Investigation of the role of Nrf2 in man (360G-Wellcome-094128_Z_10_Z)

This research proposal aims to address the question of whether the Nrf2 transcription factor pathway is a critical regulator of cellular defence in man. In order to answer this question, sensitive and specific biomarkers are required that will allow us to define the natural variability of the system in the human population, and also the extent to which Nrf2 activity can be induced by exposure to drugs and other chemicals. Nrf2 is a transcription factor that, in animal models, regulates the adap tive cellular response to chemical stress, including up-regulation of antioxidant proteins, drug metabolizing enzymes and cellular transporters, each aimed at reducing the potential chemical hazard. Our recent proteomic investigation of Nrf2 null mice also points to an important role in hepatic lipid metabolism. Using a combined proteomic and metabolomic approach, we will characterize tissue and biofluid samples from three different experimental models: Nrf2 null mice, hepatocyte-derived rodent and human cell lines and freshly-isolated human hepatocytes. These studies will yield candidate biomarkers which will undergo performance analysis in two proof of concept studies, using samples obtained from a panel of patients treated for 7 days with the Nrf2 inducer, resveratrol, and in a longitudinal cohort of paracetamol overdose patients.