The gut-lung axis influences the development of bronchopulmonary dysplasia

该提案提出了一个为期五年的研究职业发展计划，重点关注新生儿时期的肠道真菌共生生态学（真菌生物组），以促进对支气管肺发育不良（BPD）肠肺轴的机制理解。该研究发展计划旨在为阿拉巴马大学伯明翰分校的儿科助理教授和新生儿学家候选人提供所需的指导、培训和研究经验，以加速他成长为新生儿粘膜免疫学领域的独立临床科学家。为了实现候选人领导一项富有成效的转化研究计划的长期目标，重点是了解 BPD 中的粘膜免疫学并促进其向独立过渡，候选人和他既定的导师制定了一项全面的发展计划，该计划基于：1）来自具有丰富的指导历史的团队的密集的个人指导； 2）深入的体验式和有针对性的教学培训，以增进他对分子真菌学、知生学和临床研究方法的理解； 3) 一项创新研究计划，以提供肠道菌群参与 BPD 发展的因果证据。候选人的研究发展计划概述了获得所需知识、技能和经验的重点路径，以加速其发展成为一名独立的临床科学家，对新生儿粘膜免疫学产生持久影响。 BPD是早产最严重的肺部并发症。目前缺乏改变 BPD 发育风险因素的治疗方法。其他肺部疾病中肠肺轴的新生儿模型、将抗生素暴露与 BPD 发展风险增加联系起来的流行病学研究，以及候选人在小鼠和早产新生儿中进行的广泛初步研究强烈表明，肠道菌群代表了影响 BPD 发展的治疗靶点。该提案建立在候选人之前的经验和导师的专业知识的基础上，探索新生儿肠肺轴的机制。我们将检验两个假设。 1) 产前抗生素暴露引起的真菌组变化通过扰乱肠肺轴而导致 BPD 严重程度增加。 2）共生真菌的定殖有利地改变肺粘膜对高氧的免疫反应。确定肠道共生微生物群落的破坏是否会导致 BPD 肺损伤的发生，将为缓解 BPD 的治疗方法的开发提供信息。这些研究预计将为人类早产新生儿的转化研究奠定基础。

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.