Modelling, analysis and control for systems biology: application to bacterial growth models

A Carta - 2014 - theses.hal.science
2014theses.hal.science
This thesis deals with modelling, analysis and control of gene regulatory networks in the
bacterium E. coli, with tools of Control Theory. Different mathematical methodologies
(qualitative/quantitative, deterministic/stochastic) have been used to best describe the
different biological systems under investigation. Notably, in the first part of the thesis we
mainly addressed the problem of controlling the growth rate of bacterial cells. Growth control
is essential in industrial biotechnology and fundamental research of this kind could pave the …
This thesis deals with modelling, analysis and control of gene regulatory networks in the bacterium E. coli, with tools of Control Theory. Different mathematical methodologies (qualitative/quantitative, deterministic/stochastic) have been used to best describe the different biological systems under investigation. Notably, in the first part of the thesis we mainly addressed the problem of controlling the growth rate of bacterial cells. Growth control is essential in industrial biotechnology and fundamental research of this kind could pave the way to novel types of antimicrobial strategies. To this aim we developed new qualitative mathematical formalisms, derived from piecewise linear systems, to couple gene expression with growth rate. We applied these formalisms to small E. coli synthetic gene circuit models (conceived with our collaborators from Ibis, Inria Grenoble) implementing both open and closed loop configurations. By means of phase plane analysis and bifurcation diagrams we showed that the proposed qualitative control strategies, which act on the gene expression machinery (GEM), can mathematically control the cell growth rate. Moreover, in order to identify the key components of GEM that mostly determine the bacterial growth rate, we also tested several growth rate models using Boolean computational tools. In the second part of the thesis, we developed a coarse-grained, but quantitative, ODE model of E. coli GEM whose parameter values have been identified from published experimental data at different steady state growth rate values.
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