The gut-lung axis influences the development of bronchopulmonary dysplasia

肠肺轴影响支气管肺发育不良的发展

• 批准号: 10559262
• 负责人: Kent Avery Willis
• 金额: $ 2.7万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10559262
• 关键词: Address; Affect; Alabama; Antibiotics; Blood Vessels; Bronchopulmonary Dysplasia; Cell Wall; Chronic lung disease; Clinical Research; Communities; Complication; Development; Development Plans; Disease; Ecology; Education; Exhibits; Exposure to; Feces; Germ-Free; Gnotobiotic; Goals; Human; Hyperoxia; Immune; Immune response; Immune system; Immunologics; Immunology; Incidence; Infant; Inflammation; Intestines; Knowledge; Lead; Life; Link; Long-Term Effects; Lung; Lung diseases; Lymphoid Cell; Machine Learning; Mentors; Mentorship; Modeling; Molecular; Morphology; Mucosal Immune Responses; Mucous Membrane; Mus; Neonatal; Newborn Infant; Outcome; Pediatrics; Perinatal; Phenotype; Play; Population; Premature Birth; Premature Infant; Prevention; Program Development; Public Health; Pulmonary Fibrosis; Pulmonary Inflammation; Recording of previous events; Research; Research Methodology; Risk; Risk Factors; Role; Scientist; Severities; Shapes; Specificity; Structure; Testing; The science of Mycology; Therapeutic; Time; Training; United States National Institutes of Health; Universities; bacterial community; base; career development; critical developmental period; density; design; epidemiology study; experience; fungus; gut microbiome; gut microbiota; gut-lung axis; improved; innovation; insight; interstitial; lung development; lung injury; member; microbial community; microbiome; microbiome alteration; microbiome components; microbiome composition; mortality; mouse model; mycobiome; neonatal mice; neonatal period; neonate; pneumonia model; pre-clinical; prenatal; preterm newborn; professor; protective effect; pulmonary function; research and development; respiratory microbiome; screening; skills; standard of care; therapeutic development; therapeutic target; translational research program; translational study

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.

摘要 该提案提出了一个为期五年的研究职业发展计划，重点是肠道真菌真菌 生态学，真菌群落，在新生儿期，以推进肠肺轴的机械理解， 支气管肺发育不良（BPD）。本研究开发计划旨在为候选人提供 位于伯明翰的亚拉巴马大学的儿科助理教授和儿科医生， 导师，培训和研究经验，以加速他的发展成为一个独立的 新生儿粘膜免疫学临床科学家。为了实现候选人的长期目标， 生产性转化研究计划，重点是了解BPD的粘膜免疫学，并促进 在过渡到独立的过程中，候选人和他的导师们制定了一个全面的 发展计划基于：1）来自具有生产力历史的团队的密集的个人指导 指导; 2）深入的经验和重点教学培训，以提高他对分子生物学的理解 真菌学、知生菌学和临床研究方法;以及3）创新的研究计划， 肠道菌群参与BPD发展的证据。候选人的研究发展计划 概述了一条获得加速发展所需的知识、技能和经验的重点路径 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的影响。 BPD是早产最严重的肺部并发症。改变发育风险的治疗 缺乏BPD因素。其他肺部疾病中肠-肺轴的新生儿模型，流行病学研究 将抗生素暴露与BPD发展风险增加联系起来，以及候选人广泛的初步研究结果。 在小鼠和早产新生儿中的研究强烈表明，肠道真菌生物群代表了治疗靶点， 影响BPD的发展。这一建议建立在候选人的先前经验和他的专业知识的基础上。 导师探讨新生儿肠肺轴的机制。我们将测试两个假设。1)产前 抗生素滥用诱导的真菌生物群系变化通过破坏肠-肺轴而导致BPD严重程度增加。 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肺的发育 BPD中的损伤将为减轻BPD的治疗剂的开发提供信息。这些研究有望奠定 人类早产新生儿的基础转化研究。