Specialty Division

Cancer and Immunobiology

Research Expertise

Research Interests: Molecular mechanisms of the hypoxic response.

Key words: hypoxia, HIF, PHD2, prolyl hydroxylation, gene regulation, human high altitude 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 endothelial 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. We are also interested in understanding how this pathway is genetically altered in human populations that have adapted to the chronic hypoxia of high altitude. Tibetans possess PHD2 mutations. We have found that this results in differential effects on the interactions of PHD2 with two proteins, p23 and NACA. This could account for why Tibetans have augmented hypoxic ventilatory responses but are not predisposed to erythrocytosis. Andeans possess a HIF-2α mutation. We have found that this impairs heterodimerization with ARNT and results in a partial loss of function. These studies have provided insights into how the HIF pathway is altered in humans. We employ biochemical, molecular biologic, and mouse model approaches.

Lab Personnel:
Frank Lee (Principal investigator)
Daisheng Song (Senior Research Investigator)
Manuela Palacio (Undergraduate)
Daisy Lockshire (Undergraduate)
Jake Brewington (Undergraduate)
Dawn Williams (Administrative Assistant)

Clinical Expertise

Medical pathology

CVI Expertise

CVI Program Unit(s):
Lipid / Atherosclerosis / CAD / ACS / Prevention

CVI Research Description:
We are interested in the Hypoxia Inducible Factor (HIF) pathway, and whether manipulation of this pathway may offer benefit in models of ischemic heart disease.

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-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. We are interested in understanding mechanisms by which the HIF prolyl hydroxylase PHD2 is regulated, 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 Belfast examining the molecular basis of idiopathic erythrocytosis, and this has identified critical roles for PHD2 and HIF-2α 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. We employ biochemical, molecular biologic, and mouse model approaches.

Itmat Expertise

Molecular mechanisms of the hypoxic response.

Graduate Groups

Cell and Molecular Biology

Education

B.A. (Biochemistry), Harvard College , 1983
M.D. (Medicine), Harvard Medical School, 1991
Ph.D. (Biological Chemistry), Harvard University, 1991

Specialty Certification

American Board of Pathology (Anatomic Pathology), 1994

Postgraduate Training

Resident in Pathology, Brigham & Women’s Hospital, Boston, 1991-1993
Chief Resident in Pathology, Brigham & Women’s Hospital, Boston, 1993-1993
Fellow in Renal Pathology, Brigham & Women’s Hospital, Boston, 1993-1994
Postdoctoral Research Fellow (mentor: Tom Maniatis), Harvard University, Cambridge, MA, 1994-1998

Awards and Honors

Detur Prize, Harvard College, 1980
Phi Beta Kappa, Harvard College, 1982
Carrington Prize in Molecular Mechanisms of Disease, Stanford University School of Medicine, 2000
Transformative R01 (T-R01) Award, NIH, 2009-2014
F1000 Faculty Member (Hematology), 2016-Present

Memberships and Professional Organizations

American Association for the Advancement of Science, 1998 - Present
NIH General Medicine B Study Section, 2001 - 2001
Wellcome Trust, 2002 - 2014
American Society for Biochemistry and Molecular Biology, 2004 - Present
Jeffress Memorial Trust (Virginia), 2005 - 2005
American Federation for Aging Research National Scientific Advisory Council, 2006 - Present
Telethon Foundation (Italy), 2007 - 2007
French National Cancer Institue, 2007 - 2007
University of Texas Southwestern Medical Center Promotion Committee, 2008 - 2008
Queen's University Belfast Promotion Committee, 2009 - 2009
NIH Challenge Grants Special Emphasis Panel ZRG VH D (58), 2009 - 2009
NIH Drug Discovery Special Emphasis Panel, ZRG1 MDCN-B (91), 2009 - 2009
NIH Stem Cell and Developmental Biology Special Emphasis Panel, ZRG1 BDA-P (90) S, 2010 - 2010
NIH Cellular Signaling and Regulatory Systems Study Section, 2010 - 2010
American Heart Association, 2012 - Present
University of Colorado School of Dental Medicine Promotion Committee, 2013 - 2013
American Society of Hematology, 2014 - Present
American Heart Association Peer Review Committee, 2016 - Present
American Heart Association Collaborative Sciences Award Peer Review Pre-Proposal Committee, 2023 - 2023

Web Links

Selected Publications

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