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Section: Partnerships and Cooperations
European Initiatives
FP7 Projects
ERASysbio+ C5Sys European network.
This European program (http://www.erasysbio.net/index.php?index=272 ) has begun in April 2010 to end up in June 2013, with the title “Circadian and cell cycle clock systems in cancer”. Coordinated by F. Lévi (Villejuif) and D. Rand (Warwick), it studied both from a theoretical and from an experimental viewpoint the relationships between molecular circadian clocks and the cell division cycle, in cancer and in healthy tissues. A postdoctoral fellow (F. Billy) has been hired at Inria-Bang until November 2012 on this funding, giving rise to various publications in 2013 [7] , [8] , [9] , [27] .
NOTOX
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Coordinator: Elmar Heinzle, Universität des Saarlandes, Saarbrücken
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Partner: Centre National de la Recherche Scientifique, Strasbourg
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Partner: Stichting Het Nederlands Kanker Instituut - Antoni Van Leeuwenhoek Ziekenhuis, Amsterdam
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Partner: Institut National de Recherche en Informatique et en Automatique, Rocquencourt
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Partner: Deutsches Forschungszentrum für Künstliche Intelligenz GmbH, Saarbrücken
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Partner: Forschungsgesellschaft für Arbeitsphysiologie und Arbeitsschutz e.V, Dortmund
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Partner: European Research and Project Office GmbH, Saarbrücken
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Abstract: NOTOX will develop and establish a spectrum of systems biological tools including experimental and computational methods for (i) organotypic human cell cultures suitable for long term toxicity testing and (ii) the identification and analysis of pathways of toxicological relevance. NOTOX will initially use available human HepaRG and primary liver cells as well as mouse small intestine cultures in 3D systems to generate own experimental data to develop and validate predictive mathematical and bioinformatic models characterizing long term toxicity responses. Cellular activities will be monitored continuously by comprehensive analysis of released metabolites, peptides and proteins and by estimation of metabolic fluxes using 13C labelling techniques (fluxomics). At selected time points a part of the cells will be removed for in-depth structural (3D-optical and electron microscopy tomography), transcriptomic, epigenomic, metabolomic, proteomic and fluxomic characterisations. When applicable, cells derived from human stem cells (hESC or iPS) and available human organ simulating systems or even a multi-organ platform developed in SCREENTOX and HEMIBIO will be investigated using developed methods. Together with curated literature and genomic data these toxicological data will be organised in a toxicological database (cooperation with DETECTIVE, COSMOS and TOXBANK). Physiological data including metabolism of test compounds will be incorporated into large-scale computer models that are based on material balancing and kinetics. Various omics, data and 3D structural information from organotypic cultures will be integrated using correlative bioinformatic tools. These data also serve as a basis for large scale mathematical models. The overall objectives are to identify cellular and molecular signatures allowing prediction of long term toxicity, to design experimental systems for the identification of predictive endpoints and to integrate these into causal computer models.
ERC Starting Grant SKIPPER
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Abstract: Amyloid diseases are of increasing concern in our aging society. These diseases all involve the aggregation of misfolded proteins, called amyloid, which are specific for each disease (PrP for Prion, Abeta for Alzheimer's). When misfolded these proteins propagate the abnormal configuration and aggregate to others, forming very long polymers also called fibrils. Elucidating the intrinsic mechanisms of these chain reactions is a major challenge of molecular biology: do polymers break or coalesce? Do specific sizes polymerize faster? What is the size of the so-called nucleus, i.e., the minimum stable size for polymers? On which part of the reactions should a treatment focus to arrest the disease ? Up to now, only very partial and partially justified answers have been provided. This is mainly due to the extremely high complexity of the considered processes, which may possibly involve an infinite number of species and reactions (and thus, an infinite system of equations).
The great challenge of this project is to design new mathematical methods in order to model fibril reactions, analyse experimental data, help the biologists to discover the key mechanisms of polymerization in these diseases, predict the effects of new therapies. Our approach is based on a new mathematical model which consists in the nonlinear coupling of a size-structured Partial Differential Equation (PDE) of fragmentation-coalescence type, with a small number of Ordinary Differential Equations. On the one hand, we shall solve new and broad mathematical issues, in the fields of PDE analysis, numerical analysis and statistics. These problems are mathematically challenging and have a wide field of applications. On the other hand we want to test their efficacy on real data, thanks to an already well-established collaboration with a team of biophysicists. With such a continuing comparison with experiments, we aim at constantly aligning our mathematical problems to biological concerns.