Fungal Exposure and the Respiratory Tract Microbiome

真菌暴露和呼吸道微生物组

基本信息

批准号：
8791901
负责人：
Christopher M Evans
金额：
$ 31.05万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-15 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8791901
关键词：
Address Aerosols Affect Alveolar Animal Model Antifungal Agents Applications Grants Area Aspergillus Aspergillus oryzae Asthma Automobile Driving Bacteria Biology Breathing Child Chronic Chronic Obstructive Airway Disease Chronic lung disease Complex Data Deposition Development Disease Distal Economics Environment Environmental Exposure Environmental Health Exposure to Extrinsic allergic alveolitis Extrinsic asthma Fostering Funding Mechanisms Future Genetic Polymorphism Genus staphylococcus Glycoproteins Growth Health Health Care Costs Histopathology Host Defense Human Immune Immunity Impairment In Vitro Infection Inflammation Inflammatory Inflammatory Response Inhalation Exposure Investigation Knockout Mice Link Lower respiratory tract structure Lung Lung diseases MUC5AC gene MUC5B gene Measures Modeling Molds Mucins Mucociliary Clearance Mucositis Mucous Membrane Mucous body substance Mus Nature Nose Occupational Organism Oropharyngeal Particulate Pathogenesis Pathology Patients Personal Satisfaction Play Population Predisposition Process Production Regulation Relative (related person)Research Research Proposals Respiratory System Respiratory Tract Infections Respiratory tract structure Rest Role Saline Sinus Site Staphylococcus aureus Surface Taxon Testing Tissues Toxicant exposure Tracheobronchial Viral Wild Type Mouse Work aerosolized airway hyperresponsiveness allergic airway disease antimicrobial base body system design environmental agent in vivo interest man microbial microbiome mouse model novel overexpression particle pathogen respiratory response toxicant

项目摘要

DESCRIPTION (provided by applicant): The respiratory system is a central host-environment interface that is exposed to billions of particles and pathogens daily. Airway mucus is critical fo eliminating deposited environmental agents and limiting pathogen accumulation through a process called mucociliary clearance (MCC). Mucus production and composition are dramatically altered in numerous lung diseases. Recent studies have identified changes in the lung microbiome in asthma and COPD, but direct links between altered MCC function and changes in the respiratory microbiome have not been tested. In this exploratory grant proposal, mechanisms by which fungal toxicant exposure elicits changes will be identified in the upper and lower respiratory tract microbiomes along with the functional consequences of these changes. This work focuses on the major macromolecular components of airway mucus - mucin glycoproteins encoded by the MUC5AC and MUC5B genes. Recent studies in patients with asthma and COPD show that alterations in mucus production are related to differential regulation of MUC5AC (which goes up) and MUC5B (which remains stably expressed or goes down). To address whether mucins determine respiratory microbial diversity, Muc5ac and Muc5b knockout mice were recently generated. In the absence of an inflammatory challenge, Muc5b (but not Muc5ac) deficiency causes spontaneous lethal infections marked by acquisition of pulmonary Staphylococcus aureus infection. Thus, Muc5b is essential for controlling homeostatic and pathological microbial populations in the lungs. Here, the intent is to accomplish the primary purpose of this RFA - to test "how environmental exposures impact the composition and/or function of the microbiome" - in mouse models of respiratory inflammation. Aspergillus fungal exposure is a major cause of asthma exacerbations and several types of hypersensitivity pneumonitis, a related occupational lung disease. In preliminary studies, wild type mice exposed to an aerosol Aspergillus oryzae extract (AOE) show inflammation, increased Muc5ac, and reduced Muc5b expression similar to that seen in humans with asthma. Thus, it is hypothesized that AOE-induced changes in respiratory microbiome composition are dependent upon Muc5b expression levels and that these changes affect disease pathology and susceptibility to opportunistic pathogen infection. To test this, wild type mice will be exposed to aerosolized AOE. Changes will be measured in the upper and lower airway microbiota, and we will assess changes in inflammation, histopathology, and susceptibility to S. aureus. These data will be compared to that seen in Muc5b deficient and Muc5b overexpressing mice. Collectively, these studies will be used to develop a framework for designing and analyzing subsequent investigations in mice and in humans. MUC5B expression varies significantly in humans, and common genetic polymorphisms significantly regulate its expression. In addition treatments such as inhaled hypertonic saline enhance MCC effectively. Thus, successful completion of the proposed studies may significantly impact human health in the near-term.

描述（由申请人提供）：呼吸系统是宿主与环境的中央接口，每天暴露于数十亿颗粒和病原体。气道粘液对于消除沉积的环境因子和通过粘膜纤毛清除 (MCC) 过程限制病原体积累至关重要。在许多肺部疾病中，粘液的产生和成分发生了巨大的改变。最近的研究已经确定了哮喘和 COPD 中肺部微生物组的变化，但 MCC 功能改变与呼吸道微生物组变化之间的直接联系尚未得到测试。在这项探索性拨款提案中，将确定真菌毒物暴露引起上呼吸道和下呼吸道微生物组变化的机制以及这些变化的功能后果。这项工作的重点是气道粘液的主要大分子成分——由 MUC5AC 和 MUC5B 基因编码的粘蛋白糖蛋白。最近对哮喘和慢性阻塞性肺病患者的研究表明，粘液产生的变化与 MUC5AC（上升）和 MUC5B（保持稳定表达或下降）的差异调节有关。为了解决粘蛋白是否决定呼吸道微生物多样性，最近培育了 Muc5ac 和 Muc5b 基因敲除小鼠。在没有炎症挑战的情况下，Muc5b（但不是 Muc5ac）缺陷会导致自发性致命感染，其特征是获得肺部金黄色葡萄球菌感染。因此，Muc5b 对于控制肺部的稳态和病理微生物种群至关重要。在这里，目的是实现该 RFA 的主要目的 - 在呼吸道炎症的小鼠模型中测试“环境暴露如何影响微生物组的组成和/或功能”。接触曲霉菌是哮喘恶化和几种类型的过敏性肺炎（一种相关的职业性肺病）的主要原因。在初步研究中，暴露于气溶胶米曲霉提取物 (AOE) 的野生型小鼠表现出炎症、Muc5ac 表达增加和 Muc5b 表达减少，与人类哮喘患者相似。因此，推测 AOE 诱导的呼吸道微生物组组成变化取决于 Muc5b 表达水平，并且这些变化影响疾病病理学和对机会性病原体感染的易感性。为了测试这一点，野生型小鼠将暴露于雾化AOE。将测量上呼吸道和下呼吸道微生物群的变化，我们将评估炎症、组织病理学和对金黄色葡萄球菌的易感性的变化。这些数据将与 Muc5b 缺陷和 Muc5b 过表达小鼠中观察到的数据进行比较。总的来说，这些研究将用于开发一个框架，用于设计和分析小鼠和人类的后续研究。 MUC5B 的表达在人类中存在显着差异，常见的基因多态性显着调节其表达。此外，吸入高渗盐水等治疗可有效增强 MCC。因此，成功完成拟议的研究可能会在短期内显着影响人类健康。