The relative resistance of children to sepsis mortality: from pathways to drug candidates
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,...
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-05-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.15252/msb.20177998 |
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| author | Rose B Joachim Gabriel M Altschuler John N Hutchinson Hector R Wong Winston A Hide Lester Kobzik |
| author_facet | Rose B Joachim Gabriel M Altschuler John N Hutchinson Hector R Wong Winston A Hide Lester Kobzik |
| author_sort | Rose B Joachim |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-86ad80da54b44ec7883fcedd89ffa052 |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2018-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-86ad80da54b44ec7883fcedd89ffa0522025-08-20T03:46:32ZengSpringer NatureMolecular Systems Biology1744-42922018-05-0114511710.15252/msb.20177998The relative resistance of children to sepsis mortality: from pathways to drug candidatesRose B Joachim0Gabriel M Altschuler1John N Hutchinson2Hector R Wong3Winston A Hide4Lester Kobzik5Department of Environmental Health, Harvard T.H. Chan School of Public HealthDepartment of Neuroscience, Sheffield Institute for Translational Neurosciences, University of SheffieldDepartment of Biostatistics, Harvard T.H. Chan School of Public HealthDivision of Critical Care Medicine, Cincinnati Children's Hospital Medical CenterDepartment of Neuroscience, Sheffield Institute for Translational Neurosciences, University of SheffieldDepartment of Environmental Health, Harvard T.H. Chan School of Public HealthAbstract 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.https://doi.org/10.15252/msb.20177998connectivity mapdrug discoverypathwayssepsis |
| spellingShingle | Rose B Joachim Gabriel M Altschuler John N Hutchinson Hector R Wong Winston A Hide Lester Kobzik The relative resistance of children to sepsis mortality: from pathways to drug candidates Molecular Systems Biology connectivity map drug discovery pathways sepsis |
| title | The relative resistance of children to sepsis mortality: from pathways to drug candidates |
| title_full | The relative resistance of children to sepsis mortality: from pathways to drug candidates |
| title_fullStr | The relative resistance of children to sepsis mortality: from pathways to drug candidates |
| title_full_unstemmed | The relative resistance of children to sepsis mortality: from pathways to drug candidates |
| title_short | The relative resistance of children to sepsis mortality: from pathways to drug candidates |
| title_sort | relative resistance of children to sepsis mortality from pathways to drug candidates |
| topic | connectivity map drug discovery pathways sepsis |
| url | https://doi.org/10.15252/msb.20177998 |
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