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VALAPODYN Report Summary

Project ID: 37277
Country: France

Final Report Summary - VALAPODYN (Validated Predictive Dynamic Models of Complex Intracellular Pathways Related to Cell Death and Survival)

The main objective of VALAPODYN was to show the feasibility of developing a new Systems Biology approach to model the dynamics of Molecular interaction networks (MIN) related to neuronal death and survival, and to perform in silico simulations to identify new potential drug targets to treat Neurodegeneration (NDG). The experimental model used was obtained by intracerebral injection in mice of kainate, a neurotoxic compound, known to result in NDG. The development of the MIN model required the production of accurate experimental data that were obtained after high throughput RNA and protein analysis of brain samples at 10 different time-points. This data was fed into the model, along with data collected from an exhaustive compilation of current molecular knowledge on NDG derived from the literature and organised in established databases.

This led to the first version of the dynamic MIN model of kainate-induced neuronal death which described the behaviour of a large signalling network including 521 molecules (genes/proteins) connected by 3 069 direct and oriented interactions that are all downstream of the kainate signal.

The model obtained has over 4 500 parameters and is one of the largest dynamic models of a signalling network ever published, with an overall relative error of 16 %. The simulations performed with this model identified a list of nine potential therapeutic targets. Out of these targets, three were selected for either:
(i) their coherence with the existing literature (i.e. brain derived neurotrophic factor or BDNF);
(ii) the possibility to inhibit their action with already existing chemical compounds (Vala09); or
(iii) their innovative aspects and potential 'added value' for development as a therapeutic target (Vala01). Inhibition of Vala09 by a chemical compound led to an aggravation of kainate-induced NDG. In contrast, inhibition of the expression of BDNF or of Vala01 by local application of shRNA-lentivirus, reduced kainate-induced NDG, as indicated by three different biomarkers of neuronal death.

These results validate the proof of principle of the relevance of the systems biology approach in modelling the dynamics of MIN and identifying innovative therapeutic targets in Neurology research. They will allow us to improve the model and generate more appropriate targets.

Contractors involved

The VALAPODYN consortium consists of seven partners, from five European countries. It utilises expertise developed during many years of research in different complementary fields including genomics (Academy of Athens, FBRAA), proteomics (University of Liege, ULg), molecular interactions (HELIOS Biosciences SARL, BIOBASE GmbH), RNA interference (Hebrew University of Jerusalem, HUJI), Neuroscience (Institut National de la Sante et de la Recherche Medicale, INSERM) and management expertise (Alma Consulting Group, ALMA).

Scientific approach

To achieve its ambitious objectives, the VALAPODYN work programme has been organised into six scientific work packages (WPs):

- three work packages (WPs 1-3) were dedicated to large scale data collection, the preparation and construction of the dynamic models as well as bioinformatics analysis of high throughput data generated by the consortium;
- one work package (WP4) was dedicated to the validation of the dynamic models;
- one work package (WP5) was dedicated to the preparation of the biological material for the construction of the dynamic models and for their validation;
- one work package (WP6) was dedicated to the management of the consortium and of knowledge (intellectual property rights, dissemination activities and exploitation plan).

The objectives of the technical WPs are detailed below:

WP1: Adaptation / construction of intracellular cascades
WP1 was aimed to adapt the network of interactions to the pathology studied. The MIN of both signal transduction events as well as transcription regulatory events occurring in the central nervous system was investigated. Relevant information in the literature was collected, including the scanning of appropriate and curated databases. The objective was to build a network reflecting the biological process which will be modelised.

WP2: Collection of the relevant biological data for construction of the dynamic model and design of an integrated database
This WP included the generation of gene and protein expression profiles and evaluation of the activity of selected cascade proteins.

WP3: Construction of the dynamic models and simulation / selection of therapeutic targets
This work package aimed at integrating known signalling cascades and novel biological data to train the dynamic model at selecting therapeutic targets from different simulation conditions. The output of this model was a selection of putative therapeutic targets that was then validated in WP4. Another aim of this work package was to provide bioinformatics support for the consortium, to organise genomics and proteomics data generated by the consortium in a database and to perform advanced bioinformatical analysis.

WP4: Validation of predictive value of model
The aim of this WP was to conduct RNA interference in cell culture and in vivo in order to verify the effect of limiting or suppressing expression on neurodegeneration - i.e. the neuroprotective potential.

WP5: Biological material
This WP was dedicated to provide the most appropriate biological material for the realisation of WP2 and WP4.

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