CC16: A Link between Airway Infection and Obstructive Lung Disease

CC16：气道感染与阻塞性肺病之间的联系

基本信息

批准号：
10221771
负责人：
Julie Gunnells Ledford
金额：
$ 51.61万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221771
关键词：
5 year old Adrenal Cortex Hormones Adult Affect Age Airway Resistance Animal Model Antibodies Asthma Attenuated Automobile Driving Bacteria Binding Binding Sites Biological Markers Cell Adhesion Molecules Cells Child Childhood Childhood Asthma Chronic Obstructive Airway Disease Chronic lung disease Data Development Diagnosis Disease Distal Emergency department visit Epidemiology Epithelial Cells Exposure to Foundations Gene Expression General Population Genes Growth Human Immune system Impairment Individual Infection Inflammation Inflammatory Integrin Binding Integrin alpha4beta1 Integrins International Lead Life Ligands Link Longitudinal Studies Longitudinal cohort Lung Lung Inflammation Mediator of activation protein Modeling Mus Mycoplasma pneumoniae Obstructive Lung Diseases Oral Participant Patients Persons Play Predisposition Proteins Pulmonary Function Test/Forced Expiratory Volume 1 Pulmonary Inflammation Reporting Research Respiratory Tract Infections Risk Risk Factors Role Saline Sampling School-Age Population Secretory Cell Serum Severities Site Testing Time United States Uteroglobin Weaning airway epithelium airway hyperresponsiveness airway inflammation airway obstruction airway remodeling asthmatic cell injury chronic infection cohort early life exposure innovation mouse model novel novel therapeutic intervention predictive marker prevent programs pulmonary function pulmonary function decline receptor recruit respiratory pathogen response secretory protein systemic inflammatory response translational approach young adult

项目摘要

PROJECT ABSTRACT Asthma and COPD are the most commonly diagnosed chronic lung diseases in the United States. Studies have shown that asthma is the most important risk factor for COPD that develops through a course of low lung function from school age that tracks into adulthood. However, there is a fundamental gap in understanding the basic underlying mechanisms of this progression. Club cell secretory protein (CC16) has been described for its potential as a biological marker of lung epithelial cell injury and recent studies by our group concluded that low circulating CC16 levels predict impaired lung function growth in childhood and increased risk of asthma or COPD in adult life. In our cohort, adults with asthma with low serum CC16 levels and elevated levels of antibodies against M. pneumoniae (Mp) have a striking 8-fold increase in their odds of developing airflow limitation. These studies highlight the critical need for an intact immune system that protects against lung function decline and provide evidence that persistent early life infections may be a previously overlooked link in understanding progression of asthma into severe asthma with fixed airflow limitation. We developed a mouse model of early life exposure to Mp in which WT or CC16 deficient mice are infected pre-weaning and assessed for lung function in adulthood and found that CC16-/- mice have persistent airway inflammation and a striking >1000% over baseline airways resistance as compared to WT controls, which is likely attributed to inflammation and airway remodeling. The overall hypothesis is that CC16 plays a protective role during Mp-driven inflammation that is dependent on binding to its newly discovered receptor, the integrin VLA-4. The action of CC16 attenuates lung inflammation, remodeling and airway hyperresponsiveness. This hypothesis will be tested by pursuing three specific aims: 1) Determine the impact of CC16 deficiency on pulmonary inflammation, remodeling and lung function using M. pneumoniae infection mouse models that include comparisons between an early life and adult infections, 2) Determine if the mechanism by which CC16 protects against inflammation, remodeling and loss of lung function is dependent on the VLA-4 receptor, and 3) Determine the impact of CC16 deficits in association with Mp infection on inflammation, remodeling factors and lung function using data and samples from multiple human longitudinal cohorts. This proposal is innovative in that we have identified a previously unknown receptor for CC16, adhesion molecule VLA-4 and we employ a novel translational approach to test our hypothesis using ex vivo studies, animal models, and human samples from well-characterized local and international cohorts. The proposed research is significant in that these findings will describe a new mechanism by which CC16 functions in a protective manner and may be immediately applicable to other pulmonary pathogens. Since CC16 is an informative and predictive biomarker, our studies may provide a novel therapeutic approach for treating individuals with low circulating CC16 in order to prevent lung function decline over time.

项目摘要哮喘和慢性阻塞性肺病是美国最常诊断的慢性肺部疾病。研究有研究表明，哮喘是慢性阻塞性肺病 (COPD) 的最重要危险因素，慢性阻塞性肺病 (COPD) 是通过肺功能低下的过程发展而来的从学龄期一直到成年期。然而，在理解基本原理方面存在着根本性的差距。这一进展的潜在机制。俱乐部细胞分泌蛋白 (CC16) 已被描述为作为肺上皮细胞损伤的生物标志物的潜力，我们小组最近的研究得出的结论是，低循环 CC16 水平可预测儿童期肺功能发育受损以及哮喘或慢性阻塞性肺病 (COPD) 风险增加在成人生活中。在我们的队列中，患有哮喘的成年人血清 CC16 水平较低且抗体水平升高肺炎支原体 (Mp) 出现气流受限的几率显着增加 8 倍。这些研究强调了对完整免疫系统的迫切需求，以防止肺功能下降并提供证据表明持续的早期生命感染可能是以前被忽视的理解环节哮喘进展为严重哮喘并伴有固定气流限制。我们开发了早期的小鼠模型终生暴露于 Mp，其中 WT 或 CC16 缺陷小鼠在断奶前被感染并评估肺功能在成年期，发现 CC16-/- 小鼠有持续性气道炎症，并且超过 1000% 与 WT 对照相比，基线气道阻力，这可能归因于炎症和气道重塑。总体假设是 CC16 在 Mp 驱动的炎症过程中发挥保护作用，即依赖于与其新发现的受体整合素 VLA-4 的结合。 CC16 的作用会减弱肺功能炎症、重塑和气道高反应性。这个假设将通过追求三个具体目标：1) 确定 CC16 缺乏对肺部炎症、重塑和肺部的影响使用肺炎支原体感染小鼠模型进行功能，包括早期和成年之间的比较感染，2) 确定 CC16 是否通过机制防止炎症、重塑和丧失肺功能依赖于 VLA-4 受体，并且 3) 确定 CC16 缺陷的相关影响使用多个数据和样本研究 Mp 感染对炎症、重塑因子和肺功能的影响人类纵向队列。这个提议的创新之处在于我们发现了一个以前未知的 CC16 受体、粘附分子 VLA-4，我们采用一种新颖的翻译方法来测试我们的使用离体研究、动物模型和来自充分表征的当地和人类样本的假设国际队列。拟议的研究意义重大，因为这些发现将描述一种新机制 CC16 以保护性方式发挥作用，并可立即适用于其他肺部疾病病原体。由于 CC16 是一种信息性和预测性生物标志物，我们的研究可能提供一种新的治疗方法治疗低循环 CC16 个体的方法，以防止肺功能随着时间的推移而下降。