Identification of Early Metabolomic and Immune Endotypes of Allergy and Asthma: An Integrated Multiomics Approach

过敏和哮喘早期代谢组学和免疫内型的鉴定：综合多组学方法

• 批准号: 10038057
• 负责人: Kedir Nesha Turi
• 金额: $ 16.18万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10038057
• 关键词: Acute respiratory infection; Address; Amino Acids; Anti-Inflammatory Agents; Antioxidants; Arachidonic Acids; Asthma; Bilirubin; Biological Availability; Biological Markers; Birth; Childhood; Chronic Disease; Computing Methodologies; Data; Development; Development Plans; Disease; Dose; Early identification; Environment; Environmental Exposure; Fatty Acids; Feces; Goals; Heme; Hypersensitivity; Immune; Immune response; Immune system; Incidence; Infant; Inflammation; Inflammatory; Knowledge; Life; Lipids; Lung; Lung Inflammation; Metabolic; Metabolic Pathway; Metabolism; Molecular; Nose; Oxidative Stress; Pathogenesis; Pathway Analysis; Pathway interactions; Pattern; Phenotype; Plasma; Population; Primary Prevention; Property; Recurrence; Research; Research Personnel; Resolution; Risk; Role; Supervision; Syndrome; System; Systems Biology; Testing; Time; Training; United States National Institutes of Health; Urine; Wheezing; Work; airway inflammation; atopy; career development; cohort; disorder prevention; early childhood; experience; in utero; infancy; insight; interest; learning network; lipid mediator; metabolome; metabolomics; molecular subtypes; multiple omics; novel; oxidation; population based; public health priorities; response; statistics; two-dimensional; unsupervised learning

PROJECT SUMMARY Metabolic dysregulation due to in utero and early-life environmental exposures has lasting consequences on the developing immune system and lung and that these changes underlie the pathobiology of childhood atopy and wheeze. However, significant gaps remain in understanding the dysregulated metabolic-immune pathways and mechanisms involved in early childhood atopy and wheeze. Our preliminary study of the infant untargeted metabolome demonstrated that dysregulation in the unconjugated bilirubin (UCB) and lipid mediator's pathway are associated with number of wheeze episodes in a dose-response manner, which suggests the involvement of endogenous antioxidant and lipid mediator pathways. In another preliminary study of the infant immunome, we demonstrated that two distinct infant immune response profiles to acute respiratory infection, with an immune response pattern characterized by increased Type-2 and Type-17 and decreased non-interferon Type- 1 immune responses to with increased risk of recurrent wheeze. While these single omics studies can identify dysregulated metabolites and immune-responses in wheeze phenotypes, they alone fail to capture the full spectrum of underlying pathobiology. The integration of omics data has advanced the understanding of other chronic disease pathogenesis, as it is likely to do for childhood atopy and wheeze. Therefore, we hypothesize that the integration of early-life metabolome (including lipidome) and immunome can elucidate molecular pathways relevant to atopy and wheeze development. To test this hypothesis, the candidate will capitalize on existing carefully phenotyped population-based birth cohort of healthy infants (INSPIRE) and a replication cohort from the NIH ECHO initiative (ECHO-CREW asthma consortium) and accomplish the following specific aims: 1) To investigate whether increased unconjugated bilirubin (UCB) levels reduce early life atopy and wheeze incidence by enhancing the bioavailability of pro-resolving lipid mediators and antioxidants and decreasing pro-inflammatory lipid mediators, 2) To discover novel immunome profiles and network modules that characterize atopy and wheeze phenotypes, and 3) To uncover novel metabolic-immune molecular pathways associated with the development of atopy and wheeze phenotypes by integrating metabolome and immunome data. Successful completion of these aims will: (1) provide novel insights into the role of the early- life metabolome and immunome in the pathogenesis of atopy and wheeze and (2) identify targets for disease prevention. The proposal builds on the candidate's previous work, expertise, and interest in systems approaches to understand disease development. The goal of this career development proposal is for the candidate to emerge as an independent investigator in the field of asthma and allergy with unique knowledge and application of systems approaches to understand disease mechanisms. The candidate is in an outstanding academic environment, has a well thought out training and research plan, which will propel him into an independent expert in the field of immuno-metabolism of atopy and asthma.

项目概要 由于子宫内和生命早期的环境暴露而导致的代谢失调会对人体产生持久的影响 免疫系统和肺部的发育，这些变化是儿童特应性病理学的基础 和喘息。然而，对于失调的代谢免疫途径的理解仍然存在重大差距 以及涉及幼儿期特应性和喘息的机制。我们对婴儿非针对性的初步研究 代谢组显示非结合胆红素 (UCB) 和脂质介质通路的失调 以剂量反应方式与喘息发作次数相关，这表明参与 内源性抗氧化剂和脂质介质途径。在另一项婴儿免疫组的初步研究中， 我们证明了婴儿对急性呼吸道感染的两种不同的免疫反应特征， 免疫反应模式的特点是 2 型和 17 型增加以及非干扰素 17 型减少 1 免疫反应会增加反复喘息的风险。虽然这些单一组学研究可以确定 喘息表型中代谢物和免疫反应失调，仅靠它们无法捕获完整的 基础病理学谱。组学数据的整合促进了对其他学科的理解 慢性疾病的发病机制，因为它可能与儿童特应性和喘息有关。因此，我们假设 早期生命代谢组（包括脂质组）和免疫组的整合可以阐明分子生物学 与特应性和喘息发展相关的途径。为了检验这个假设，候选人将利用 现有的基于人群的仔细表型健康婴儿出生队列（INSPIRE）和复制 来自 NIH ECHO 倡议（ECHO-CREW 哮喘联盟）的队列并完成以下具体任务 目的： 1) 研究增加的非结合胆红素 (UCB) 水平是否会减少早期特应性和 通过增强促分解脂质介质和抗氧化剂的生物利用度来减少喘息的发生率 减少促炎脂质介质，2) 发现新的免疫组谱和网络模块 表征特应性和喘息表型的特征，以及 3) 发现新的代谢免疫分子 通过整合代谢组和与特应性和喘息表型的发展相关的途径 免疫组数据。成功完成这些目标将：（1）为早期的作用提供新颖的见解。 特应性和喘息发病机制中的生命代谢组和免疫组，以及 (2) 确定疾病靶标 预防。该提案建立在候选人之前的工作、专业知识和对系统的兴趣的基础上 了解疾病发展的方法。本职业发展提案的目标是 具有独特知识的哮喘和过敏领域独立研究者的候选人 以及应用系统方法来了解疾病机制。该候选人表现出色 学术环境，有一个深思熟虑的培训和研究计划，这将推动他成为一个 特应性和哮喘免疫代谢领域的独立专家。