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.

Public Health Relevance

Chronic obstructive pulmonary disease (COPD) is the third-leading cause of death in the U.S. and is more often found in veterans than non-veterans. COPD is a chronic disease that generates significant health care costs to the Veterans Affairs Health Care System. Unfortunately, the clinical course of this lung disorder is difficult to predict and poorly understood. Our results may determine key features that differentiate the upper airway and lung microbiota of patients with frequent COPD exacerbations from those who experience less frequent COPD exacerbations. We may identify new targets for COPD treatment by identifying two new mechanisms of COPD progression: 1) aspiration of oral bacteria and 2) emergence of specific bacteria in the lung microbiota. Identification of new disease mechanisms may improve the care of veterans with COPD and decrease costs for the Veterans Affairs Health Care System.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (IK2)
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Minneapolis VA Medical Center
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Kunisaki, Ken M; Dransfield, Mark T; Anderson, Julie A et al. (2018) Exacerbations of Chronic Obstructive Pulmonary Disease and Cardiac Events. A Post Hoc Cohort Analysis from the SUMMIT Randomized Clinical Trial. Am J Respir Crit Care Med 198:51-57
Pragman, Alexa A; Lyu, Tianmeng; Baller, Joshua A et al. (2018) The lung tissue microbiota of mild and moderate chronic obstructive pulmonary disease. Microbiome 6:7