Airway metagenome & metabolome in bronchiolitis and risk of asthma: MARC-35 cohort

项目总结/摘要 细支气管炎是美国婴儿住院的主要原因。然而， 急性严重程度不能用传统的危险因素来解释。此外，虽然婴儿 毛细支气管炎住院患者发生哮喘的风险非常高， 这两个条件仍然不明确。这些重大的知识差距阻碍了 制定细支气管炎治疗策略，并在这一高危人群中预防哮喘。的 第35次多中心气道研究协作组（MARC-35）研究（U 01 AI-87881; Camargo，PI） 是一项正在进行的17中心队列研究，完成了1016名住院婴儿的入组， 2014年的支气管炎在这个多样化的队列中（54%为非洲裔美国人或西班牙裔）， 在索引中收集了高质量的生物标本，包括鼻咽样本 住院（中位年龄，3个月）。后续数据包括一年两次的家长访谈， 医疗记录审查和6岁时的亲自检查，迄今为止随访率>90%。的 目前的R 01项目将通过定义 毛细支气管炎背景下的鼻咽气道宏基因组学和代谢组学特征， 并通过检查它们与急性（细支气管炎严重程度）和慢性（事件）的关系， 哮喘）在儿童期的结果。在目标1中，我们将确定气道之间的关系 微生物组（宏基因组）谱、代谢组谱和急性细支气管炎严重程度。在 目的2，我们将研究呼吸道微生物组和代谢组学之间的关系， 毛细支气管炎的婴儿，以及发展为哮喘的风险。最后，使用系统生物学 方法，目标3将通过整合临床，病毒，分子数据来定义毛细支气管炎的内在型 (e.g.,呼吸道微生物组和代谢组），并确定它们与急性和 慢性结果。我们的试点数据证明了我们的假设令人信服的支持。的 目前的R 01项目将提供一个独特的机会，以确定毛细支气管炎的病理生物学 通过检查微生物组（宏基因组）的功能能力以及小的 代表微生物组和宿主（代谢组）功能活性的分子。在 此外，通过调查患有细支气管炎的婴儿-一个关键时期的自然实验， 肺发育期-我们还将确定细支气管炎与事件的联系机制， 哮喘该研究将为毛细支气管炎和哮喘的治疗提供有力的证据基础 通过今后制定有针对性的干预措施（例如，调制 微生物组和代谢途径）。研究人员是NIH资助的研究人员， 该领域的国际专业知识。该研究与2013年NIAID战略计划相吻合。

Project Summary/Abstract Bronchiolitis is the leading cause of hospitalization in US infants. However, the differences in acute severity are not explained by traditional risk factors. In addition, although infants hospitalized with bronchiolitis are at very high risk for incident asthma, the mechanisms linking these two conditions remain unclear. These major knowledge gaps have hindered efforts to develop bronchiolitis treatment strategies and to prevent asthma in this high-risk population. The 35th Multicenter Airway Research Collaboration (MARC-35) study (U01AI-87881; Camargo, PI) is an ongoing 17-center cohort study that completed enrollment of 1016 hospitalized infants with bronchiolitis in 2014. In this diverse cohort (54% African-American or Hispanic), investigators have collected high-quality biospecimens, including nasopharyngeal samples at the index hospitalization (median age, 3 months). Follow-up data include biannual parent interviews, medical record reviews, and in-person exam at age 6 years, with >90% follow-up to date. The current R01 project would extend this large well-characterized bronchiolitis cohort by defining nasopharyngeal airway metagenomic and metabolomic profiles in the setting of bronchiolitis, and by examining their relations to both acute (bronchiolitis severity) and chronic (incident asthma) outcomes in childhood. In Aim 1, we will determine the relations among the airway microbiome (metagenome) profiles, metabolome profiles, and acute bronchiolitis severity. In Aim 2, we will examine the relations among the airway microbiome and metabolomic profiles in infants with bronchiolitis, and the risk of developing asthma. Lastly, using a systems biology approach, Aim 3 will define bronchiolitis endotypes by integrating clinical, virus, molecular data (e.g., airway microbiome and metabolome), and determine their associations with the acute and chronic outcomes. Our pilot data demonstrate compelling support for our hypotheses. The current R01 project will provide a unique opportunity to define the pathobiology of bronchiolitis through examining the functional capacity of microbiome (metagenome) as well as the small molecules representing functional activity of both microbiome and host (metabolome). In addition, by investigating young infants with bronchiolitis – a natural experiment during a crucial period of lung development – we will also define the mechanisms linking bronchiolitis to incident asthma. The study will provide a strong evidence base for bronchiolitis treatment and asthma prevention strategies through the future development of targeted interventions (e.g., modulation of microbiome and metabolic pathways). The investigators are NIH-funded researchers with international expertise in the field. The study matches well with the 2013 NIAID Strategic Plan.