CORDIS
EU research results

CORDIS

English EN
Generation of an adverse outcome pathway network on cholestatic liver injury for mechanism-based in vitro testing of chemicals.

Generation of an adverse outcome pathway network on cholestatic liver injury for mechanism-based in vitro testing of chemicals.

Objective

Cholestasis refers to toxic bile acid accumulation mainly in the liver and can be induced by many chemical compounds, in particular drugs. At present, drug-induced cholestatic injury (DICI) is poorly predictable and is an important reason for drug withdrawal from the market as well as a major clinical issue. A solution lies in better understanding the mechanisms of DICI. A pragmatic tool to visually and rationally capture the mechanistic basis of toxic effects is the adverse outcome pathway (AOP). Current AOP constructs frequently provide a too simplistic reflection of the mechanisms underlying toxicity by underestimating initiating events and biological responses.
This project aims to establish a realistic mechanistic scenario of DICI by producing an advanced AOP network that considers known initiating events of DICI and that quantitatively describes mechanisms of the adverse response as such as well as of the adaptive response activated by the body to counteract the adversity. This will be used as the basis for generating an in vitro test battery to accurately predict DICI. Such human-based and animal-free approaches to assess the safety of chemicals are urgently needed because of scientific and ethical reasons. AOP network development will rely on in vivo and clinical data collected from re-used samples (animal models of cholestasis and clinical cholestasis patients) and new in vitro data (human 3D spheroid model of cholestasis).
This multidisciplinary and timely project will lead to a conceptual change in toxicology by introducing an innovative type of AOP network. Additionally, it will equally meet a ubiquitous medical need regarding the prediction of cholestatic liver toxicity, therefore, perfectly matching the objectives of this Work Programme. It is anticipated that this project will serve as a generic prototype to mechanistically and reliably predict any other type of chemical-induced toxicity without using animals.
Leaflet | Map data © OpenStreetMap contributors, Credit: EC-GISCO, © EuroGeographics for the administrative boundaries

Coordinator

VRIJE UNIVERSITEIT BRUSSEL

Address

Pleinlaan 2
1050 Brussel

Belgium

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 178 320

Project information

Grant agreement ID: 833095

Status

Ongoing project

  • Start date

    15 May 2019

  • End date

    14 May 2021

Funded under:

H2020-EU.1.3.2.

  • Overall budget:

    € 178 320

  • EU contribution

    € 178 320

Coordinated by:

VRIJE UNIVERSITEIT BRUSSEL

Belgium