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.
In this renewal, we build upon the findings from our previous integrative-metabolomics based R01, R01HL123915, to study the role of dysregulated sphingolipid, n-3/n-6 PUFA, and steroid metabolism in asthma. Using absolute quantification of these targeted metabolites, we will test the hypothesis that metabolic dysregulation associated with asthma-influencing metabolites is partially regulated by interconnected genetic, epigenetic and transcriptomic features, and together these create informative metabolomic endotypes of asthma. This will enable us to move beyond hypothesis generation to clinical translation, and will provide the most comprehensive characterization of metabolomic profiles of asthma to date.
|Kelly, R S; Sordillo, J E; Lasky-Su, J et al. (2018) Plasma metabolite profiles in children with current asthma. Clin Exp Allergy 48:1297-1304|
|Zeleznik, O A; Poole, E M; Lindstrom, S et al. (2018) Metabolomic analysis of 92 pulmonary embolism patients from a nested case-control study identifies metabolites associated with adverse clinical outcomes. J Thromb Haemost 16:500-507|
|Laíns, Inês; Kelly, Rachel S; Miller, John B et al. (2018) Human Plasma Metabolomics Study across All Stages of Age-Related Macular Degeneration Identifies Potential Lipid Biomarkers. Ophthalmology 125:245-254|
|Lasky-Su, Jessica A; Zeleznik, Oana A; Eliassen, A Heather (2018) Using Metabolomics to Explore the Role of Postmenopausal Adiposity in Breast Cancer Risk. J Natl Cancer Inst 110:547-548|
|Kelly, Rachel S; Giorgio, Rachel T; Chawes, Bo L et al. (2017) Applications of Metabolomics in the Study and Management of Preeclampsia; A Review of the Literature. Metabolomics 13:|
|Bowler, Russell P; Wendt, Chris H; Fessler, Michael B et al. (2017) New Strategies and Challenges in Lung Proteomics and Metabolomics. An Official American Thoracic Society Workshop Report. Ann Am Thorac Soc 14:1721-1743|
|Blighe, Kevin; Chawes, Bo L; Kelly, Rachel S et al. (2017) Vitamin D prenatal programming of childhood metabolomics profiles at age 3 y. Am J Clin Nutr 106:1092-1099|
|Kelly, Rachel S; Virkud, Yamini; Giorgio, Rachel et al. (2017) Metabolomic profiling of lung function in Costa-Rican children with asthma. Biochim Biophys Acta Mol Basis Dis 1863:1590-1595|
|Lasky-Su, Jessica; Dahlin, Amber; Litonjua, Augusto A et al. (2017) Metabolome alterations in severe critical illness and vitamin D status. Crit Care 21:193|
|Kelly, Rachel S; Dahlin, Amber; McGeachie, Michael J et al. (2017) Asthma Metabolomics and the Potential for Integrative Omics in Research and the Clinic. Chest 151:262-277|
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