Project description
Mapping the mechanisms of drug-induced cholestatic liver injury
Many drugs induce toxic bile acid accumulation mainly in the liver, a condition known as cholestasis. Drug-induced cholestatic injury (DICI) is a major clinical issue, but the underlying mechanisms are poorly understood. The EU-funded ChOLLATERAL project is putting together an adverse outcome pathway (AOP) network for DICI which combines toxicity mechanisms of adverse responses and adaptive processes of the body. The information will be collected from in vivo and clinical data as well as from in vitro 3D models of cholestasis. Collectively, the AOP network will help develop a battery of in vitro tests for the prediction of DICI both at the clinical level and for drug development purposes.
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2018
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
1050 Bruxelles / Brussel
Belgium
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.