Research

Research

Our laboratory focuses on the mechanisms by which cells maintain homeostasis of iron and oxygen, with particular attention to hypoxia-inducible factors (HIFs) and iron regulatory proteins (IRPs).

We have identified regulatory factors for each pathway that sense both iron and oxygen levels and maintain mammalian iron and oxygen homeostasis at both the cellular and systemic levels: hydroxylases for HIF and the hemerythrin-containing FBXL5 for IRPs.

We have also found that overlapping control of gene expression creates cross-talk between the HIF and IRP pathways, and are investigating new mechanisms by which various metabolites influence these pathways. With these findings, we search for small-molecule antagonists of the pathways to validate their potential as therapeutic targets.  

Our observations provide new insights and opportunities to address diseases stemming from misregulation of oxygen and iron homeostasis including anemia, iron overload disorders, infection, stroke, heart attack, and cancer.

In mammalian cells, both iron and oxygen are sensed by hydroxylases and a hemerythrin-like domain to regulate HIF and IRP2 stability, respectively.  In addition, the HIF and IRP pathways are intertwined at the level of target gene expression, as translation of HIF-2α is regulated by IRP1 while both HIF and IRPs mediate expression of genes involved in cellular and systemic iron homeostasis.