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: 10896779
• 负责人: Kedir Nesha Turi
• 金额: $ 16.2万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10896779
• 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; Metabolic; Metabolic Pathway; Molecular; Nose; Oxidative Stress; Pathogenesis; Pathway Analysis; Pathway interactions; Pattern; Phenotype; Plasma; Population; Primary Prevention; Property; Pulmonary Inflammation; Recurrence; Research; Research Personnel; Resolution; Risk; Role; Syndrome; System; Systems Biology; Testing; Time; Training; United States National Institutes of Health; Urine; Wheezing; Work; airway inflammation; atopy; career development; cohort; data integration; disorder prevention; early childhood; experience; in utero; infancy; insight; interest; lipid mediator; lipidome; metabolome; metabolomics; molecular subtypes; multiple omics; novel; oxidation; population based; public health priorities; response; statistics; supervised learning; 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.

项目摘要 因子宫和早期生活环境暴露导致的代谢失调对 发展中的免疫系统和肺 和喘息。但是，在理解失调的代谢免疫途径方面仍然存在显着差距 和幼儿期和喘息的机制。我们对婴儿未靶向的初步研究 代谢组表明未结合的胆红素（UCB）和脂质介质的途径失调 以剂量反应方式与喘息发作的数量有关，这表明参与 内源性抗氧化剂和脂质介质途径。在对婴儿免疫组的另一项初步研究中， 我们证明了两个针对急性呼吸道感染的两种不同的婴儿免疫反应特征 免疫反应模式为2型和17型和降低非Interferon型 - 1对复发喘息风险增加的免疫反应。尽管这些单一的OMICS研究可以识别 在喘息表型中的代谢物和免疫反应失调，它们单独无法捕获完整 潜在病理生物学的频谱。 OMICS数据的集成已提出了对其他的理解 慢性疾病发病机理，因为它很可能在儿童期和喘息的过程中。因此，我们假设 早期寿命代谢组（包括脂肪组）和免疫组的整合可以阐明分子 与特应性和喘息发育有关的途径。为了检验这一假设，候选人将大写 现有的精心表型基于人群的健康婴儿（Inspire）和复制 来自NIH Echo倡议（回声哮喘联盟）的队列，完成以下特定 目的：1）调查未结合的胆红素（UCB）水平是否降低了早期生命植物和 通过增强促进脂质介质和抗氧化剂的生物利用度以及 减少促炎性脂质介质，2）发现新颖的免疫组轮廓和网络模块 这是特征和喘息表型的特征，以及3）发现新型的代谢免疫分子 通过整合代谢组和 免疫组数据。这些目标的成功完成将：（1）提供有关早期作用的新见解。 生命代谢组和免疫组在特应性和喘息的发病机理中，（2）确定疾病的靶标 预防。该提案以候选人的先前工作，专业知识和对系统的兴趣为基础 了解疾病发展的方法。这项职业发展建议的目标是 候选人成为哮喘和过敏领域的独立研究者，并具有独特的知识 并应用系统方法来理解疾病机制。候选人处于杰出 学术环境，有一个经过深思熟虑的培训和研究计划，这将使他进入 在特纳和哮喘的免疫代谢领域的独立专家。

项目成果

Detection of respiratory syncytial virus defective genomes in nasal secretions is associated with distinct clinical outcomes.

• DOI: 10.1038/s41564-021-00882-3
• 发表时间: 2021-05
• 期刊: Nature microbiology
• 影响因子: 28.3

Association between asthma status and prenatal antibiotic prescription fills among women in a Medicaid population.

• DOI: 10.1080/02770903.2021.1993247
• 发表时间: 2022-10
• 期刊: The Journal of asthma : official journal of the Association for the Care of Asthma

Involving Urban Single Low-Income African American Mothers in Genomic Research: Giving Voice to How Place Matters in Health Disparities and Prevention Strategies.

让城市单身低收入非裔美国母亲参与基因组研究：表达如何在健康差异和预防策略中放置问题的声音。

• DOI: 10.29011/2688-7460.100048
• 发表时间: 2020
• 期刊: Family medicine and primary care -- open access
• 作者: Mendenhall,Ruby;Henderson,Loren;Scott,Barbara;Butler,Lisa;Turi,KedirN;Greenlee,Andrew;Robinson,GeneE;Roberts,BrentW;Rodriguez-Zas,SandraL;Brooks,JamesE;Lleras,ChristyL
• 通讯作者: Lleras,ChristyL