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A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target
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s41467-018-06008-4.pdf | Published version | 1.11 MB | Adobe PDF | View/Open |
Title: | A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target |
Authors: | Srivastava, P Van Eyll, J Godard, P Manuela, M Delahaye-Duriez, A Van Steenwinckel, J Gressens, P Danis, B Vandenplas, C Patrik, F Leclercq, K Mairet-Coello, G Cardenas, A Vanclef, F Laaniste, L Niespodziany, I Keaney, J Gasser, J Gillet, G Shkura, K Chong, S-A Behmoaras, J Kadiu, I Petretto, EG Kaminski, R Johnson, M |
Item Type: | Journal Article |
Abstract: | The identification of drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a general computational framework for drug target discovery that combines gene regulatory information with causal reasoning (“Causal Reasoning Analytical Framework for Target discovery”—CRAFT). Using a systems genetics approach and starting from gene expression data from the target tissue, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof of concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a potential therapeutic target. The predicted effect of Csf1R blockade in attenuating epilepsy seizures was validated in three pre-clinical models of epilepsy. These results highlight CRAFT as a systems-level framework for target discovery and suggest Csf1R blockade as a novel therapeutic strategy in epilepsy. CRAFT is applicable to disease settings other than epilepsy. |
Issue Date: | 3-Sep-2018 |
Date of Acceptance: | 3-Aug-2018 |
URI: | http://hdl.handle.net/10044/1/62827 |
DOI: | 10.1038/s41467-018-06008-4 |
ISSN: | 2041-1723 |
Publisher: | Nature Publishing Group |
Journal / Book Title: | Nature Communications |
Volume: | 9 |
Copyright Statement: | © The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/ |
Sponsor/Funder: | Commission of the European Communities UCB Biopharma SPRL Imperial College Healthcare NHS Trust- BRC Funding Medical Research Council (MRC) Medical Research Council (MRC) |
Funder's Grant Number: | 602102 4400109351 RDA03 MR/M004716/1 MR/N01121X/1 |
Keywords: | Science & Technology Multidisciplinary Sciences Science & Technology - Other Topics TEMPORAL-LOBE EPILEPSY GENE-EXPRESSION PILOCARPINE MODEL NETWORK SEIZURES DRIVERS OPINION DISEASE CELL EEG Animals Anticonvulsants Computer Simulation Disease Models, Animal Drug Discovery Epilepsy Epilepsy, Temporal Lobe Gene Expression Profiling Gene Expression Regulation Genetic Association Studies High-Throughput Nucleotide Sequencing Humans Mice Molecular Targeted Therapy Muscarinic Agonists Pilocarpine Receptors, Granulocyte-Macrophage Colony-Stimulating Factor Sequence Analysis, RNA Systems Biology Animals Humans Mice Epilepsy Epilepsy, Temporal Lobe Disease Models, Animal Pilocarpine Receptors, Granulocyte-Macrophage Colony-Stimulating Factor Muscarinic Agonists Anticonvulsants Gene Expression Profiling Sequence Analysis, RNA Systems Biology Gene Expression Regulation Computer Simulation Drug Discovery Genetic Association Studies Molecular Targeted Therapy High-Throughput Nucleotide Sequencing |
Publication Status: | Published |
Article Number: | 3561 |
Online Publication Date: | 2018-09-03 |
Appears in Collections: | Department of Immunology and Inflammation National Heart and Lung Institute Institute of Clinical Sciences Faculty of Medicine Department of Brain Sciences |