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Research: Project 1

The role of HIF1 in metal-induced toxicity

Cobalt and other divalent metals have been used as hypoxic mimics for many years. In fact, exposure to these metals leads to HIF1a stabilization and HIF1-dependent transcription. Metal exposure can also lead to cellular damage and premature cell death. We have begun exploring the hypothesis that this metal-induced damage is dependent upon HIF1 signaling. We have used genetically engineered cell lines to show that hypoxia signaling is important in metal-induced toxicity and genomic screens have revealed that the expression patterns between hypoxia and metals are very similar. This project is now focused on identifying specific genes that are important in this process using genomics and RNAi based models. In addition, we are attempting to elucidate the in vivo role of HIF1 signaling in metal-induced toxicity using engineered mice and exposure studies. Finally we are beginning to look at the metabolic consequences of metal exposure and attempting to link these changes to HIF1a genotype and specific metals. The ultimate goal of the project is to understand how metals influence HIF1 signaling and how this impacts the cell to promote a toxic response.