Host-microbiome interactions after lung transplantation and chronic lung allograft dysfunction

PROJECT SUMMARY/ABSTRACT This project describes a 5-year mentored career development plan with the goal of training the principal investigator to become an independent physician-scientist who investigates host-microbe interactions in lung disease. The applicant is a Clinical Instructor in the Pulmonary and Critical Care Division of the Department of

Medicine at the Perelman School of Medicine at the University of Pennsylvania. He is mentored by Ronald Collman, MD who is a Professor of Medicine and Microbiology and a pioneer in the lung microbiome field and also an expert in molecular virology. Jason Christie, MD, MSCE is a Professor of Medicine and Epidemiology

who is a molecular epidemiologist with expertise in complications of lung transplantation and the use of biostatistical methods to model complex lung disease. The research plan uses clinical-translational methodology and computational biology to gain mechanistic understanding of host-microbiome interactions in the lung after

transplantation and their role in chronic lung allograft dysfunction (CLAD)—the most common cause of graft failure and death after one-year post-transplant. This proposal responds directly to NHLBI’s Strategic Vision objective to understand the influence of the microbiome on lung health. With the support of this K23 award, Dr. McGinniss will in Aim 1 analyze the microbiome of bronchoalveolar

lavage fluid (BAL) from a longitudinal cohort study of lung transplant patients at risk of CLAD. He will use advanced biostatistical approaches to understand the relation of early lung microbiome dysbiosis—changes in the composition, relative abundance, or function of microbes—in the first year after transplant and later CLAD.

In Aim 2 he will create a CLAD case-control study of 24 cases and 24 matched controls. He will enroll the final 12 cases and 12 controls. He will use this case-control study to perform a multi-omic analysis of the microbiome and host responses to understand mechanisms of CLAD. In Aim 3, he will use unbiased metabolomics to

discover novel biomarkers and to interrogate metabolic dysregulation in CLAD. He will also assess the role the metabolome has in mediating pathological host-microbe interactions. In addition, he will do targeted analysis of the metabolome and inflammatory markers in longitudinal cohort study to assess if they are aberrant before the

diagnosis of CLAD. Dr. McGinniss has outlined a rigorous training plan of coursework, skills acquisition (with a focus on clinical- translational methods, computational biology, and advanced metagenomics), and career development. He has assembled a distinguished, multidisciplinary mentorship team to realize this vision. Penn provides an exceptional

intellectual and collaborative environment for this proposal with considerable resources in the PennCHOP Microbiome Program and the Institute of Translational Medicine Therapeutics (ITMAT) that will be leveraged in this award. Dr. McGinniss is well-positioned to successfully compete the aims and training plan so that he will

be a competitive applicant for an R01 award further exploring host-microbe interactions in chronic lung disease.