Collaboration UM and LCSB

finalized

Analysis of Environmental-Genome Interactions in the development of neurodegenerative diseases

Background: The objective of this study is to elucidate environmental-genome interactions that can lead to Parkinson's disease. In this specific project the role of ROS-generating chemicals will be analyzed with respect to mitochondrial function and dysfunction. In order to fully explore the role of mitochondria we will carry out a combination of experimental and computational approaches. For this purpose, we will extend the concept of the PD map that has been developed at the LCSB to integrate toxicogenomic information developed by Maastricht University. The Maastricht University will carry out the majority of the experimental analysis with respect to measuring the molecular and phenotypic consequences of toxin exposure, while the LCSB will focus on the computational modeling and analysis.

The project is composed of the following work packages:

1. Further development of the Parkinson's disease map

• Extending and development of graphical user interfaces and programmatic interfaces of the PD-Map to and from simulation tools.
• Developing kinetic models to simulate the responses of cellular systems to toxic compounds
• Carrying out experimental studies with known and new compounds and analysing molecular responses (metabolomics and transcriptomics) that will be used to parameterise the computational toxicogenomic model
• Validating the results obtained by the computational models (induces pluripotent stem cells, metabolomics and toxicogenomics)

2. Creation and validation of experimental models

Creating of the following models:

• Using the human retinoic acid-controlled SH-SY5Y neuroblastoma cell line established at the Maastricht Institute for Mental Health and Neuroscience;
• iPSC-derived neuronal e.g. dopaminergic cell models from healthy individuals established at the LCSB Developmental and Cellular Biology group;
• Cellular responses after exposure to a range of prototypical chemicals:
  1. Sequencing of the transcriptome and of the epigenome, focusing on mitochondrial genes, by TGX Maastricht;
  2. Metabolomics analysis, by LCSB;
  3. Analysis of intracellular catecholamine levels, by the LCSB Metabolomics group;
  4. Electron spin resonance measurements of mitochondrial ROS generation, by TGX Maastricht;
  5. Fluorimetric mesasurements of apoptosis and mitochondrial transmembrane potential, by TGX Maastricht;
  6. Validating signaling networks by knocking down key response genes by RNA interference methods, by TGX Maastricht.

3. Creation of the predictive in silico model (jointly)

• Selecting test compounds (pesticides) for the training phase, exploiting available molecular information from the toxicological literature;
• Creating a hypothetical response network;
• Exposing the cell models to this training set of compounds;
• Retrieving integrated response networks;
• Creating an initial predictive model, by connecting these networks to the PD Map, using advanced data integration tools such as Connectivity Mapping;
• Subjecting the cellular models to validation sets of compounds (other pesticides, metals, drugs, etc), using the resulting data for informing and optimizing the in silico model;
• Evaluating structure-activity relationships among PD-inducing toxicants, allowing for the grouping of new chemical entities based on their chemical structure.