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

项目总结 儿童哮喘是美国最常见的慢性呼吸道疾病，而 流行病学研究确定了儿童的危险因素(如严重毛细支气管炎)。 哮喘，哮喘发生的潜在机制(及其不同表型) 人们对此仍然知之甚少。这一重大的知识差距阻碍了发展哮喘的努力。 预防策略。第35次多中心呼吸道研究合作(MARC-35)研究 (U01AI087881；Camargo，PI)是一项正在进行的17中心队列研究，招募了921人 2011-2014年间因毛细支气管炎住院的婴儿(年龄中位数为3个月)。在这 种族/民族-和地理-多样化的队列，调查人员收集了高质量的 生物检疫，包括鼻咽部呼吸道和血液样本的入院指数。 后续数据包括一年两次的家长访谈、病历审查和面对面检查 在6岁时，到目前为止有大约80%的随访率。目前的K01项目将扩大这一大型项目 整合基因组、代谢组和微生物组的特征良好的毛细支气管炎队列 (16S rRNA基因和元基因组测序)数据，这不仅将阐明 哮喘的发病机制，也确定其内型。在目标1中，我们将确定 婴幼儿鼻咽癌宿主基因组与鼻咽代谢组的整合关系 6岁时出现哮喘。在目标2中，我们将确定 婴儿期宿主基因组与鼻咽呼吸道微生物组(结构和功能) 在6岁之前有发展成哮喘的风险。最后，在目标3中，我们将在临床上识别- 通过整合临床、免疫学(如特异性IgE、 25OHD、细胞因子)和多组学数据(即宿主基因组、血清代谢组和呼吸道 微生物组)，6岁。我们的试点数据为拟议的工作提供了令人信服的支持。 K01项目将提供一个独特的机会来定义偶发哮喘的病理生物学 通过研究基因组、代谢组和微生物组的整合作用。此外， 我们还将通过利用多组学数据定义儿童哮喘内型 全面表型的MARC-35队列。这些发现将导致 针对哮喘的内型特异性预防策略(例如，通过调节新陈代谢 途径和微生物群)在儿童早期。指导团队由美国国立卫生研究院资助 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.