Hepatic and cardiac toxicity systems modelling

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Project Title: Hepatic and cardiac toxicity systems modelling
Project Number: CORDIS-109458
Project web address: Follow on CORDIS
Organization: Universiteit Maastricht, Netherlands, Maastricht
Collaborators: European Molecular Biology Laboratory, DE
King'S College London, GB
Imperial College Of Science, Technology And Medicine, GB
Max-Planck-Gesellschaft Zur Förderung Der Wissenschaften Ev, DE
Rheinisch-Westfaelische Technische Hochschule Aachen, DE
Eidgenoessische Technische Hochschule Zuerich, CH
F. Hoffmann - La Roche Ltd., CH
Genedata Ag, CH
Luxcel Biosciences Limited, IE
Microdiscovery Gmbh, DE
Fundacion Para La Investigacion Del Hospital Universitario La Fe De La Comunidad Valenciana, ES
Insphero Ag, CH
Optibrium Limited, GB
Principal Investigators (PI): Paul Labbett, GB
Arif Malik, DE
Ernst Schmachtenberg, DE
Tatjana Palalic, GB
Jason Hannon, CH
René Reijnders, NL
Tom Ratcliff, DE
Timo Wittenberger, CH
Sabrina Femenia, ES
Anke Badrow, DE
Jens Kelm, CH
Ralph Schlapbach, CH
Fred Klok, IE
Matthew Segall, GB
Project Description:
HeCaToS aims at developing integrative in silico tools for predicting human liver and heart toxicity. The objective is to develop an integrated modeling framework, by combining advances in computational chemistry and systems toxicology, for modelling toxic perturbations in liver and heart across multiple scales. This framework will include vertical integrations of representations from drug(metabolite)-target interactions, through macromolecules/proteins, to (sub-)cellular functionalities and organ physiologies, and even the human whole-body level. In view of the importance of mitochondrial deregulations and of immunological dysfunctions associated with hepatic and cardiac drug-induced injuries, focus will be on these particular Adverse Outcome Pathways. Models will be populated with data from innovative in vitro 3D liver and heart assays challenged with prototypical hepato- or cardiotoxicants; data will be generated by advanced molecular and functional analytical techniques retrieving information on key (sub-)cellular toxic evens. For validating perturbed AOPs in vitro in appropriate human investigations, case studies on patients with liver injuries or cardiomyopathies due to adverse drug effects, will be developed, and biopsies will be subjected to similar analyses. Existing ChEMBL and diXa data infrastructures will be advanced for data gathering, storing and integrated statistical analysis. Model performance in toxicity prediction will be assessed by comparing in silico predictions with experimental results across a multitude of read-out parameters, which in turn will suggest additional experiments for further validating predictions. HeCaToS, organized as a private-public partnership, will generate major socioeconomic impact because it will develop better chemical safety tests leading to safer drugs, but also industrial chemicals, and cosmetics, thereby improving patient and consumer health, and sustaining EU’s industrial competitiveness.
Project Terms:
life sciences