Méthodologie semi-formelle pour l’étude de systèmes biologiques : application à l'homéostasie du fer

Abstract : The major part of this PhD consists in the creation of a methodology to model biological systems. This methodology considers models based on differential equations, and uses formal methods (interval solver, verification of STL formula), analytical methods (study of stability) and numerical methods (optimization algorithm, statistical analysis). Moreover, many kind of data, like behavioral response to perturbation, or quantitative data (metabolite half-life and concentration) can be incorporated. In collaboration with a biologist team, this methodology is successfully applied to the iron homeostasis network : we study the response of the system to an iron depletion, at the intracellular level, based on specific regulatory proteins (IRP proteins). A major output of this study is insight into the level of iron cells need to proliferate : this concentration is pointed out by the study of the model, and is experimentally validated.The second part of the PhD is the creation of a tool to model genetic regulatory networks, using Thomas' formalism. This tool, developed using ASP (Answer Set Programming) programming language, can integrate many kind of data, like mutation data, or the existence of many steady states. It automatically avoids inconsistency in case of contradiction between different hypotheses. It also infers biological properties such as relationships between kinetic parameters.
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Nicolas Mobilia. Méthodologie semi-formelle pour l’étude de systèmes biologiques : application à l'homéostasie du fer. Hématologie. Université Grenoble Alpes, 2015. Français. ⟨NNT : 2015GREAS042⟩. ⟨tel-01561060⟩

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