Description of Research Expertise

Research Interests: Molecular mechanisms of the hypoxic response.

Key words: hypoxia, HIF, PHD2, prolyl hydroxylation, gene regulation, human adaptation

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, erythropoietin, endothelin, and vascular enthothelial growth factor. HIF is regulated by a distinctive mechanism. Under normoxic conditions, the enzyme PHD2 prolyl hydroxylates the alpha subunit of HIF (HIF-α), 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. We are interested in understanding mechanisms by which PHD2 is regulated, and in understanding the physiologic relevance of the pathway. We have an ongoing collaboration with Professor Terence Lappin’s group at Belfast City Hospital and Queen’s University Belfast examining the molecular basis of idiopathic erythrocytosis, and this has identified critical roles for PHD2 and HIF-2α in the control of red cell mass in humans. In other studies, we have found that PHD2 binds to the ribosomal chaperone NACA and to the HSP90 cochaperone p23. The former interaction is important for regulation of red cell mass; the latter interaction is important for control of respiration. We are also interested in understanding the molecular basis for Tibetan adaptation to the chronic hypoxia of high altitude. Tibetans possess PHD2 mutations that impair its interaction with p23 but not with NACA. This provides an explanation for why Tibetans have augmented hypoxic ventilatory responses but are not predisposed to erythrocytosis. We employ biochemical, molecular biologic, and mouse model approaches.

Lab Personnel:
Frank Lee (Principal investigator)
Daisheng Song (Senior Research Investigator)
Liu Hong (Visiting Scholar)
Jake Brewington (Undergraduate, Penn Undergraduate Research Mentoring program)
Dawn Williams (Administrative Assistant)

Description of Clinical Expertise

Medical (autopsy) pathology