Microbial Dysbiosis Among Veterans Following Deployment-Related Airborne Exposures

以下是传染病专科医生Alexa A.Pragman博士荣誉奖的申请书 明尼阿波利斯退伍军人事务部的疾病专家和明尼苏达大学的助理教授。普拉格曼医生的 目前关于慢性阻塞性肺疾病肺微生物区系的工作是由五年的职业生涯资助的 发展奖-2由退伍军人事务部研发办公室颁发。普拉格曼博士已经建立了一种 年她在肺微生物区系方面以病人为中心的工作成就和出版物记录 慢性炎症性肺部疾病。这项荣誉奖将提供必要的资源来研究 驻西南地区空气细颗粒物污染对退伍军人肺微生物区系的影响 亚洲(伊拉克、阿富汗或邻国)。 在被部署到西南亚后，退伍军人受到慢性肺部问题的影响不成比例 包括咳嗽、喘息和呼吸急促。在部署期间，这些退伍军人接触到了 季节性沙尘导致空气中≤2.5μm的颗粒物浓度超标 暴风雨、焚烧矿井烟雾和工业污染。PM2.5暴露导致急性和慢性呼吸道疾病 问题，并可能导致疾病，如哮喘和慢性阻塞性肺疾病。PM2.5 在人类和啮齿动物模型中，暴露与呼吸道和肠道微生物区系失调有关，提示 这种生物失调是炎症、症状和持续的肺组织破坏的潜在媒介。 过多的PM2.5暴露已经停止很久了。生物失调被定义为一种不平衡或适应不良 栖息在特定地点的微生物群落。 在这份功勋奖申请书中，普拉格曼博士提出了一项前瞻性病例对照研究，以评估 PM2.5暴露、微生物区系失调和炎症之间的关系。这将在#年完成 与退伍军人事务部合作研究#595，已部署退伍军人的服务和健康(SHADE)， 旨在了解部署期间PM2.5暴露与随后呼吸之间的关系 症状。普拉格曼博士的研究将招募140名患有慢性肺部症状(咳嗽、 呼吸急促或喘息)和140名无慢性肺部症状的阴影参与者。所有受试者都将 每年提供唾液和粪便样本，用于微生物区系分析，为期3年。痰标本： 微生物区系分析也将在相同的时间表上从受试者的子集中获得。我们将评估 微生物区系失调和炎症的组织特异性和系统性标记物。我们的分析将考虑到 考虑PM2.5暴露水平(从阴影研究中获得)、组织或站点特定的影响，并结合 微生物生态失调的其他风险因素。在目标1中，普拉格曼博士将确定 与部署相关的PM2.5暴露和特定部位的生物失调。在《目标2》中，普拉格曼博士将确定 特定部位的生物失调与呼吸道症状之间的关系。在《目标3》中，普拉格曼博士将确定 特定部位的生物失调和炎症之间的联系。我们的总体目标是建立微生物 作为PM2.5暴露和呼吸道症状之间的中介的生物失调。我们的中心假设是 部署退伍军人的PM2.5暴露使他们面临更高的生物失调风险，这反过来又增加了 出现慢性呼吸道症状和疾病。这些发现可能会确定退伍军人患心脏病的风险很高 发展中的肺部疾病，并可能确定一个新的治疗目标-微生物区系-原发和继发性 在这一高危退伍军人群体中预防肺病。

This is an application for a Merit Award to Dr. Alexa A. Pragman, M.D., Ph.D., a Staff Physician in Infectious Disease at the Minneapolis VA and an Assistant Professor at the University of Minnesota. Dr. Pragman’s current work on the chronic obstructive pulmonary disease lung microbiota is funded by a 5-year Career Development Award-2 from the VA Office of Research and Development. Dr. Pragman has established a record of accomplishments and publications related to her patient-oriented work on the lung microbiota in chronic inflammatory pulmonary diseases. This Merit Award will provide the resources necessary to study the effects of fine particle airborne pollution on the lung microbiota of veterans following deployment to southwest Asia (Iraq, Afghanistan, or neighboring countries). Following deployment to southwest Asia, veterans are disproportionately affected by chronic lung problems including coughing, wheezing, and shortness of breath. While deployed, these veterans were exposed to excessive concentrations of airborne particulate matter of ≤2.5 μm in size (PM2.5) as a result of seasonal dust storms, burn pit smoke, and industrial pollution. PM2.5 exposure causes acute and chronic respiratory problems, and may lead to diseases such as asthma and chronic obstructive pulmonary disease. PM2.5 exposure has been linked to airway and gut microbiota dysbiosis in humans and rodent models, suggesting that dysbiosis is a potential mediator for the inflammation, symptoms, and lung tissue destruction that continue long after excessive PM2.5 exposure has stopped. Dysbiosis is defined as an imbalance or maladaptation in the community of micro-organisms inhabiting a particular site. In this Merit Award application, Dr. Pragman proposes a prospective case-control study to assess the relationships between PM2.5 exposure, microbiota dysbiosis, and inflammation. This will be accomplished in collaboration with VA Cooperative Study #595, Service and Health Among Deployed Veterans (SHADE), which aims to understand the association between PM2.5 exposures during deployment and subsequent respiratory symptoms. Dr. Pragman’s study will recruit 140 SHADE participants with chronic lung symptoms (coughing, shortness of breath, or wheezing) and 140 SHADE participants without chronic lung symptoms. All subjects will provide saliva and stool samples for microbiota analyses on an annual basis for 3 years. Sputum samples for microbiota analysis will also be obtained from a subset of subjects on the same schedule. We will assess microbiota dysbiosis and tissue-specific and systemic markers of inflammation. Our analysis will take into account PM2.5 exposure levels (obtained from the SHADE study), tissue or site-specific effects, and incorporate other risk factors for microbial dysbiosis. In Aim 1, Dr. Pragman will determine associations between deployment-related PM2.5 exposure and site-specific dysbiosis. In Aim 2, Dr. Pragman will determine associations between site-specific dysbiosis and respiratory symptoms. In Aim 3, Dr. Pragman will determine site-specific associations between dysbiosis and inflammation. Our overall objective is to establish microbial dysbiosis as a mediator between PM2.5 exposure and respiratory symptoms. Our central hypothesis is that deployed veterans’ PM2.5 exposures place them at increased risk for dysbiosis, which in turn increases risk of developing chronic respiratory symptoms and disease. These findings may identify veterans at high risk for developing lung disease, and may identify a new treatment target—the microbiota—for primary and secondary prevention of lung disease in this high-risk veteran population.