The gut-lung axis influences the development of bronchopulmonary dysplasia

这项建议提出了一个为期五年的研究生涯发展计划，重点是新生儿时期的肠道真菌共生生态学，真菌生物群，以促进对支气管肺发育不良(BPD)肠道-肺轴的机械理解。这项研究发展计划旨在为候选人、阿拉巴马大学伯明翰分校儿科学和新生儿专家助理教授提供所需的指导、培训和研究经验，以加速他发展成为新生儿粘膜免疫学的独立临床科学家。为了实现候选人领导专注于了解BPD黏膜免疫学的富有成效的翻译研究项目并促进他向独立性过渡的长期目标，候选人和他的既定导师设计了一个全面的发展计划，其基础是：1)来自具有成熟指导历史的团队的密集的个人指导；2)深入的体验式和专注的教学培训，以加深他对分子真菌学、生理学和临床研究方法的理解；以及3)创新的研究计划，以提供肠道真菌生物群参与BPD发展的因果证据。候选人的研究发展计划勾勒出一条有重点的途径，以获得所需的知识、技能和经验，以加速他成为对新生儿粘膜免疫学产生持久影响的独立临床科学家。 BPD是早产最严重的肺部并发症。缺乏改变BPD发展风险因素的治疗方法。其他肺部疾病中肠道-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，以及候选动物在小鼠和早产儿中的广泛初步研究强烈表明，肠道真菌菌群代表着影响BPD发展的治疗靶点。这项建议建立在候选人先前的经验和他的导师的专业知识的基础上，以探索新生儿肠道-肺轴的机制。我们将检验两个假设。1)产前接触抗生素引起的霉菌群改变通过破坏肠道-肺轴而导致BPD严重程度增加。2)共生真菌的定植有利于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有助于BPD肺损伤的发展，将为减轻BPD的治疗方法的发展提供信息。这些研究有望为人类早产儿的翻译研究奠定基础。

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.