Towards quantitative modeling of cell metabolism and its control by external environment

Context :Understanding the evolution of eukaryote cells metabolism is the goal of a collaboration with L. Schwartz (physician, associated with LIX). He suggested, with M. Israel, several leads to interpret some perturbations by the modifications of the global cell environment. These perturbations are correlated with crucial phases in cycles that control glycolysis, notably methylation mechanisms for phoasphatases proteins such as PP2A. The main schemes of these cycles have been been identified on the basis of logical reconstruction and experiments, in a joint work with biologists (A. Demidem, Inra). Cycle complexity and their interactions prevent from a global analytic understanding of possible behaviours. Moreover, the approximate knowledge of coefficients and kinetic parameters makes difficult a precise modeling with classical differential systems.

A recent thesis in AMIB team studied the mecanism that produce phospholipides, a major component of cell membranes. Exchanges with external environment remained simplified and, notably, ignore the Krebs cycle. Ultimate goal is to build a general model that allows for a simulation of complex systems of intra-cellular interactions that take into account external environment (acidity, osmolarity and ionic fluxes).

A first step is to complete our existing model. Main reactions and components will be identified in a collaboration with L. Schwartz (AP-HP) and their formal definition realized in a collaboration with C. Poignard (MC2-Inria Bordeaux). This modeling will face a high number of parameters and qualitative models will be introduced in order to understand possible emerging behaviours. As they delimit the space of parameters, guaranteeing a given behaviour, qualitative models will drive the instantiation of a valid quantitative model.

Background Quantitative modeling (ODE and their discrete abstraction).
Simulation tools (Scilab).
A background in physics or biology will be appreciated.

Contact mireille.regnier@inria.fr
Thesis advisor :Jean-Marc Steyaert
Graduate school : Ecole Polytechnique

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