The gut-lung axis influences the development of bronchopulmonary dysplasia

该提案提出了一项为期五年的研究职业发展计划，重点是新生儿期的肠道真菌群落生态学，即真菌群落，以促进对支气管肺发育不良（BPD）肠肺轴的机械理解。该研究开发计划旨在为候选人（伯明翰亚拉巴马大学的儿科助理教授和儿科医生）提供所需的指导、培训和研究经验，以加速其发展成为新生儿粘膜免疫学的独立临床科学家。为了实现候选人的长期目标，即领导一个富有成效的转化研究项目，重点是了解BPD中的粘膜免疫学，并促进他向独立的过渡，候选人和他的导师制定了一个全面的发展计划，该计划基于：1）来自一个具有生产指导历史的团队的密集的个人指导; 2）深入的经验和重点教学培训，以提高他对分子真菌学，gnotobiotics和临床研究方法的理解;和3）创新的研究计划，以产生肠道真菌组参与BPD发展的因果证据。候选人的研究发展计划概述了一个重点路径，以获得加速发展成为独立的临床科学家所需的知识，技能和经验，这将对新生儿粘膜免疫学产生持久的影响。 BPD是早产最严重的肺部并发症。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儿中的广泛初步研究，强烈表明肠道真菌生物群是影响BPD发展的治疗靶点。这个建议建立在候选人的先前经验和他的导师的专业知识，以探索新生儿肠肺轴的机制。我们将测试两个假设。1)产前抗生素暴露诱导的真菌生物群系变化通过破坏肠-肺轴来增加BPD的严重程度。2)真菌定植可有利地改变肺粘膜对高氧的免疫反应。确定肠道微生物群落的破坏是否有助于BPD肺损伤的发展，将为缓解BPD的治疗方法的开发提供信息。这些研究有望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.