The Role of Airway Microbiota in Nontuberculous Mycobacterial Infection in Cystic Fibrosis

项目摘要/摘要 林赛·卡弗利医学博士是密歇根大学的儿科肺病专家和科学家。这份K23建议书 将完成卡弗利博士的培训，朝着她改善儿童健康的长期职业目标前进 通过对肺部疾病的微生物生态学有更好的了解。这项提议将建立在Dr。 Civerly之前在肺部病理生理学和非结核分枝杆菌方面获得的专业知识 (NTM)感染，为她提供临床研究方法学和计算生物学方面的新专业知识。 在拟议的项目中，她将结合她已建立的和新获得的技能来阐明 呼吸道微生物区系在囊性纤维化患者NTM感染发病机制中的作用这项研究 培训将由她的主要导师John J.LiPuma MD、共同导师Patrick D.Schlos博士和 一个由在临床研究方法、计算方法方面有专长的资深科学家组成的顾问委员会 生物学、微生物生态学和生物统计学，以及指导初级内科科学家的成功。卡弗利医生的 三年计划包括正式课程，以获得生物信息学硕士学位，专业 发展活动和逐步独立的研究。尽管NTM肺部感染导致 作为非传染性支气管炎肺部疾病的决定因素，慢性阻塞性肺疾病患者的显著发病率和死亡率， 包括获得NTM的风险因素和影响疾病进展的变量，在很大程度上是未知的。 越来越多的人认识到，CF航空公司拥有复杂的微生物群落，这为 探讨呼吸道微生物区系在NTM病发病机制中的作用。目标1将测试 假设CF呼吸道微生物区系的特征将预测NTM的获得，而Aim 2将测试 假设CF型呼吸道微生物区系特征可以预测NTM的病程。为了实现这些目标，Dr。 Cverly将利用现有的CF痰样本存储库和一个全面的数据库 临床信息。她还将对患有CFM和NTM的患者进行前瞻性、观察性研究 感染以补充现有样本，并在临床研究方法方面获得专业知识。卡弗利博士 将使用最先进的DNA测序和代谢组学平台来表征结构和 CF呼吸道微生物区系的代谢活性，并将使用新的 计算生物学的分析技术，以建立与患者相关的结果的预测模型。Dr。 卡弗利预计，这些结果将对NTM的风险预测产生重要的积极影响 感染，指导临床决策，照亮新生物学。这项K23奖项将建立一个 为了解呼吸道微生物区系在慢性支气管炎和非传染性支气管炎中的作用的程序性研究路线奠定基础 感染，并将使卡弗利博士具备成为以患者为导向的儿科领域的领导者的技能 肺部研究。

PROJECT SUMMARY/ABSTRACT Lindsay Caverly, MD is a pediatric pulmonologist and scientist at the University of Michigan. This K23 proposal will complete Dr. Caverly's training towards her long-term career goal of improving the health of children with lung diseases through a better understanding of the lung microbial ecology. This proposal will build on Dr. Caverly's previously acquired expertise in pulmonary pathophysiology and nontuberculous mycobacterial (NTM) infection to provide her with new expertise in clinical research methodology and computational biology. In the proposed project, she will integrate her established and newly-acquired skills to elucidate the role of airway microbiota in the pathogenesis of NTM infection in individuals with cystic fibrosis (CF). This research and training will be guided by her primary mentor, John J. LiPuma MD, co-mentor Patrick D. Schloss PhD, and an advisory board of accomplished senior scientists with expertise in clinical research methods, computational biology, microbial ecology, and biostatistics, and success in mentoring junior physician-scientists. Dr. Caverly's three year plan includes formal coursework to obtain a Master's Degree in Bioinformatics, professional development activities, and progressively independent research. Although NTM pulmonary infections cause significant morbidity and mortality for individuals with CF, the determinants of NTM pulmonary disease, including risk factors for NTM acquisition and variables impacting disease progression, are largely unknown. The increasing appreciation that the CF airways harbor complex microbial communities provides an opportunity to investigate the role of airway microbiota in the pathogenesis of NTM disease. Aim 1 will test the hypothesis that features of CF airway microbiota will predict NTM acquisition, while Aim 2 will test the hypothesis that features of CF airway microbiota will predict NTM disease course. To complete these aims, Dr. Caverly will capitalize on an existing repository of CF sputum samples and a comprehensive database of clinical information. She will also execute a prospective, observational study of individuals with CF and NTM infection to complement the existing samples and to gain expertise in clinical research methods. Dr. Caverly will use state-of-the art DNA sequencing and metabolomics platforms to characterize the structure and metabolic activities of CF airway microbiota, and will integrate the microbial and clinical data using novel analytic techniques of computational biology to build predictive models of patient-relevant outcomes. Dr. Caverly anticipates that these results will have an important positive impact in informing risk prediction for NTM infection, guiding clinical decision making, and illuminating novel biology. This K23 award will establish a foundation for a programmatic line of research to understand the role of airway microbiota in CF and NTM infection, and will equip Dr. Caverly with the skills to be a leader in the field of patient-oriented pediatric pulmonary research.