102
IRUS Total
Downloads
  Altmetric

A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target

File Description SizeFormat 
s41467-018-06008-4.pdfPublished version1.11 MBAdobe PDFView/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