Project title

Cellular oxygen sensors in hepatic, inflammatory and immunological diseases and cancer

We have shown that activation of the hypoxia response by genetic or pharmacologic means that inhibit the HIF-P4H enzyme protected mice from obesity, metabolic syndrome and atherosclerosis. Fatty liver is closely associated with overweight, metabolic dysfunction and alcohol abuse. We expect that HIF-P4H inhibition would be a novel treatment strategy for liver diseases and some inflammatory and immunological diseases. We will carry out experiments with gene-modified mice, preclinical drugs and disease models to study these. Our second hypothesis is that some of the epigenetic regulator demethylase enzymes acting on histones sense cellular oxygen levels similarly to the HIF-P4Hs and alter gene transcription by modulating DNA conformation. We anticipate this to play a role in cancer. We will perform experiments in cell culture and with recombinant enzymes in test tubes to investigate this hypothesis.