Joachim, R.B., Altschuler, G.M., Hutchinson, J.N. orcid.org/0000-0002-7804-7576 et al. (3 more authors) (2018) The relative resistance of children to sepsis mortality: from pathways to drug candidates. Molecular Systems Biology, 14 (5). e7998. ISSN 1744-4292
Abstract
Attempts to develop drugs that address sepsis based on leads developed in animal models have failed. We sought to identify leads based on human data by exploiting a natural experiment: the relative resistance of children to mortality from severe infections and sepsis. Using public datasets, we identified key differences in pathway activity (Pathprint) in blood transcriptome profiles of septic adults and children. To find drugs that could promote beneficial (child) pathways or inhibit harmful (adult) ones, we built an in silico pathway drug network (PDN) using expression correlation between drug, disease, and pathway gene signatures across 58,475 microarrays. Specific pathway clusters from children or adults were assessed for correlation with drug-based signatures. Validation by literature curation and by direct testing in an endotoxemia model of murine sepsis of the most correlated drug candidates demonstrated that the Pathprint-PDN methodology is more effective at generating positive drug leads than gene-level methods (e.g., CMap). Pathway-centric Pathprint-PDN is a powerful new way to identify drug candidates for intervention against sepsis and provides direct insight into pathways that may determine survival.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. (http://creativecommons.org/licenses/by/4.0/) |
Keywords: | connectivity map; drug discovery; pathways; sepsis |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 05 Jun 2018 14:22 |
Last Modified: | 30 Oct 2018 14:23 |
Published Version: | https://doi.org/10.15252/msb.20177998 |
Status: | Published |
Publisher: | Wiley Open Access |
Refereed: | Yes |
Identification Number: | 10.15252/msb.20177998 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:131511 |