Report presented by Hidde de Jong (INRIA Rhône-Alpes), in order to obtain the Habilitation à Diriger des Recherches (HDR) awarded by the Joseph Fourier University in Grenoble

Date and time: September 30, 2004, 2 PM

Abstract

In case of nutritional stress, the bacterium Escherichia coli abandons its exponential growth phase and enters stationary phase, that is, a physiological state in which the cells are more resistant and their growth has slowed down. This transition between the two growth phases is controlled by a genetic regulatory network, composed of genes, proteins, small molecules, and their mutual interactions. How does the response of the cell to a nutritional stress emerge from these interactions? And which modifications of the network would allow the bacterium to better adapt to its environment?

These are some examples of fundamental questions posed by biologists. In order to answer these, in addition to powerful experimental methods, tools for the modeling and simulation of genetic regulatory networks are indispensable. Today the application of these methods is submitted to two major constraints. First of all, the biochemical reaction mechanisms underlying the interactions are usually not or incompletely known. A second constraint arises from the almost complete absence of quantitative information on the kinetic parameters and molecular concentrations. As a consequence, traditional methods for the modeling and simulation of genetic regulatory networks are difficult to apply.

During the public defense, I present a method for the qualitative modeling and simulation of genetic regulatory networks that is well-adapted to the current constraints. This method, based on a class of piecewise-linear differential equations whose properties have been well-studied in mathematical biology, has been implemented in the computer tool Genetic Network Analyzer (GNA). I explain how, by using the method and the computer tool, my colleagues and me have begun to answer questions concerning the regulation of the stress response of Escherichia coli and other bacteria. Finally, I review the mathematical, computational, and biological problems raised by our preliminary results, problems on which I intend to work in the next few years.

Committee

Jean Della Dora (Institut National Polytechnique de Grenoble, Chairman)

François Rechenmann (INRIA Rhône-Alpes, Supervisor)

Leon Glass (McGill University, Montreal, Expert)

Albert Goldbeter (Free University of Brussels, Expert)

Jan van Schuppen (National Research Institute for Mathematics and Computer Science (CWI) and Free University of Amsterdam, Expert)

Nicolaas Mars (University of Groningen, Member)

Location

Grand Amphithéâtre

INRIA Rhône-Alpes

655, avenue de l'Europe, Montbonnot

38334 Saint Ismier CEDEX

Contact

Hidde de Jong

Institut National de Recherche en Informatique et en Automatique (INRIA)

Unite de recherche Rhone-Alpes

655 avenue de l'Europe, Montbonnot, 38334 Saint Ismier CEDEX, France

Tel +33 4 76 61 53 35

Fax +33 4 76 61 54 08

Secretariat (Francoise de Coninck) Tel +33 4 76 61 53 63