title: Signaling networks in MS: a systems-based approach to developing new pharmacological therapies.
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.
authors.affiliation: 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.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Kotelnikova
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, UK.
authors.forename: Marti
authors.initials: M
authors.lastname: Bernardo-Faura
authors.affiliation: Unit of Computational Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Sweden.
authors.forename: Gilad
authors.initials: G
authors.lastname: Silberberg
authors.affiliation: Unit of Computational Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Sweden.
authors.forename: Narsis A
authors.initials: NA
authors.lastname: Kiani
authors.affiliation: ProtATonce Ltd, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Messinis
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, UK/ProtATonce Ltd, Greece/National Technical University of Athens, Greece.
authors.forename: Ioannis N
authors.initials: IN
authors.lastname: Melas
authors.affiliation: Anaxomics Biotech, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Artigas
authors.affiliation: Ariadne Diagnostics LLC, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Schwartz
authors.affiliation: Ariadne Diagnostics LLC, USA.
authors.forename: Ilya
authors.initials: I
authors.lastname: Mazo
authors.affiliation: Bionure Farma SL, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Masso
authors.affiliation: ProtATonce Ltd, Greece/National Technical University of Athens, Greece.
authors.forename: Leonidas G
authors.initials: LG
authors.lastname: Alexopoulos
authors.affiliation: Anaxomics Biotech, Spain.
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Mas
authors.affiliation: Karolinska University Hospital, Sweden.
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.affiliation: Unit of Computational Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Sweden.
authors.forename: Jesper
authors.initials: J
authors.lastname: Tegner
authors.affiliation: University of Zurich, Switzerland.
authors.forename: Roland
authors.initials: R
authors.lastname: Martin
authors.affiliation: Bionure Farma SL, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Zamora
authors.affiliation: NeuroCure Clinical Research Center and Department of Neurology, Charité University Medicine Berlin, Germany.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Paul
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, UK.
authors.forename: Julio
authors.initials: J
authors.lastname: Saez-Rodriguez
authors.affiliation: 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.
authors.forename: Pablo
authors.initials: P
authors.lastname: Villoslada
mesh_terms: D055808:Drug Discovery; D006801:Humans; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*
keywords: Multiple sclerosis; drug discovery; pathways; signaling; systems biology