Advancing our Understanding of the Development, Phenotypes, and Progression of Chronic Rejection after Lung Transplantation

Project Summary/Abstract Michael Combs, MD, MS is a Pulmonary and Critical Care physician at the University of Michigan. This K23 proposal outlines the mentored research and training required for Dr. Combs to achieve his long-term goal of becoming an independent physician-scientist and a leader in understanding the factors which cause and perpetuate chronic rejection after lung transplantation. The leading cause of long-term morbidity and mortality after lung transplant is chronic rejection, also called chronic lung allograft dysfunction (CLAD). Currently, no effective prediction models exist either for 1) the development of CLAD among healthy lung transplant recipients and 2) survival after CLAD development. This key research gap limits both clinicians’ ability to personalize care and researchers’ ability to design, power, and stratify clinical trials. CLAD develops and evolves within a complex interplay of 1) altered lung microbiota, 2) recipient-derived immune responses, and 3) fibrotic remodeling orchestrated by activated allograft-derived mesenchymal cells. In previously published studies, Dr. Combs has demonstrated that signals in bronchoalveolar lavage (BAL) fluid from across these biological domains represent novel risk factors for CLAD with plausible roles in disease pathogenesis. In this proposal, Dr. Combs will develop clinical risk prediction models for CLAD development and post-CLAD survival which integrate patient-specific clinical data and the biological signals in BAL fluid. By completing these Aims, Dr. Combs will develop new experience and expertise in patient-oriented clinical research, microbiome-focused computational biology, advanced statistical analysis (including machine learning approaches), and transplant-focused lung immunology. His training will be supervised by his co-mentors, Robert Dickson, MD, and Vibha Lama, MD, MS, who have decades of experience and expertise in clinical research, mentorship of aspiring physician-scientists, and the translational study of lung transplantation, the lung microbiome (Dr. Dickson), and mesenchymal cell biology (Dr. Lama). His training will further be supported by an advisory committee with expertise in advanced computational biology and statistical modeling/machine learning approaches (Susan Murray, ScD) and pulmonary immunology (Bethany Moore, PhD). Completion of this progressively independent research project will lead to subsequent R03 and R01 applications validating these prediction models of CLAD development and post-CLAD survival in prospective, multi-center cohorts.