The relative resistance of children to sepsis mortality: from pathways to drug candidates

Molecular Systems Biology
Rose B JoachimLester Kobzik

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.

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Citations

Nov 14, 2018·Future Microbiology·Rose B Joachim, Lester Kobzik
May 19, 2018·Molecular Systems Biology·Steven Timmermans, Claude Libert
Aug 30, 2019·Molecular Systems Biology·Nimrod Rappoport, Ron Shamir
Dec 19, 2020·Evolution, Medicine, and Public Health·Bernard Crespi

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Datasets Mentioned

BETA
GPL570

Methods Mentioned

BETA
in silico methods

Software Mentioned

CMap
Limma
Graphia Pro
R package Pathprint
fdrtool
fRMA
Connectivity Map ( CMap )
GraphPad
Connectivity Map ( CMap ) Library of Network Based Cellular Si...
Pathway Fingerprint Pathprint

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