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

整合儿童哮喘的基因组、代谢组和微生物组：风险和内型

• 批准号: 10361511
• 负责人: Zhaozhong Zhu
• 金额: $ 15.73万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361511
• 关键词: 6 year old; African American; Age; Allergic Disease; American; Asthma; Blood; Blood specimen; Bronchiolitis; Child; Childhood; Childhood Asthma; Chronic; Clinical; Cohort Studies; Collaborations; Data; Development; Diagnosis; Enrollment; Environmental Epidemiology; Funding; Genetic; Genetic Risk; Genome; Genomics; Geography; Hispanic; Hospitalization; IL17 gene; IgE; Immune; Immunologics; Infant; Inflammatory; International; Interview; Knowledge; Lead; Learning; Measurement; Medical Records; Mentors; Metabolic; Metabolism; Methods; Mission; Moraxella; Morbidity - disease rate; Multiomic Data; National Institute of Allergy and Infectious Disease; Parents; Participant; Pathogenesis; Pathway interactions; Persons; Phenotype; Play; Population; Population Attributable Risks; Positioning Attribute; Prevention strategy; Primary Prevention; Process; Prospective cohort study; Public Health; Recording of previous events; Research; Research Personnel; Risk; Risk Factors; Role; Sampling; Serum; Severities; Sphingolipids; Spirometry; Strategic Planning; Structure; Testing; United States National Institutes of Health; Variant; Work; airway inflammation; asthma prevention; clinical phenotype; clinically relevant; cohort; cytokine; early childhood; eosinophil; epidemiology study; evidence base; follow-up; genetic association; genetic epidemiology; genetic variant; genome wide association study; genomic locus; gut microbiota; high risk; indexing; infancy; innovation; metabolome; metabolomics; metagenomic sequencing; microbiome; novel; novel strategies; prevent; rRNA Genes; racial and ethnic; respiratory; respiratory microbiome; respiratory microbiota; risk variant; skills

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.

项目概要 儿童哮喘是美国最常见的慢性呼吸道疾病 流行病学研究已确定儿童期的危险因素（例如严重细支气管炎） 哮喘，哮喘发展的潜在机制（及其不同的表型） 仍然知之甚少。这一重大知识差距阻碍了开发哮喘的努力 预防策略。第 35 次多中心气道研究合作 (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 名患者 2011 年至 2014 年期间因细支气管炎住院的婴儿（中位年龄为 3 个月）。在这个 在种族/民族和地理上多样化的队列中，研究人员收集了高质量的 生物样本，包括住院时的鼻咽气道样本和血液样本。 后续数据包括每年两次的家长访谈、病历审查和现场检查 6 岁时，迄今为止的随访率约为 80%。目前的K01项目将扩建这个大型 通过整合基因组、代谢组和微生物组来描述细支气管炎队列 （16S rRNA基因和宏基因组测序）数据，这不仅会阐明 哮喘发生的机制，同时也确定其内型。在目标 1 中，我们将确定 婴儿期宿主基因组与鼻咽气道代谢组的整合关系 6岁时出现哮喘。在目标 2 中，我们将确定以下的整合关系： 婴儿时期的宿主基因组和鼻咽气道微生物组（结构和功能） 6岁时有患哮喘的风险。最后，在目标 3 中，我们将在临床上确定： 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岁时。我们的试点数据为拟议的工作提供了令人信服的支持。 该 K01 项目将为定义哮喘发病的病理学提供独特的机会 通过检查基因组、代谢组和微生物组的综合作用。此外， 我们还将利用多组学数据来定义儿童哮喘内型 全面表型的 MARC-35 队列。这些发现将导致开发 哮喘的内型特异性预防策略（例如，通过调节代谢 途径和微生物组）在幼儿期。指导团队由 NIH 资助的 在所有相关领域具有国际专业知识的研究人员。该研究与 2017 NIAID 战略计划，其最终目标都是预防过敏性疾病，例如 哮喘。