Integrative Metabolomics of Asthma Severity

哮喘严重程度的综合代谢组学

• 批准号: 10439787
• 负责人: JESSICA A LASKY-SU
• 金额: $ 89.49万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439787
• 关键词: Address; Affect; Age; Airway Disease; Asthma; Biological; Biological Assay; Body mass index; Characteristics; Childhood Asthma; Clinic; Clinical; Collaborations; Communities; Costa Rica; Data; Development; Diagnosis; Epigenetic Process; Etiology; Fasting; Formulation; Gender; Generations; Genetic; Genomics; Goals; Heterogeneity; Hypersensitivity; IgE; Individual; Inflammatory; International; Investigation; Knowledge; Manuscripts; Meta-Analysis; Metabolic; Metabolic Pathway; MicroRNAs; Molecular Target; Multiomic Data; Participant; Pathway interactions; Pattern; Peer Review; Pharmaceutical Preparations; Phenotype; Plasma; Polyunsaturated Fatty Acids; Principal Investigator; Prognosis; Progress Reports; Prospective cohort; Public Health; Publications; Pulmonary Function Test/Forced Expiratory Volume 1; Race; Research; Resources; Risk; Role; Sampling; Seeds; Severities; Smoking; Sphingolipids; Testing; Translations; Validation; Work; affection; asthmatic; base; clinical translation; clinically translatable; cohort; early childhood; epidemiology study; experience; forging; genetic epidemiology; large scale data; metabolic profile; metabolomics; multiple omics; programs; pulmonary function; steroid metabolism; study characteristics; success; therapeutic target; transcriptomics

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.

项目概要 哮喘仍然是全球重大的公共卫生负担。在我们之前基于综合代谢组学的 R01 中， R01HL123915，我们超出了我们的总体目标，即为理解 代谢失调是哮喘表型的基础，已发表的 30 篇同行评审论文证明了这一点 手稿，还有超过 20 个正在开发中。我们通过以下方式远远超出了最初提案的范围 (i) 生成并分析多个额外队列中的代谢和多组学数据； (ii) 开发一个 协作“代谢流行病学”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 提升 Lasky-Su 博士作为这一新兴领域全球公认的领导者的地位。在这次更新中，我们将 利用我们的数据、经验、专业知识以及最重要的是生成的强大组合 科学假设，特别是与失调的鞘脂、n-3/n-6 PUFA 和 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是 部分受到相互关联的遗传、表观遗传和转录组特征的调节，这些特征对于 对哮喘代谢组内型的最佳理解。为了检验这个假设，我们建议 (i) 使用来自 50,000 名以上的个体对哮喘表型进行迄今为止最大规模的代谢组学荟萃分析 >30 个国际队列（AIM ONE）； (ii) 利用靶向测定来绝对量化关键的哮喘影响因素 通过我们之前在 R01HL123915 中的工作确定了三个不同哮喘队列中的代谢物 由目标 1（目标 2）增强。这将使我们能够超越假设生成进入临床 通过生成代谢组学概况和临床信息内型（即哮喘 由其底层机制定义的子类型）。独特的是，我们将集成五种额外的组学数据类型 与目标代谢物来完善这些内型并确定潜在的上游组学驱动因素 区分它们的机制差异（目标三）。这些目标的成功实现将使 我们要实现这次更新的总体目标：提供最全面的特征 迄今为止哮喘的代谢组学特征。它还将为代谢组学和 哮喘社区以大规模数据生成、统计发展的形式将不同的 代谢组学研究（通过 COMETS-Analytics），并通过解决跨领域的异质性问题 代谢组学研究。此次更新将扩展并建立在 R01HL123915 的巨大成功之上， 实现临床可转化性，并形成有能力改变当前格局的知识 哮喘代谢组学。