Final Report Summary - NR INTEGRATIVE MODEL (An Integrative Model for Nuclear Receptor Signaling: towards understanding of NR signaling in health and disease)
Marie Curie European Reintegration Grant (ERG) (2009 - 2011) sponsored the studies of nuclear receptor (NR) signalling started earlier within Marie Curie RTN NUCSYS framework (2007 - 2009). In NUCSYS consortium, the Hans Westerhoff's group (MCF, VUA, the Netherland) provided a computational support for several experimental groups (University of Surrey in United Kingdom (UK)), Erasmus Medical Centre (the Netherlands), Medizinische Universität Wien (Austria), Wageningen University (the Netherlands), University of Kuopio (Finland), etc.) and participated in model-driven experimental design. The PhD project of Alexey Kolodkin has been launched as a part of this collaboration and was devoted to study the role of nucleo-cytoplasmic transport of nuclear receptors in the signalling process. At the time point of termination of MC RTN NUCSYS grant, a detailed mechanism based kinetic model describing the role of nucleo-cytoplasmic transport of glucocorticoid nuclear receptors (GRs) has been built. The preliminary results provoked next scientific questions. First of all, since other groups of nuclear receptors are similar in the network structures, there was proposed to expand GR model as a blueprint model of nuclear receptor signalling and to re-parameterise it for other nuclear receptors, e.g. vitamin D receptors (VDRs) and pregnane X receptors (PXRs). Secondly, individual model for the most important members of NR family were proposed use for studying the more general principle of NR signalling functioning - so-called NR signalling design principles. Finally, the next challenge was to integrate different nuclear receptor signalling pathways into a bigger NR signalling integrative model and to study the role of the entire network in health and disease. These three main goals formed the core for ERG grant proposals. They all have been successfully fulfilled.
During two years of the research funded by ERG grant, several 'blue-print' models NR signalling have been built. By adjusting several experimentally measured parameters we were able to parameteris blueprint models for the GR, PXR and VDR instantiations. Models have allowed us to discover five important design principles of NR signalling:
(i) cytosolic 'nuclear' receptor may shuttle signal molecules to the nucleus;
(ii) the active export of NRs may ensure that there is sufficient receptor protein to capture ligand at the cytoplasmic membrane;
(iii) a two conveyor belts design dissipating GTP free energy, greatly aids response;
(iv) the active export of importins may prevent sequestration of NRs by importins in the nucleus; and
(v) the unspecific nature of the nuclear pore may ensure signal-flux robustness.
Then, individual NR signalling models have been integrated into large NR integrative model. The latter has been used for studding practical biological questions in the field of the physiology of stress.
ERG grant has covered 50 % of the two-year of PhD research of Alexey Kolodkin. Thanks to the grant, A. Kolodkin has received an excellent guidance in kinetic modelling and systems approaches, had a productive cooperation with experimental groups of former NUCSYS colleagues and successfully defended his thesis in systems biology of nuclear receptor at VU university of Amsterdam in September 2011 that has enabled him to continue scientific career as a researcher at the Luxembourg Centre for Systems Biomedicine. Scientific results obtained due to the financial support of ERG grant, have been presented in four peer reviewed open-access journals including the journal of Molecular Systems Biology, three book chapters, one PhD thesis and discussed in four oral and three poster presentations on international systems biological conferences.
During two years of the research funded by ERG grant, several 'blue-print' models NR signalling have been built. By adjusting several experimentally measured parameters we were able to parameteris blueprint models for the GR, PXR and VDR instantiations. Models have allowed us to discover five important design principles of NR signalling:
(i) cytosolic 'nuclear' receptor may shuttle signal molecules to the nucleus;
(ii) the active export of NRs may ensure that there is sufficient receptor protein to capture ligand at the cytoplasmic membrane;
(iii) a two conveyor belts design dissipating GTP free energy, greatly aids response;
(iv) the active export of importins may prevent sequestration of NRs by importins in the nucleus; and
(v) the unspecific nature of the nuclear pore may ensure signal-flux robustness.
Then, individual NR signalling models have been integrated into large NR integrative model. The latter has been used for studding practical biological questions in the field of the physiology of stress.
ERG grant has covered 50 % of the two-year of PhD research of Alexey Kolodkin. Thanks to the grant, A. Kolodkin has received an excellent guidance in kinetic modelling and systems approaches, had a productive cooperation with experimental groups of former NUCSYS colleagues and successfully defended his thesis in systems biology of nuclear receptor at VU university of Amsterdam in September 2011 that has enabled him to continue scientific career as a researcher at the Luxembourg Centre for Systems Biomedicine. Scientific results obtained due to the financial support of ERG grant, have been presented in four peer reviewed open-access journals including the journal of Molecular Systems Biology, three book chapters, one PhD thesis and discussed in four oral and three poster presentations on international systems biological conferences.