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

项目总结 宫内和早期环境暴露导致的代谢失调对 发育中的免疫系统和肺，这些变化是儿童特应症病理生物学的基础 还有喘息声。然而，在理解代谢-免疫失调的途径方面仍然存在显著的差距。 以及与儿童早期特应性和喘息有关的机制。婴幼儿非靶向性的初步研究 代谢组学研究表明，未结合胆红素(UCB)和脂质介质途径的调节失调 与喘息发作的次数呈剂量-反应关系，这表明参与 内源性抗氧化剂和脂质介体途径。在对婴儿免疫组的另一项初步研究中， 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， 以2型和17型增加和非干扰素减少为特征的免疫反应模式- 1免疫应答增加反复喘息的风险。虽然这些单一的组学研究可以确定 喘息表型的代谢产物和免疫反应失调，单靠它们不能完全捕捉到 潜在的病理生物学的光谱。组学数据的集成促进了对其他数据的理解 慢性病的发病机制，就像它很可能会对儿童的特应性和喘息一样。因此，我们假设 早期生命代谢组(包括脂质体)和免疫组学的整合可以阐明分子 与特应性和喘息发展相关的通路。为了检验这一假设，候选人将利用 现有基于人群的健康婴儿出生队列的仔细表型(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)研究升高的未结合胆红素(UCB)水平是否能降低早期特应性生活和 通过提高促分解脂质介体和抗氧化剂的生物利用度和 减少促炎脂质介质，2)发现新的免疫组谱和网络模块 以表征特应性和喘息表型，以及3)发现新的代谢-免疫分子 与特应性和喘息表型发展相关的途径--通过整合代谢组和 免疫组数据。这些目标的成功实现将：(1)为早期- 生命代谢组和免疫组学在特应性和喘息发病机制中的作用和(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的基础上 了解疾病发展的方法。这份职业发展提案的目标是为 成为哮喘和过敏领域具有独特知识的独立调查员的候选人 以及系统方法的应用以了解疾病机制。这位候选人表现出色。 学术环境，有深思熟虑的培训和研究计划，这将推动他进入 特应性和哮喘免疫代谢领域的独立专家。

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.