Systems level architecture of GDNF mediated neurotrophic action
Project leader: professor MART SAARMA
Institute of Biotechnology, University of Helsinki
Doctoral students of the project:
Matthew Phillips, Institute of Biotechnology
Anu Planken, Institute of Biotechnology
Other researchers of the project:
Petri Auvinen, Institute of Biotechnology
Anna-Liisa Hänninen, Institute of Biotechnology
Imre Västrik, European Bioinformatics Institute
Key words: neurotrophic factors, receptors, signalling, DNA microarray, genome knowledgebase, modelling
Project description and main results:
The central focus of this research will be the dissection and mapping of signaling networks associated with gross cellular state-transitions in neuronal cell types. The project will involve a synergy of bench, mathematical, and informatic methods, focused on the production of a causal model for the description of an important signaling network. The major cellular transitions to outgrowth, survival, and differentiation will be studied for a single stimulus: the glial cell line-derived neurotrophic factor (GDNF). GDNF has a potent effect on the morphology and survival of numerous neuronal cell types in the central and peripheral nervous systems. These effects are both well studied, and of considerable clinical importance in the treatment of neurodegenerative disorders such as Parkinson's disease.
Our group has been working vigorously on the application of biochemical, cellular, and transgenic, as well as microarray technology to the problem of defining the neurotrophic and morphogenic properties of GDNF and its family members. An initial study of the mouse Neuro2A cell line done with the Affymetrix© system, has allowed us to refine our methodology and yielded many potentially useful insights into the processes supporting neuronal survival and neurite outgrowth in this system. A similar study on the genome-wide effects in the midbrain region containing dopamine neurons of GDNF heterozygous mutant mice, in its early stages, has also produced encouraging results and provided evidence for a common set of genes regulated in both GDNF responsive neuroblastoma, and in GDNF-dependent central neurons.
One of the key features of this project will be the development and refinement of new bioinformatics tools for the analysis of microarray data, and the construction of a formal model for the GDNF signaling system. These efforts will include: a system for identifying hypotheses based on lists of differentially regulated genes; a computational methodology for identifying, with confidence, the activity of distinct signaling pathways affecting a microarray experiment; a formal model of GDNF signaling embedded in the EBI Genome knowledgebase, whose principal architect (Dr. Västrik) is a member of our team.
We propose to carry out this program with an interdisciplinary team representing expertise in neuroscience, bioinformatics, mathematics, and computer science - with significant emphasis placed on the development of quantitative models and analytical tools for the interpretation of microarray data.
Publications: