Biomarkers of Atopy Beginning Early (BABE)

项目总结/摘要-总体 特应性皮炎（AD）常先于食物过敏原致敏和临床食物过敏的发展 (FA)这是由于受损的皮肤屏障功能允许过敏原通过皮肤致敏。大量的数据 来自欧洲和北美的研究表明，生活在农场与哮喘风险降低有关， 特应性疾病哮喘一直是农业生活方式研究的焦点;然而，对哮喘的发病机制知之甚少。 农业生活方式对AD和FA发展的保护机制通常先于呼吸道疾病 过敏和哮喘农场生活方式对过敏性疾病的保护可能包括三个先决条件： 1)先天免疫训练和再暴露后的修饰的免疫应答，2）产生抑制性免疫应答， 调节性T细胞，和3）保留屏障功能。在这里，我们建议在一个 一项在旧秩序门诺会（OOM）中进行的扩展纵向出生队列研究， 传统的单一家庭农业，哮喘和过敏性疾病（包括特应性皮炎）的发病率较低 和食物过敏。特应性早发型（BABE）的生物标志物将测试整体 皮肤屏障功能紊乱、免疫环境和微生物组驱动特应性疾病发展假说 皮炎，Th 2炎症，过敏性致敏和FA，而健康的肠道微生物组调节 保护性代谢物库，如短链脂肪酸和色氨酸代谢物以及保护性Treg 免疫发育项目1利用深度宏基因组测序评估婴儿肠道微生物组 组成和相应的代谢组，以表明OOM婴儿肠道微生物组不同于城市 婴儿。项目2评估过敏性致敏和保护性免疫发育的标志物， 多参数谱流，无偏聚类分析和转录组学研究，以证明城市， 婴儿早期有较高数量的炎症单核细胞和Th 2-偏斜T细胞亚群， 婴儿期，而OOM具有肠道归巢记忆THERM。项目3将表征皮肤屏障功能， 微生物组和免疫细胞转录组。我们的纵向出生队列ZOOM 1，由U 01赠款资助， 目前已有2-5年的历史，是三个项目（78 OOM和79 urban）的共同基础。我们将添加另一个 120名婴儿作为ZOOM 2队列（80名城市和40名OOM）。我们还将在更大的细胞中复制关键的T细胞生物标志物， 婴儿队列（开始吃早期饮食“种子”和微生物组和过敏性哮喘精确预防 “MAAP 2”）。招募、收集和共享样本和数据的基础设施由队列管理和 生物储存库和数据管理与生物信息学核心。管理核心将提供全面的财务和 行政基础设施。这些研究旨在确定生物标志物、机制和保护策略 抗过敏和食物过敏。

PROJECT SUMMARY/ABSTRACT – OVERALL Atopic dermatitis (AD) often precedes sensitization to food allergens and the development of clinical food allergy (FA) due to compromised skin barrier function allowing allergen sensitization through skin. A large body of data from Europe and North America suggest that living on farms is associated with a decreased risk of asthma and atopic diseases. Asthma has been a focus of farming lifestyle studies; however, little is known about the protective mechanisms of farming lifestyle on development of AD and FA which often precede respiratory allergies and asthma. The farm lifestyle protection against allergic diseases comprises likely three prerequisites: 1) innate immune training and a modified immune response upon re-exposure, 2) generation of suppressive regulatory T cells, and 3) preserved barrier function. Here, we propose to assess these preconditions in an extended longitudinal birth cohort study among the Old Order Mennonites (OOM), a population practicing traditional, single-family farming with a lower rate of asthma and allergic diseases, including atopic dermatitis and food allergies in early childhood. Biomarkers of Atopy Beginning Early (BABE) will test the overall hypothesis that perturbed skin barrier function, immune millieu and microbiome drive the development of atopic dermatitis, Th2 inflammation, allergic sensitization and FA, whereas a healthy gut microbiome modulates the protective metabolite pool such as short chain fatty acids and tryptophan metabolites and protective Treg immune development. Project 1 utilizes deep metagenomic sequencing to assess infant gut microbiome composition and corresponding metabolome to show that OOM infant gut microbiome is distinct from urban infants. Project 2 assesses markers of allergic sensitization and protective immune development utilizing multiparameter spectral flow, unbiased clustering analysis and transcriptomic studies to demonstrate that urban infants have a higher number of hyperinflammatory monocytes and Th2-skewed T cell subsets detected in early infancy, whereas OOM have gut-homing memory Tregs. Project 3 will characterize skin barrier function, microbiome and immune cell transcriptome. Our longitudinal birth cohort ZOOM1, funded by a U01 grant, is now 2-5 years old and is a shared foundation for the three projects (78 OOM and 79 urban). We will add another 120 infants as a ZOOM2 cohort (80 urban and 40 OOM). We will also replicate key T cell biomarkers in larger infant cohorts (Start Eating Early Diet ”SEED” and Microbiome and Allergic Asthma Precision Prevention “MAAP2”). The infrastructure to recruit, collect and share samples and data is provided by the Cohort Admin & Biorepository and Data Management & Bioinformatics Cores. The Admin Core will provide overall financial and administrative infrastructure. These studies aim to identify biomarkers, mechanisms, and protective strategies against atopic and food allergy.