Description of Research Expertise
Research Interests: Molecular mechanisms of the hypoxic response.
Key words: hypoxia, HIF, PHD2, prolyl hydroxylation, gene regulation
Research Details: An important cellular response to hypoxia is the activation of the transcription Hypoxia Inducible Factor (HIF). 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 enthothelial growth factor. We are interested in the regulation and physiologic importance of this pathway. We and others have shown that HIF is regulated by a distinctive mechanism. Under normoxic conditions, the alpha subunit of HIF (HIF-a) is site-specifically hydroxylated on proline, which in turn constitutively targets HIF-a for degradation by the ubiquitin-proteasome pathway. Under hypoxic conditions, this modification is inhibited, thereby allowing HIF-a to escape degradation and activate transcription. We are interested in characterizing novel regulators of the HIF pathway, determining whether prolyl hydroxylation plays a more general role in the hypoxic response, and in understanding the physiologic relevance of the pathway. With regard to the latter, we have an ongoing collaboration with Professor Terence Lappin’s group at Belfast City Hospital and Queen’s University examining the molecular basis of idiopathic erythrocytosis, and this has identified critical roles for HIF-2a and the HIF prolyl hydroxylase, PHD2, in the control of erythropoietin in humans. We are also interested in understanding the molecular basis for Tibetan adaptation to the chronic hypoxia of high altitude.
Lab Rotation Projects:
1. Examine mechanisms by which HIF-a is regulated.
2. Determine whether proline hydroxylation plays a more general role in hypoxia.
3. Develop mouse models for examining the HIF pathway.
Frank Lee (Principal investigator)
Daisheng Song (Senior research investigator)
Patrick Arsenault (NIH T32 Postdoctoral fellow)
Andrew Ravaschiere (Undergraduate)
Marla Knob (Administrative assistant)