Integrative Metabolomics of Asthma Severity

项目总结 哮喘仍然是一个重大的全球公共卫生负担。在我们之前基于整合代谢组学的R01中， R01HL123915，我们超出了我们的总体目标，即为理解 哮喘表型背后的代谢紊乱--30篇同行评议论文的发表证明 手稿，还有20多份正在开发中。我们远远超出了最初提案的范围，通过 (I)生成和分析多个额外队列中的代谢和多组体数据；和(Ii)制定 协作性的“代谢流行病学”研究团队和打造关键的跨学科全球合作， 包括接触到多个大的潜在队列。这些成就共同推动了 提升Lasky-Su博士作为这一新兴领域全球公认的领导者。在这次更新中，我们将 充分利用我们的数据、经验、专业知识的强大组合，最重要的是 科学假说，特别是当它们与失调的鞘脂、n-3/n-6多不饱和脂肪酸的作用有关时，以及 哮喘中的类固醇代谢。这些发现构成了这一更新的假设和方向的基础 我们假设与影响哮喘的代谢物相关的代谢失调 部分受相互关联的遗传、表观遗传和转录特征的调控，这些特征对 对哮喘代谢体内型的最佳理解。为了检验这一假设，我们建议 (I)使用来自&gt；50,000人对哮喘表型进行迄今最大规模的代谢组学荟萃分析 &gt；30个国际队列(AIM One)；(2)利用有针对性的分析绝对量化影响哮喘的关键因素 通过我们先前在R01HL123915和R01HL123915中的工作确定了三个不同哮喘队列中的代谢物 增加了目标1(目标2)。这将使我们能够超越假设生成而进入临床 通过生成代谢组谱和临床信息内型(即哮喘)进行翻译 由其底层机制定义的子类型)。独一无二的是，我们将集成五种额外的OMIC数据类型 与靶向代谢物一起提炼这些内型，并确定潜在的上游基因组驱动因素 区别它们的机械性差异(目标三)。这些目标的成功实现将使 我们要实现这次更新的首要目标：提供最全面的 迄今为止哮喘的代谢组学研究。它还将为代谢组学和 哮喘界以大规模数据生成的形式，将各种统计发展相结合 代谢组学研究(通过彗星分析)，并通过解决异质性问题 代谢组学研究。此次更新将在R01HL123915相当成功的基础上扩展和发展， 实现临床可译性，并制定具有改变当前格局的能力的知识 哮喘代谢组学的研究。

PROJECT SUMMARY Asthma remains a significant global public health burden. In our previous integrative-metabolomics based R01, R01HL123915, we exceeded our overarching goal of substantially contributing to the understanding of the metabolic dysregulation underlying asthma phenotypes, as evidenced by the publication of 30 peer-reviewed manuscripts, with >20 more in development. We extended well beyond the scope of the initial proposal through (i) generating and analyzing metabolic and multi-omic data in multiple additional cohorts; and (ii) developing a collaborative ‘metabolomic epidemiology’ research team and forging key cross-disciplinary global collaborations, including access to multiple large prospective cohorts. Together these accomplishments have driven the advancement of Dr. Lasky-Su as a globally recognized leader in this emerging field. In this renewal, we will leverage the powerful combination of our data, experience, expertise, and most importantly the generated scientific hypotheses, specifically as they relate to the role of dysregulated sphingolipid, n-3/n-6 PUFA, and steroid metabolism in asthma. These findings form the basis of the hypotheses and direction of this renewal, in which we hypothesize that metabolic dysregulation associated with asthma-influencing metabolites is partially regulated by interconnected genetic, epigenetic and transcriptomic features that are crucial for optimal understanding of metabolomic endotypes of asthma. In order to test this hypothesis, we propose to (i) conduct the largest metabolomics meta-analysis of asthma phenotypes to date using >50,000 individuals from >30 international cohorts (AIM ONE); (ii) utilize targeted assays to absolutely quantify key asthma-influencing metabolites in three diverse asthma cohorts, identified through our previous work in R01HL123915 and augmented by Aim 1 (AIM TWO). This will enable us to move beyond hypothesis generation to clinical translation, through the generation of metabolomic profiles and clinically informative endotypes (i.e. asthma subtypes defined by their underlying mechanisms). Uniquely, we will integrate five additional omic data types with the targeted metabolites to refine these endotypes and identify the upstream omic drivers underlying the mechanistic differences that distinguish them (AIM THREE). The successful completion of these aims will enable us to achieve the overarching objective of this renewal: to provide the most comprehensive characterization of metabolomic profiles of asthma to date. It will also generate new resources for both the metabolomics and the asthma communities in the forms of large-scale data generation, statistical developments for combining diverse metabolomics studies (via COMETS-Analytics), and by addressing questions of heterogeneity across metabolomics studies. This renewal will expand and build upon the considerable success of R01HL123915, enabling clinical translatability, and the formulation of knowledge with power to transform the current landscape of asthma metabolomics.