The gut-lung axis influences the development of bronchopulmonary dysplasia

点击翻译按钮获取中文摘要

ABSTRACT This proposal presents a five-year research career development program focused on gut fungal commensal ecology, the mycobiome, in the neonatal period to advance mechanistic understanding 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 Alabama at Birmingham, with the mentorship, training and research experience required to accelerate his development into an independent clinician scientist in neonatal mucosal immunology. To achieve the candidate’s long-term goal of leading a productive translational research program focused on understanding 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 experiential 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 gut mycobiome involvement in BPD development. The candidate’s research development plan outlines a focused path to obtain the knowledge, skills and experience required to accelerate his development into an independent clinician scientist who will have a lasting impact on neonatal mucosal immunology. BPD is the most serious pulmonary complication of preterm birth. Treatments 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 of BPD development, and the candidate’s extensive preliminary studies in mice and preterm newborns strongly suggest the gut mycobiome represents a therapeutic target to influence BPD development. This proposal builds on the candidate’s prior experience and the expertise of his mentors to explore the mechanisms of the neonatal gut-lung axis. We will test two hypotheses. 1) Prenatal antibiotic exposure-induced mycobiome changes drive increased BPD severity by disrupting the gut-lung axis. 2) Colonization with commensal fungi favorably alters the pulmonary mucosal immune response to hyperoxia. Determining if disruption of intestinal commensal microbial communities contributes to the development of lung injury in BPD will inform the development of therapeutics for mitigating BPD. These studies are expected to lay the groundwork translational studies in human preterm newborns.