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Eteindre et rallumer la machinerie d'expression génique chez les bactéries: de modèles mathématiques aux applications biotechnologiques (RESET)


Action : Bio-informatique


N° de convention : 11-BINF-0005

Informations générales

  • Référence projet : 11-BINF-0005
  • RST : Hidde DE JONG
  • Etablissement Coordinateur : INRIA Rocquencourt
  • Région du projet : Auvergne-Rhône-Alpes
  • Discipline : 5 - Bio Med
  • Aide allouée : 1 500 000 €
  • Date de début du projet : 01/10/2012
  • Date de fin du projet : 30/09/2017
  • Site web du projet : https://project.inria.fr/reset/
  • Mots clés : systems biology; bioinformatics; biotechnology; biophysics; proteomics; microbiology; molecular biology; mathematical biology

Résumé du projet

One of the key issues in biotechnology is the redesign of microorganisms to optimize the yield of products of interest, such as biofuels, bulk and fine chemicals, or molecules of medical interest. The redesign modifies the metabolic flux distribution such that, ideally, the cells switch from growth, i.e., biomass production, to product synthesis. The aim of the RESET project is to propose a novel strategy for achieving this redirection of metabolic fluxes. Instead of interfering with the functioning of specific pathways, we will focus on a global control system of the microbial cell, the gene expression machinery (GEM). The synthesis of all proteins and RNAs, and thus the production of biomass, is dependent on RNA polymerase, ribosome, and other components of the GEM. The basic idea of our approach is to arrest the GEM in a precise and controlled way, so as to create non-growing cells with a functional metabolism utilizing substrates for the synthesis of specific target compounds rather than for biomass. Conversely, when the degradation of enzymes and other proteins threatens the stability of metabolic fluxes, the GEM is switched on again, thus alternating phases of growth and product synthesis. In the fourth full year of the project, the partners have worked on improving the genetic stability of the existing system, based on external control of RNA polymerase, and developed an alternative system, based on replication control. Moreover, the preparation of the main cross-platform experiment to quantify cellular physiology in the growth arrest/restart regime has continued. The transfer of the RESET strain to the industrial partner has been completed, involving the integration of the system for controlling RNA polymerase expression into proprietary strains. A first calibrated version of the GEM model has been completed and is currently further improved. A valorization project based on the RESET patent was selected for further development by the SATT Linksium.

(L'auteur de ce résumé est le coordinateur du projet, qui est responsable du contenu de ce résumé. L'ANR décline par conséquent toute responsabilité quant à son contenu.)