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

• 批准号: 10002121
• 负责人: Julie Gunnells Ledford
• 金额: $ 50.3万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 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/10002121
• 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; Respiratory physiology; 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; pathogen; predictive marker; prevent; programs; receptor; recruit; response; secretory protein; translational approach; young adult

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COPD是美国最常见的慢性肺部疾病。研究有 表明哮喘是通过低肺功能发展而发展的COPD的最重要危险因素 从学龄前到成年。但是，理解基本的基本差距 这种进展的基本机制。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学标志物的潜力和我们小组的最新研究得出的结论是，低 循环CC16水平预测儿童期肺功能增长受损，哮喘或COPD的风险增加 在成人生活中。在我们的队列中，患有低血清CC16水平且抗体水平升高的成年人 针对肺炎支原体（MP），其发展气流限制的几率增加了8倍。 这些研究强调了对防止肺功能下降的完整免疫系统的关键需求 并提供证据表明持续的早期生活感染可能是以前被忽视的理解联系 哮喘的进展为严重的哮喘，并具有固定的气流限制。我们开发了早期的鼠标模型 WT或CC16缺乏小鼠被感染的预性和评估肺功能的MP的生命暴露于MP中 成年后发现CC16 - / - 小鼠的气道发炎持续炎症，超过1000％ 与WT对照相比，基线气道电阻，这可能归因于炎症和气道 重塑。总体假设是CC16在MP驱动的炎症过程中起保护作用 取决于结合其新发现的受体，整联蛋白VLA-4。 CC16的作用减弱了肺 炎症，重塑和气道高反应性。该假设将通过追求三个 具体目的：1）确定CC16缺乏对肺部炎症，重塑和肺的影响 使用肺炎支原体感染小鼠模型的功能，其中包括早期生活与成人之间的比较 感染，2）确定CC16保护炎症，重塑和丧失的机制是否是否 肺功能取决于VLA-4受体，3）确定CC16缺陷的影响 使用来自多个的数据和样品的炎症，重塑因子和肺功能感染MP感染 人类纵向人群。该建议具有创新性，因为我们已经确定了以前未知的 CC16，粘附分子VLA-4的受体，我们采用一种新型的翻译方法来测试我们的 使用体内研究，动物模型和人类样本的假设 国际队列。拟议的研究很重要，因为这些发现将描述一种新的机制 CC16以保护方式起作用，并可能立即适用于其他肺部 病原体。由于CC16是一种有益且预测性的生物标志物，因此我们的研究可能提供一种新颖的治疗性 治疗低循环CC16的个体以防止肺功能随着时间的推移而下降的方法。