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 mic...