Research project
TLR signalling in Nephrotoxicity
Central goal: development of a high content imaging screening system for testing the organ toxic properties of compounds as an alternative to the chronic rodent toxicity assays for long term toxicity.
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- Bob van de Water
Adverse drug toxicity is a major problem in all phases of clinical drug development and the most frequent cause of post-marketing warnings and withdrawals. Todays, no adequate translational strategies are available to predict safety. Thus the central goal of my PhD is to develop a high content imaging screening system for testing the organ toxic properties of compounds as an alternative to the chronic rodent toxicity assays for long term toxicity. This method will be focused on one major target organ, the kidney and specifically proximal tubular cells.
Many renal biotransformation reactions bioactivate drugs and other xenobiotics to reactive chemical species that induce nephrotoxicity. These reactive intermediates initiate signal transduction events. The prominent pathways activated in the response to chemical-induced stress are the Nrf2 pathway (oxidative stress and covalent modifications) and the NF-kB pathway (oxidative stress and inflammation). Alternatively, innate immune response activation through Toll-like receptors by their ligands primes cell systems for injury responses. The synergistic activities of these pathways in the context of renal toxicity are poorly understood.
During my PhD, I will establish a reliable live cell reporter toxicity assay mimicking more closely the combination of toxicant metabolism and immune system activation and giving a real insight on the toxicity of future drug compounds. But mostly, knowledge will be gained in the synergy between the different pathways involved as well as the role of the immune system in chronic toxicity.