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Unfolding the regulation of stress response pathways upon liver injury

Drug-induced liver injury (DILI) is one of the main reasons for drug attrition during pre-clinical and clinical phases of drug development as well as for drug withdrawal post-marketing.

Niemeijer, M.C.
07 februari 2023
Thesis in Leiden Repository

The development of DILI can result in severe outcomes giving high risk for liver failure. The activation of adaptive stress response pathways is a way for cells to cope with drug-induced stress and is one of the early key events in the development of DILI. In this thesis, the regulation of the activation of adaptive stress responses has been studied using high content imaging, gene silencing and high throughput transcriptomics approaches to improve the understanding and prediction of DILI. The tight regulation of the unfolded stress response was dissected by combining computational modelling and RNA interference screening. Improved insight in the crosstalk between oxidative stress and DNA damage response during chemical exposure was obtained. Different liver test systems were compared for their capability to identify stress response activation, which allows for well-considered selection of models fit-for-purpose for drug screening. Furthermore, the inter-individual variability in stress response activation was mapped to enable the usage of accurately defined uncertainty factors to account for human population variability for DILI liabilities during safety testing.

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