Integrating the genome, metabolome, and microbiome for childhood asthma: Risk and endotypes

项目摘要 儿童哮喘是美国最常见的慢性呼吸道疾病， 流行病学研究已经确定了风险因素（例如，严重毛细支气管炎） 哮喘，哮喘发展的潜在机制（及其不同表型） 仍然知之甚少。这一重大的知识差距阻碍了哮喘的发展 预防战略。第35届多中心气道研究协作组（MARC-35）研究 （U01AI087881; Camargo，PI）是一项正在进行的17中心队列研究，入组了921例 2011 - 2014年期间患有细支气管炎的住院婴儿（中位年龄，3个月）。在这 种族/民族和地理多样化的队列，研究人员收集了高质量的 生物标本，包括鼻咽气道和血液样本在索引住院。 随访数据包括一年两次的家长访谈、医疗记录审查和亲自检查 6岁时，迄今为止约80%的随访率。目前的K01项目将扩大这一大 通过整合基因组、代谢组和微生物组，充分表征毛细支气管炎队列 (both 16S rRNA基因和宏基因组测序）数据，这不仅将阐明 哮喘发病机制，但也确定其内源性。在目标1中，我们将确定 婴儿期宿主基因组和鼻咽气道代谢组的整合关系 6岁时发生哮喘。在目标2中，我们将确定 婴儿期宿主基因组和鼻咽气道微生物组（结构和功能） 在6岁时有患哮喘的风险。最后，在目标3中，我们将确定临床- 通过整合临床，免疫学（例如，特异性IgE， 25OHD，细胞因子）和多组学数据（即，宿主基因组、血清代谢组和气道 微生物组）6岁。我们的试验数据为拟议的工作提供了令人信服的支持。 这个K01项目将提供一个独特的机会，以确定发病哮喘的病理生物学 通过研究基因组、代谢组和微生物组的整合作用。此外，委员会认为， 我们还将通过利用多组学数据来定义儿童哮喘的内在型。 MARC-35综合表型队列。这些发现将导致发展 哮喘的内型特异性预防策略（例如，通过调节新陈代谢 途径和微生物组）。指导小组由NIH资助的 在所有相关领域拥有国际专业知识的研究人员。这项研究与 2017年NIAID战略计划，两者的最终目标都是预防过敏性疾病，如 哮喘

PROJECT SUMMARY Childhood asthma is the most common chronic respiratory condition in the U.S. While epidemiological studies have identified risk factors (e.g., severe bronchiolitis) for childhood asthma, the underlying mechanisms of asthma development (and its different phenotypes) remain poorly understood. This major knowledge gap has hindered efforts to develop asthma prevention strategies. The 35th Multicenter Airway Research Collaboration (MARC-35) study (U01AI087881; Camargo, PI) is an ongoing 17-center cohort study that enrolled 921 hospitalized infants with bronchiolitis (median age, 3 months) during 2011-2014. In this racially/ethnically- and geographically-diverse cohort, investigators have collected high-quality biospecimens, including nasopharyngeal airway and blood samples at the index hospitalization. Follow-up data include biannual parent interviews, medical record reviews, and in-person exam at age 6 years, with ~80% follow-up to date. The present K01 project would extend this large well-characterized bronchiolitis cohort by integrating genome, metabolome, and microbiome (both 16S rRNA gene and metagenomic sequencing) data, which will not only elucidate the mechanisms of incident asthma but also identify its endotypes. In Aim 1, we will determine the integrated relationships of host genome and nasopharyngeal airway metabolome in infancy with asthma development by age 6 years. In Aim 2, we will determine the integrated relationships of host genome and nasopharyngeal airway microbiome (both structure and function) in infancy with the risk of developing asthma by age 6 years. Finally, in Aim 3, we will identify clinically- relevant endotypes of childhood asthma by integrating clinical, immunological (e.g., specific IgE, 25OHD, cytokines), and multi-omics data (i.e., host genome, serum metabolome, and airway microbiome) at age 6 years. Our pilot data provide compelling support to the proposed work. This K01 project will provide a unique opportunity to define the pathobiology of incident asthma through examining the integrative role of genome, metabolome, and microbiome. Furthermore, we will also define childhood asthma endotypes by leveraging multi-omics data in the comprehensively-phenotyped MARC-35 cohort. These findings will lead to the development of endotype-specific prevention strategies for asthma (e.g., through modulation of metabolism pathways and microbiome) during early childhood. The mentoring team consists of NIH-funded researchers with international expertise in all relevant fields. The study matches well with the 2017 NIAID Strategic Plan, which both ultimately aim to prevent allergic diseases, such as asthma.