Integrative Metabolomics of Asthma Severity

项目摘要 哮喘仍然是一个重大的全球公共卫生负担。在我们之前的基于整合代谢组学的R 01中， R 01 HL 123915，我们超过了我们的总体目标，大大有助于了解 代谢失调是哮喘表型的基础，30篇同行评审的文章证明了这一点。 手稿，与>20更多的发展。我们的范围远远超出了最初的建议， (i)生成和分析多个附加群组中的代谢和多组学数据;以及（ii）开发一个 协作的“代谢组流行病学”研究团队，并建立关键的跨学科全球合作， 包括访问多个大型前瞻性队列。这些成就共同推动了 Lasky-Su博士在这一新兴领域的全球公认的领导者的进步。在这次更新中，我们将 利用我们的数据、经验、专业知识，最重要的是， 科学假设，特别是当它们与神经鞘脂，n-3/n-6 PUFA失调的作用有关时， 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、表观遗传和转录组学特征的调控，这些特征对 对哮喘代谢组学内型的最佳理解。为了验证这一假设，我们建议 (i)进行迄今为止最大的哮喘表型代谢组学荟萃分析，使用来自 >30个国际队列（AIM ONE）;（ii）利用靶向测定绝对量化影响哮喘的关键因素 通过我们先前在R 01 HL 123915中的工作确定的三个不同哮喘队列中的代谢物， 目标1（AIM 2）这将使我们能够超越假设生成到临床 翻译，通过代谢组学谱和临床信息内型（即哮喘）的产生 由其潜在机制定义的亚型）。独特的是，我们将整合五个额外的omic数据类型 与靶向代谢物，以完善这些内型，并确定上游组学驱动程序的基础， 区别它们的机械差异（目的三）。这些目标的成功实现将使 我们要实现这一更新的总体目标：提供最全面的特点， 哮喘的代谢组学特征。它还将为代谢组学和生物医学产生新的资源。 哮喘社区大规模数据生成的形式，统计发展相结合的多样化 代谢组学研究（通过COMETS-Analytics），并通过解决异质性问题， 代谢组学研究。这次更新将扩大和建立在R 01 HL 123915的巨大成功， 实现临床可翻译性，以及知识的表达，以改变当前的景观 哮喘代谢组学

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.