This proposal presents a five-year research career development program focused on studying gut fungal commensal ecology, the mycobiome, in the neonatal period in order to advance mechanistic understanding of the role of the gut-lung axis in bronchopulmonary dysplasia (BPD). This research development plan is designed to provide the candidate, an Assistant Professor of Pediatrics and neonatologist at the University of Tennessee Health Science Center, with the mentorship, training and research experience required to accelerate his development into an independent clinician scientist in the field of neonatal mucosal immunology. To achieve the candidate?s long-term goal of leading a productive translational research program focused on understanding the role of mucosal immunology in BPD and facilitate his transition to independence, the candidate and his established mentors have devised a comprehensive development plan based on: 1) intensive, personal mentorship from a team with a proven history of productive mentoring, 2) in-depth experimental and focused didactic training to advance his understanding of molecular mycology, gnotobiotics and clinical research methods and 3) an innovative research plan to produce causal evidence for the role of the gut mycobiome in the development of BPD. The candidate?s research development plan outlines a focused path to obtain the knowledge, skills and experience required to accelerate his development into a leading, independent clinician scientist that will make a lasting impact on the field of neonatal mucosal immunology BPD is the most serious pulmonary complication of preterm birth. Therapeutic approaches to modify developmental risk factors for BPD are lacking. Neonatal models of the gut-lung axis in other lung diseases, epidemiological studies linking antibiotic exposure with increased risk to develop BPD and the candidate?s extensive preliminary studies in mice and preterm newborns strongly suggest that the gut mycobiome represents a novel therapeutic target to influence the development of BPD. This proposal builds on the candidate?s prior experience and the expertise of his mentors, to explore the mechanistic underpinnings of the neonatal gut-lung axis. We will test two hypotheses: 1) Prenatal antibiotic exposure-induced mycobiome alterations drive increased BPD severity by disrupting the gut-lung axis; and 2) Colonization with commensal fungi favorably alters the pulmonary mucosal immune response to hyperoxia. Achieving the objective of this proposal to determine if disruption of intestinal commensal microbial communities contributes to the development of lung injury in BPD will inform the development of therapeutics designed to mitigate BPD. These studies are expected to lay the groundwork for eventual confirmatory studies and therapeutic trials in human preterm newborns.
Bronchopulmonary dysplasia, a devastating chronic lung disease with debilitating long-term consequences, affects approximately half of all infants born extremely preterm. The objectives of this proposal are relevant to public health because they aim to establish that bacterial communities in the gut influence development of bronchopulmonary dysplasia by altering the immune responses of the developing lung. Successful completion of this proposal will provide insight into extra-pulmonary contributions to lung development and characterize new targets for therapy, which addresses goals of the NIH to seek mechanistic understanding of the microbiome in the pathobiology of lung diseases and reduce the incidence of chronic lung disease during early life.
