Evaluation of the Oral and Lung Microbiota and Inflammation in Chronic Obstructive Pulmonary Disease Frequent Exacerbators

 描述(由申请人提供) 这是对Alexa A.Pragman博士的职业发展奖-2(CDA-2)的申请，他是明尼苏达大学的助理教授，有关于肺部微生物区系的研究和出版记录。她在以患者为导向的慢性阻塞性肺疾病(COPD)肺微生物区系临床研究中确立了自己作为年轻研究员的地位。她打算加入明尼阿波利斯退伍军人事务医疗中心(MVAMC)传染病科的工作人员。CDA-2将为Pragman博士提供必要的支持和培训，以实现以下目标：1)成为涉及肺微生物区系的临床和转译研究的专家；2)将先进的生物统计分析工具应用于临床微生物区系研究；3)设计涉及COPD和肺脏微生物区系的临床试验；以及4)成为独立的临床调查员。为了实现这些目标，普拉格曼博士组建了一个导师团队，成员包括研究分子流行病学的MVAMC研究员和传染病临床医生James R.Johnson博士；在COPD临床研究方面有专长的MVAMC肺科主任Christine Wendt博士；在微生物组研究方面有专长的高级研究员Richard E.Isaacson博士；以及在元基因组数据集的统计方法方面有专长的生物统计学家Cavan S.Reilly博士。他们将监督Pragman博士的职业发展，因为她参加了4门生物统计学课程，参加了两个国家基因组学研讨会，参加了MVAMC和明尼苏达大学的系列研讨会，发展了她的赠款撰写技能，在全国会议上发表了讲话，并提交了基金会赠款和功勋奖申请。COPD有多种疾病表型，导致这种异质性的机制尚不清楚。COPD肺微生物区系引起的炎症是一些患者频繁加重而其他患者不经常加重的潜在机制之一。在目标1中，Pragman博士将确定接受临床指征的肺叶切除术的患者，并以避免上呼吸道污染的方式对他们的口腔、鼻腔、痰和肺组织微生物群进行采样。这项研究将确定一种准确的、非侵入性的肺微生物区系采样方法。这项工作将确定COPD肺和没有上呼吸道污染的健康肺的微生物区系，并将建立一种研究肺微生物区系的非侵入性技术。在目标2中，Pragman博士将进行一项前瞻性研究，比较频繁加重者和罕见加重者的肺微生物区系和肺炎性生物标志物。她将确定特定的共同变化的微生物区系和痰炎症生物标志物，这些生物标志物可以识别病情恶化的表型，也可以作为新的COPD治疗的靶点。这两个目标都将利用先进的生物统计学工具，这将使普拉格曼博士能够将肺部微生物区系的特定特征与肺部炎症联系起来。拟议项目的总体目标是确定区分COPD患者的上呼吸道和肺微生物区系的关键特征，该患者具有频繁的恶化表型和罕见的恶化表型。普拉格曼博士的长期目标是了解肺部微生物区系在炎症性肺部疾病发病机制中的作用。这项工作将为进一步的临床和 肺微生物区系在COPD发病机制中的作用机制的翻译研究。这些研究将在CDA-2期间结束前在功绩奖申请中提出。

 DESCRIPTION (provided by applicant) This is an application for a Career Development Award-2 (CDA-2) to Dr. Alexa A. Pragman, M.D., Ph.D., an Assistant Professor at the University of Minnesota with a record of research and publications on the lung microbiota. She is establishing herself as a young investigator in patient-oriented clinical research of the chronic obstructive pulmonary disease (COPD) lung microbiota. She intends to join the staff at the Minneapolis Veterans Affairs Medical Center (MVAMC) in the Infectious Diseases Section. This CDA-2 will provide Dr. Pragman with the support and training necessary to achieve the following goals: 1) become an expert in clinical and translational research involving the lung microbiota; 2) apply advanced biostatistical analysis tools in clinical microbiota studies; 3) design clinical trials involving COPD and the lun microbiota; and 4) become an independent clinical investigator. To achieve these goals, Dr. Pragman has assembled a mentorship team consisting of Dr. James R. Johnson, a MVAMC researcher and infectious disease clinician who studies molecular epidemiology; Dr. Christine Wendt, the Pulmonary Section chief at MVAMC, with expertise in COPD clinical studies; Dr. Richard E. Isaacson, a senior researcher with expertise in microbiome studies; and Dr. Cavan S. Reilly, a biostatistician with expertise in statistical approaches to metagenomic data sets. They will monitor Dr. Pragman's career development as she takes 4 biostatistics courses, attends two national genomics workshops, participates in seminar series at MVAMC and the University of Minnesota, develops her grant-writing skills, presents at national conferences, and submits foundation grants and a Merit Award application. COPD has multiple disease phenotypes and the mechanisms responsible for this heterogeneity are poorly understood. Inflammation in response to the COPD lung microbiota is one potential mechanism by which some patients suffer frequent exacerbations and others do not. In Aim 1, Dr. Pragman will identify patients undergoing clinically indicated lung lobectomy and sample their oral, nasal, sputum, and lung tissue microbiota in a manner that avoids upper airway contamination. This study will identify a method for accurate, non- invasive sampling of the lung microbiota. This work will define the microbiota of the COPD lung and the healthy lung without upper airway contamination and will establish a non-invasive technique for studying the lung microbiota. In Aim 2, Dr. Pragman will conduct a prospective study comparing the lung microbiota and lung inflammatory biomarkers of frequent exacerbators to infrequent exacerbators. She will identify specific co-varying microbiota and sputum inflammatory biomarkers that can identify exacerbation phenotype and also serve as targets for new COPD therapies. Both aims will utilize advanced biostatistical tools, which will allow Dr. Pragman to correlate specific features f the lung microbiota with lung inflammation. The overall objective in the proposed project is to determine key features that differentiate the upper airway and lung microbiota of COPD patients with a frequent exacerbator phenotype from those with the infrequent exacerbator phenotype. Dr. Pragman's long-term goal is to understand the role of the lung microbiota in the pathogenesis of inflammatory lung disorders. This work will form the basis for further clinical and translational research to establish the mechanisms by which the lung microbiota contributes to COPD pathogenesis. These studies will be proposed in a Merit Award application before the end of the CDA-2 period.