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Mult Scler. 2015 Feb;21(2):138-46. doi: 10.1177/1352458514543339. Epub 2014 Aug 11.

Signaling networks in MS: a systems-based approach to developing new pharmacological therapies.

Author information

1
Institute Biomedical Research August Pi Sunyer (IDIBAPS) - Hospital Clinic of Barcelona, Spain/Personal Biomedicine ZAO, and A. A. Kharkevich Institute for Information Transmission Problems, Russian Academy of Sciences, Russia.
2
European Molecular Biology Laboratory, European Bioinformatics Institute, UK.
3
Unit of Computational Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Sweden.
4
ProtATonce Ltd, Greece.
5
European Molecular Biology Laboratory, European Bioinformatics Institute, UK/ProtATonce Ltd, Greece/National Technical University of Athens, Greece.
6
Anaxomics Biotech, Spain.
7
Ariadne Diagnostics LLC, USA.
8
Bionure Farma SL, Spain.
9
ProtATonce Ltd, Greece/National Technical University of Athens, Greece.
10
Karolinska University Hospital, Sweden.
11
University of Zurich, Switzerland.
12
NeuroCure Clinical Research Center and Department of Neurology, Charité University Medicine Berlin, Germany.
13
Institute Biomedical Research August Pi Sunyer (IDIBAPS) - Hospital Clinic of Barcelona, Spain/Personal Biomedicine ZAO, and A. A. Kharkevich Institute for Information Transmission Problems, Russian Academy of Sciences, Russia pvilloslada@clinic.ub.es.

Abstract

The pathogenesis of multiple sclerosis (MS) involves alterations to multiple pathways and processes, which represent a significant challenge for developing more-effective therapies. Systems biology approaches that study pathway dysregulation should offer benefits by integrating molecular networks and dynamic models with current biological knowledge for understanding disease heterogeneity and response to therapy. In MS, abnormalities have been identified in several cytokine-signaling pathways, as well as those of other immune receptors. Among the downstream molecules implicated are Jak/Stat, NF-Kb, ERK1/3, p38 or Jun/Fos. Together, these data suggest that MS is likely to be associated with abnormalities in apoptosis/cell death, microglia activation, blood-brain barrier functioning, immune responses, cytokine production, and/or oxidative stress, although which pathways contribute to the cascade of damage and can be modulated remains an open question. While current MS drugs target some of these pathways, others remain untouched. Here, we propose a pragmatic systems analysis approach that involves the large-scale extraction of processes and pathways relevant to MS. These data serve as a scaffold on which computational modeling can be performed to identify disease subgroups based on the contribution of different processes. Such an analysis, targeting these relevant MS-signaling pathways, offers the opportunity to accelerate the development of novel individual or combination therapies.

KEYWORDS:

Multiple sclerosis; drug discovery; pathways; signaling; systems biology

PMID:
25112814
DOI:
10.1177/1352458514543339
[Indexed for MEDLINE]
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