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

Ekaterina Kotelnikova, Marti Bernardo-Faura, Gilad Silberberg, Narsis A. Kiani, Dimitris Messinis, Ioannis N. Melas, Laura Artigas, Elena Schwartz, Ilya Mazo, Mar Masso, Leonidas G. Alexopoulos, Jose Manuel Mas, Tomas Olsson, Jesper Tegner, Roland Martin, Albert Zamora, Friedemann Paul, Julio Saez-Rodriguez, Pablo Villoslada*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)138-146
Number of pages9
JournalMultiple Sclerosis Journal
Volume21
Issue number2
DOIs
StatePublished - Feb 17 2015

Keywords

  • Drug discovery
  • Multiple sclerosis
  • Pathways
  • Signaling
  • Systems biology

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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