管支气管（大）气道的体外模型来确定最小的集合 在体外和离体纤毛组织之间保守的结构和功能参数（AIM 2）； 3） 应用基于物理的最先进的计算方法来开发一种计算机模型 预测纤毛组织的结构功能关系（AIM 3）和4）使用最小的参数集 这将体外和离体模型中的功能性MCC定义为对计算机模型的输入，以预测区域 - 由于大型和小气道的睫状缺陷，MCC的特定变化（所有目的）。我们的具体目标 建立我们的长期目标，即将体外和硅材模型组合为临床前，精密医学 用于评估小分子或基因编辑疗法的工具 肺部疾病的治疗方案，其特征在于粘膜钙清除率不良。