Nuclear receptors (NR) are transcription factors activated by nuclear hormones, dietary components and xenobiotics. Nucleo-cytoplasmic shuttling is an important part of NR signalling: NR nucleo-cytoplasmic shuttling is regulated by external NR ligands and different intra-cellular processes.
In close collaboration with experimental groups within the Marie Curie RTN NucSys (Sept 2007-Sept 2009) we have build a mechanism based kinetic model, integrating nucleo-cytoplasmic shuttling and signalling processes. This model was created for one class of nuclear receptors, i.e., steroid hormone receptors, and is presently used for systems biological studies of the role of nucleo-cytoplasmic shuttling in steroid hormone receptor signalling. However, other groups of nuclear receptors have similar network structures. We here propose that the steroid hormone receptor signalling model can be used as canonical model and re-parameterised so as to become relevant for any of the most important nuclear receptor groups.
In the project proposed in this application for a European Reintegration Grant, the canonical model of NR signalling will be adapted to several most important classes of nuclear receptors.
Then, models of different nuclear receptor signalling pathways will be integrated in a bigger NR Signalling Integrative Model in order to begin to study the role of the entire network in health and disease. In particular, the research will be focused on the process of integration of different signals impinging the same NR signalling pathway and on crosstalk between different NRs. Taking into account the crucial role of both phenomena in the development of aging-related syndromes and many systems diseases such as cancer and osteoporosis, we anticipate substantial biomedical relevance of our study. In addition, our NR signaling integrative model may contribute significantly towards the “Digital Human”, i.e. the quantitative, molecules to human whole body model.
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