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.
My name is Vânia Vilas-Boas and I am a Portuguese postdoctoral researcher working at the Vrije University Brussel, in Belgium.
I am a Pharmacist (PharmD, 2005) and I hold a Master (2009) and a PhD (2017) in Toxicology. My main research interest is the development and use of advanced human-cells-based in vitro models to study drug/ chemical/ nanoparticles toxicity in the context of 3R.
I am fond of traveling, hiking, food and friends.
My host supervisor is Prof. Mathieu Vinken. He is a full professor of Toxicology at the Vrije University Brussel, in Belgium.
His main research interests are:
the mechanistic study of cholestatic liver injury using AOPs as the basis for improved in vitro prediction of liver toxicity;
the development and testing of inhibitors of connexin hemichannels and pannexin channels as liver therapeutics.
More detailed information about Prof. Vinken can be found here.