ayout 1 - EMBL Grenoble

EMBL Research at a Glance 2009
Nicolas Le
Novère
PhD 1998, Pasteur Institute,
Paris.
Postdoctoral research at the
University of Cambridge.
Research fellow, CNRS,
Paris.
Group leader at EMBL-EBI
since 2003.
Computational systems neurobiology
Previous and current research
The Le Novère group’s research interests revolve around signal transduction in neurons, ranging
from the molecular structure of membrane proteins involved in neurotransmission to modelling
signalling pathways. In particular, we focus on the molecular and cellular basis of neuroadaptation
in neurons of the basal ganglia. The supra-macromolecular structure of the postsynaptic membrane
strongly influences signal transduction. Moreover, the whole structure is dynamic and
evolves, for example, under the control of neuronal activity. By building detailed and realistic computational
models, we try to understand how neurotransmitter-receptor movement and clustering,
interactions between membrane and cytoplasmic proteins, and spatial location influence
synaptic signalling. Downstream from the transduction machinery, we build quantitative models
of the integration of signalling pathways known to mediate the effects of neurotransmitters, neuromodulators
and drugs of abuse. We are particularly interested in understanding the processes
of cooperativity, pathway switch and bistability.
The group provides community services that facilitate research in computational systems biology.
In particular, we are leading the efforts in encoding and annotating kinetic models in chemistry
and cellular biology, including the creation of standard representations, the production of databases
and software development. The Systems Biology Markup Language (SBML) is designed to
facilitate the exchange of biological models between different types of software. As editors of the
language, we also work on increasing its coverage, and are developing software to support SBML
usage. The Systems Biology Graphical Notation is an effort to develop a common visual notation for biochemists and modellers. Moving
from the form to the content, we are also developing standards for model curation (MIRIAM, MIASE), and controlled vocabularies to improve
the models (the Systems Biology Ontology, the TErminology for the Description of DYnamics etc.). Finally, a model is only useful if it
can be easily accessed and reused. BioModels Database (www.ebi.ac.uk/biomodels) is now the reference resource where scientists can store,
search and retrieve published mathematical models of biological interest.
Future projects and goals
In forthcoming years, the activity of the group will continue along two orthogonal directions. Our research work on modelling neuronal signalling
at the level of the dendritic spine will expand to include other signalling pathways (MAPK, TrkB, PI3K) and tackle problems such as
the role of scaffolding proteins or the synchronisation of calcium waves and phosphorylation gradients. Building on the growth of the Bio-
Models Database, we will also carry out research on model composition, with the aim of improving component identification and reaction
matching to build large-scale models of cellular
compartments such as dendritic spines. Our involvement
in the development of standards and
resources for systems biology will continue, with
the goal of completing the puzzle of representations
and ontologies so as to efficiently integrate
the different levels of description of biochemical
and cellular processes, qualitative, quantitative
and experimental.
An example of SBGN in action, showing the
catalysis of ERK phosphorylation by MEK in the
growth factor signalling pathway.
Selected references
Le Novère, N. et al. (2008). DARPP-32: Molecular integration of
phosphorylation potential. Cell. Mol. Life Sci., 65, 2125-2127
Stefan, M.I. et al. (2008). An allosteric model of calmodulin explains
differential activation of PP2B and CaMKII. Proc. Natl. Acad. Sci.
USA, 105, 10768-10773
Taylor, C.F. et al. (2008). Promoting coherent minimum reporting
guidelines for biological and biomedical investigations: The MIBBI
project. Nat. Biotechnol., 26, 889-896
Laibe, C. & Le Novère, N. (2007). MIRIAM Resources: Tools to
generate and resolve robust cross-references in Systems Biology.
BMC Syst. Biol., 1, Article 58
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