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

项目摘要 子宫内和生命早期环境暴露引起的代谢失调对 发育中的免疫系统和肺，这些变化是儿童特应性的病理学基础 和喘息声。然而，在理解代谢免疫途径失调方面仍然存在重大差距 以及儿童早期特应性和喘息的机制。我们对婴儿非靶向的初步研究 代谢组学研究表明，非结合胆红素（UCB）和脂质介质途径的失调 与喘息发作次数呈剂量-反应关系，提示参与 内源性抗氧化剂和脂质介质途径。在另一项关于婴儿免疫组的初步研究中， 我们证明了两种不同的婴儿对急性呼吸道感染的免疫反应， 免疫应答模式特征为2型和17型增加，非干扰素型减少， 1免疫反应与复发性喘息的风险增加。虽然这些单一的组学研究可以识别 在喘息表型中，代谢物和免疫应答失调，它们单独不能捕获完整的 潜在的病理学谱。组学数据的整合促进了对其他 慢性疾病的发病机制，因为它很可能为儿童特应性和喘息。因此，我们假设 早期代谢组（包括脂质组）和免疫组的整合可以阐明 与特应性和喘息发展相关的通路。为了验证这一假设，候选人将利用 现有的仔细表型人群为基础的健康婴儿出生队列（INSPIRE）和复制 来自NIH ECHO倡议（ECHO-CREW哮喘联盟）的队列，并完成以下具体研究 目的：1）研究未结合胆红素（UCB）水平升高是否会降低早期特应性， 通过提高促消退脂质介质和抗氧化剂的生物利用度来降低喘息发生率， 减少促炎脂质介质，2）发现新型免疫组特征和网络模块 特征性特应性和喘息表型，和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发展相关的途径 免疫组学数据。成功地完成这些目标将：（1）为早期的作用提供新的见解- 生命代谢组学和免疫组学在特应性和喘鸣发病机制中的作用，以及（2）确定疾病的靶点 预防该提案建立在候选人以前的工作，专业知识和对系统的兴趣之上 了解疾病发展的方法。本职业发展建议的目标是 候选人出现作为一个独立的研究人员在哮喘和过敏领域的独特知识 和应用系统方法来理解疾病机制。候选人在一个杰出的 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独立专家。

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.