ESNATS is divided into four main research areas, each one representing a sub-project (SP). These SPs are complemented by central work packages (cWPs) which cover transversal scientific aspects of the project.
Sub-project 1 is focussed on the development of ESC-based in vitro models for evaluating the hazard of compounds to the mammalian reproductive cycle. SP1 will provide more detailed information on the toxicological mechanisms in different sensitive phases of the reproductive cycle, such as germ cell development, preimplantation development and early embryonic development.
Sub-project 2 aims to develop reliable and cost-efficient test systems to evaluate the effect of compounds on neuronal development and neuronal viability and functionality. An integrated approach is proposed to develop an ESC-based system for neurotoxicity testing, which will allow overcoming obstacles such as variability in the cell lines and culture conditions, the influence of the mode of neuronal ESC differentiation, poor or irrelevant read-outs and extrapolation of in vitro toxicity to in vivo toxicity.
SP3 ESC-based toxicogenomics and toxicoproteomics signatures
The overall goal of SP3 is to investigate the influence of compounds on gene expression and proteomics. SP3 will therefore develop in vitro toxicity models based on high throughput genomics methods by identifying specific toxicogenomic and phosphoproteomic signatures of drug candidates on the developmental processes of ESC towards tissue specific cells and on the ESC-derived neurons, spermatocytes and hepatocytes.
SP4 Metabolism, toxciokinetics and modelling
A major difficulty in evaluating a toxicological risk in vitro is accounting for an in vivo like metabolism. This SP therefore deals with the integration of metabolising systems into the ESNATS testing approaches for neural and reproductive toxicity.
Besides comprehensive knowledge about metabolism, SP4 will also contribute with physiologically based pharmacokinetic information, i.e. the concentration of test substances and their metabolites at the target cells within the organism.
Central workpackages cover the following transversal topics:
- The requirements of stakeholders (pharmaceutical industry, regulators and ethicians) in terms of innovative evidence based toxicity testing will be gathered in cWP1 "Steering committee"
- cWP2 "Knowledge Management, Validation and Testing Strategies" ensures systematic management of knowledge and evaluation of results
- The bottleneck of provision of standardised cells (hESCs and hESC-derived cells) will be addressed in cWP03 ("Methods for automating scale up of stem cell production and cell banking")