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）：呼吸系统是一种中央宿主环境界面，每天暴露于数十亿个颗粒和病原体。气道粘液是至关重要的FO，可以消除沉积的环境药物，并通过称为粘膜钙清除（MCC）的过程限制病原体的积累。在许多肺部疾病中，粘液产生和成分发生了巨大改变。最近的研究已经确定了哮喘和COPD中肺微生物组的变化，但是尚未测试MCC功能改变与呼吸微生物组变化之间的直接联系。在此探索性批准建议中，将在上和下呼吸道微生物组中确定真菌毒物暴露的机制以及这些变化的功能后果。这项工作着重于由MUC5AC和MUC5B基因编码的气道粘液 - 粘蛋白糖蛋白的主要大分子成分。最近对哮喘和COPD患者的研究表明，粘液产生的改变与MUC5AC（上升）和MUC5B的差异调节有关（它们保持稳定表达或下降）。为了解决粘蛋白是否确定呼吸微生物多样性，最近产生了MUC5AC和MUC5B敲除小鼠。在没有炎症挑战的情况下，MUC5B（但不是MUC5AC）缺乏会导致自发致死感染，这是通过获得金黄色葡萄球菌感染的获得的。因此，MUC5B对于控制肺中的稳态和病理微生物种群至关重要。在这里，目的是实现此RFA的主要目的 - 测试“环境暴露如何影响微生物组的组成和/或功能” - 在呼吸道炎症的小鼠模型中。曲霉真菌暴露是哮喘病变和几种类型的超敏性肺炎（一种相关职业肺部疾病）的主要原因。在初步研究中，暴露于气溶胶曲霉提取物（AOE）的野生型小鼠显示炎症，MUC5AC增加，并降低MUC5B表达，类似于哮喘的人类。因此，假设AOE诱导的呼吸微生物组组成的变化取决于MUC5B的表达水平，并且这些变化会影响疾病的病理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的AOE。将在上和下气道微生物群中测量变化，我们将评估炎症，组织病理学和对金黄色葡萄球菌的敏感性的变化。这些数据将与MUC5B缺乏和MUC5B过表达小鼠中的数据进行比较。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随后研究。 MUC5B的表达在人类中有很大差异，常见的遗传多态性显着调节其表达。此外，诸如吸入高渗盐水之类的治疗方法可有效增强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。