Rheumatoid arthritis

Rheumatoid Arthritis Map (RA-MAP)

Online access and exploration: https://ramap.uni.lu
Development status: Second version is complete and published, applications demonstrated
Disease IDs: DOID:7148, MESH:D001172, MONDO:0008383
Sustainable support: Université Paris-Saclay, MINERVA Platform
Construction tool: CellDesigner
Funding: Doctoral School “Structure and Dynamics of Living Systems”
How to cite: Singh, et al. Genom Comput Biol. 2018. doi: 10.18547/gcb.2018.vol4.iss1.e100050.
Contact: Anna Niarakis, Université Paris-Saclay, Evry, France, anna.niaraki(at)univ-evry.fr

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease that causes chronic inflammation of the joints. The etiology of the disease remains still unclear. Patients with autoimmune diseases have an immune system that targets and attacks their own body tissues. Characteristic features of RA include inflammation of the tissue around the joints and hyperplasia (swelling) that can lead to bone erosion and permanent deformity. The disease can affect multiple organs in the body causing inflammation and injury and for this it is considered a systemic illness.

RA affects approximately 1% of the worldwide population. Women have a two to three higher risk developing the disease in comparison to men. It is currently believed that RA initiates as a result of complex interactions between genetic and environmental factors and that these factors are responsible for susceptibility and phenotype.

All cellular processes can be depicted as, and characterized by, their underlying complex molecular networks. This fundamental concept of viewing cells has brought up the need to develop high-quality methodologies for the construction and subsequent analysis of these molecular networks at a systems level. Quantitative kinetic models using differential or stochastic equations can provide a detailed analysis of a network’s dynamics, but they require a number of parameters that is often prohibitively large. In order to address the scarcity of kinetic data in signalling pathways, the use of discrete logic-based models is proposed as an alternative way to study the system’s qualitative dynamic behavior.

The University of Evry, Paris Saclay is working on an updated, detailed, fully annotated molecular map for RA based on exhaustive curation of the existing literature using CellDesigner. This map will serve as a template for the construction of a qualitative dynamical model, in order to explore the dynamical properties of the system and analyze its underlying regulatory networks. The model will then be used to address different biological questions such as comparing the network for different phenotypes, trying to understand the mechanisms driving variable responses to treatment and investigating the role of co- and multi-morbidities.

The construction of a map and of a dynamic model are two tasks with different purposes that are today mainly performed in an independent way. On the one hand, it is a question of creating a knowledge base in the form of a map, and on the other of defining an abstraction of the system that captures dynamic behaviours of interest. Yet these two constructs share a lot of information, including the mode of influence (e.g., activation or inhibition) and the topology of the network.

In order to bridge the gap between static and dynamic representations, the team has developed CaSQ (CellDesigner as SBML-qual), a tool for automated inference of large Boolean models, from molecular interaction maps based on network topology and semantics.

The large scale Boolean models produced can be simulated and modelled using the Cell Collective modelling platform.

Publications

Singh V, Ostaszewski M, Kalliolias GD, Chiocchia G, Olaso R, Petit-Teixeira E, Helikar T, Niarakis A. Computational Systems Biology Approach for the Study of Rheumatoid Arthritis: From a Molecular Map to a Dynamical Model. Genom Comput Biol. 2018;4(1). pii: e100050. doi: 10.18547/gcb.2018.vol4.iss1.e100050. Epub 2017 Dec 6. PubMed PMID: 29951575.

Development Team

	Vidisha Singh, MSc University of Evry, University of Paris-Saclay, France PhD Student GenHotel EA3886 European Research Laboratory for Rheumatoid Arthritis, Genopole, Evry RA-Map and CaSQ development
	Sara Sadat Aghamiri, Msc University of Evry, University of Paris-Saclay, France Master student, Department of Biology GenHotel EA3886 European Research Laboratory for Rheumatoid Arthritis, Genopole, Evry CaSQ benchmarking
	Anna Niarakis, PhD University of Evry, University of Paris-Saclay, France Associate Professor, Department of Biology GenHotel EA3886 European Research Laboratory for Rheumatoid Arthritis, Genopole, Evry RA-Map and CaSQ development
	Sylvain Soliman, PhD Inria Saclay-Île de France, Palaiseau, France Researcher CaSQ development
	Tomas Helikar, PhD University of Nebraska-Lincoln, Lincoln, NE, USA Associate Professor, Department of Biochemistry Cell Collective modelling platform

Editorial Panel

	George D. Kalliolias, MD, PhD Hospital for Special Surgery, Weill Cornell Medical College, New York City, US Director of Precision Medicine Laboratory at the Hospital for Special Surgery, Assistant Professor of Medicine at the Weill Cornell Medical College
	Elisabeth Petit-Teixeira, PhD University of Evry, University of Paris-Saclay, France Professor, Department of Biology GenHotel EA3886 European Research Laboratory for Rheumatoid Arthritis, Genopole, Evry

Former contributors

	Gilles Chiocchia, PhD University of Versailles-Saint-Quentin-en-Yvelines, France Professor - Hospital Practitioner Director INSERM UMR 1173 - Infection and Inflammation Head of Laboratory of Chronic Infection and Inflammation
	Saran Pankaew, Msc University of Evry, University of Paris-Saclay, France Master student, Department of Biology GenHotel EA3886 European Research Laboratory for Rheumatoid Arthritis, Genopole, Evry

Funding

PhD project “Integrative Modelling and Analysis of Molecular Pathways dysregulated in Rheumatoid Arthritis” is funded by the Doctoral School “Structure and Dynamics of Living Systems”, the University of Paris-Saclay.