The Frank Lee Lab is involved in investigating the Hypoxia Inducible Factor (HIF) pathway, and whether manipulation of this pathway may offer benefit in models of ischemic heart disease, as well as the molecular pathway that leads to the control of red blood cell mass and more generally, the response to low oxygen tension.
The Lee Lab is interested in the cardiovascular consequences of manipulation of the Hypoxia Inducible Factor (HIF) pathway, an important cellular response to hypoxia. A transcription factor, HIF is a master regulator of the hypoxic response and upregulates many genes involved in hypoxic adaptation, including those encoding for enzymes of glycolysis, glucose transporters, erythropoietin, and vascular endothelial growth factor.
Projects include the following:
- Examine mechanisms by which HIF-α is regulated.
- Determine whether proline hydroxylation plays a more general role in hypoxia.
- Develop mouse models for examining the HIF pathway.
We and others have shown that HIF is regulated by a distinctive mechanism. Under normoxic conditions, the alpha subunit of HIF (HIF-α) is site-specifically hydroxylated on proline, which in turn constitutively targets HIF-α for degradation by the ubiquitin-proteasome pathway. Under hypoxic conditions, this modification is inhibited, thereby allowing HIF-α to escape degradation and activate transcription. Among the interests of the Lee Lab is the characterization of novel regulators of the HIF pathway, determining whether prolyl hydroxylation plays a more general role in the hypoxic response, and understanding the physiologic relevance of the pathway. With regard to the latter, the Lab has an ongoing collaboration with Professor Terence Lappin’s group at Belfast City Hospital and Queen’s University examining the molecular basis of idiopathic erythrocytosis. This collaboration has identified critical roles for HIF-2α and the HIF prolyl hydroxylase, PHD2, in the control of erythropoietin in humans.
- Frank S. Lee, MD, PhD
- Patrick Arsenault
Brody Foundation Postdoctoral Fellow
- Yu Jin Chung
Undergraduate University Scholar
- Marla Knob
- Daisheng Song
Senior research investigator
- Qiulin Tan