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Gregg L. Semenza, M.D., Ph.D.

Photo of Dr. Gregg L. Semenza, M.D., Ph.D.

Director, Vascular Program, Institute for Cell Engineering

Professor of Pediatrics

Research Interests: Protection of the heart against ischemia-reperfusion injury; Role of HIF-1 in cancer; Gene and stem cell therapy for ischemic cardiovascular disease; Molecular mechanisms of oxygen homeostasis; Genetic syndromes due to mutations in genes encoding transcription factors ...read more

Background

Dr. Gregg L. Semenza is a professor of pediatrics, radiation oncology and molecular radiation sciences, biological chemistry, medicine, and oncology at the Johns Hopkins University School of Medicine. Dr. Semenza is the C. Michael Armstrong Professor of Pediatrics and serves as the director of the vascular program at the Institute for Cell Engineering.

One of today’s preeminent researchers on the molecular mechanisms of oxygen regulation, Dr. Semenza has led the field in uncovering how cells adapt to changing oxygen levels. He is best known for his ground-breaking discovery of the HIF-1 (hypoxia-inducible factor 1) protein, which controls genes in response to changes in oxygen availability. The finding has far-reaching implications in understanding and treating low-oxygen health conditions such as coronary artery disease and tumor growth.

He received his A.B. from Harvard University. He earned his M.D. and Ph.D. from the University of Pennsylvania, completed his residency in pediatrics at Duke University Medical Center and performed postdoctoral research in medical genetics at Johns Hopkins. Dr. Semenza joined the Johns Hopkins faculty in 1990.

Dr. Semenza’s research interests include the molecular mechanisms of oxygen homeostasis; gene and stem cell therapy for ischemic cardiovascular disease; the role of HIF-1 in cancer; and protection of the heart against ischemia-reperfusion injury. He has authored more than 250 research articles and several book chapters, and has been cited in research more than 30,000 times.

He is a founding fellow of the American College of Medical Genetics and was elected to the Association of American Physicians and the National Academy of Sciences in 2008. He serves on the editorial board of several journals, including Molecular and Cellular Biology and Cancer Research, and is editor-in-chief of the Journal of Molecular Medicine.

In 2012, Dr. Semenza was elected to the Institute of Medicine. He has been recognized with numerous other awards, including the Lefoulon-Delalande Grand Prize from the Institut de France, the Gairdner Award, the Stanley J. Korsmeyer Award, the E. Mead Johnson Award for Research in Pediatrics, the Jean and Nicholas Leone Award from the Children''s Brain Tumor Foundation, the Established Investigator Award from the American Heart Association, and the Lucille P. Markey Scholar Award in Biomedical Science.

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Titles

  • Director, Vascular Program, Institute for Cell Engineering
  • Professor of Pediatrics
  • Professor of Biological Chemistry
  • Professor of Medicine
  • Professor of Radiation Oncology and Molecular Radiation Sciences

Education

Additional Training

Ph.D., University of Pennsylvania, 1984

M.D., University of Pennsylvania, 1984

A.B., Harvard University, 1978

Research & Publications

Research Summary

The Semenza lab studies molecular mechanisms underlying angiogenesis and vascular remodeling in ischemic cardiovascular disease. A major aspect of this process is the production of multiple angiogenic cytokines and growth factors in response to hypoxia/ischemia, which is mediated by the transcription factor HIF-1 (hypoxia-inducible factor 1). HIF-1 mediates vascular and progenitor cell responses to angiogenic signals, but these processes are impaired by aging and diabetes. The team currently is studying the use of gene and stem cell therapy in mouse models of critical limb ischemia and cutaneous burn wounds.

HIF-1 plays important roles in critical aspects of cancer biology, including tumor angiogenesis, regulation of glucose and energy metabolism, invasion, and metastasis. The team is taking several approaches to inhibit HIF-1 activity, including RNA interference, dominant negative constructs, and small molecule inhibitors. A major focus of their current cancer research is using animal, cell-based, molecular, and biophysical approaches to investigate the role of HIF-1 in vascular and lymphatic metastasis of human breast cancer.

HIF-1 also is required for ischemic preconditioning, short episodes of ischemia and reperfusion that protect the heart against a subsequent prolonged ischemic insult. The team currently is exploring the cellular and molecular mechanisms underlying ischemic preconditioning using mice in which HIF-1 activity has been knocked out in specific cell types within the heart.

The team now is using mass spectroscopy techniques to identify proteins that interact with the HIF-1 subunit. By employing this taking proteomics-based approach, they have identified novel regulators of HIF-1 transcriptional activity as well as direct regulation of the DNA replication machinery by HIF-1.

Lab

Dr. Semenza’s lab is currently investigating: 

  1. Molecular mechanisms of oxygen homeostasis. They have cloned and characterized hypoxia-inducible factor 1 (HIF-1), a basic helix-loop-helix transcription factor. HIF-1 expression increases exponentialåy as cellular O2 concentration declines. HIF-1 activates transcription of genes that are essential for adaptive responses to hypoxia, such as glycolysis, erythropoiesis, angiogenesis, and vascular remodeling. They are presently investigating the role of HIF-1 in the pathophysiology of cancer, cerebral and myocardial ischemia, chronic lung disease, and diabetes.
  2. Gene and stem cell therapy for ischemic cardiovascular disease. They are performing preclinical studies to investigate the use of adenoviral vectors encoding a constitutively active form of the HIF-1 subunit to stimulate vascularization of ischemic tissue. They are also utilizing bone marrow-derived angiogenic cells and adipose-derived mesenchymal stem – cells to stimulate vascularization and tissue regeneration in preclinical models of peripheral arterial disease.
  3. Role of HIF-1 in cancer. They are investigating the effects of altered HIF-1 activity on tumor growth, metabolism, and vascularization in preclinical models. These studies are providing proof-of-principle that inhibition of HIF-1 activity represents a novel strategy of cancer therapy. They have identified several drugs that potently inhibit HIF-1 and block the growth and vascularization of human tumor xenografts in nude mice.
  4. Protection of the heart against ischemia-reperfusion injury. They have demonstrated in preclinical models that recombinant human erythropoietin induces dramatic acute protection against cell death in hearts subjected to ischemia and reperfusion via activation of the phosphatidylinositol-3-kinase signal-transduction pathway. They have shown that HIF-1 is required for ischemic preconditioning.

Lab Website: Gregg Semenza Lab

Clinical Trials

HIF-1 Regulated Endothelial Progenitor Cell (EPC) Recruitment in Burn Wound Healing

Selected Publications

View all on Pubmed

Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. USA 92: 5510-5514 (1995). Citations: 3361.

Semenza GL. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3, 721-732 (2003). Citations: 3342.

Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell. Biol. 16:4604-4613 (1996).Citations: 2334.

Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW. Overexpression of hypoxia-inducible factor 1 in common human cancers and their metastases. Cancer Res. 59:5830-5835 (1999). Citations: 1713.

Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol. Cell. Biol. 12:5447-5454 (1992). Citations: 1646.

Academic Affiliations & Courses

Graduate Program Affiliation

Cellular and Molecular Medicine
Human Genetics and Molecular Biology

Activities & Honors

Honors

  • Research Professor, American Cancer Society, 2012 - 2016
  • Lefoulon-Delalande Grand Prize, Institut de France, 2012
  • Elected to the Institute of Medicine, 2012
  • Stanley J. Korsmeyer Award, American Society for Clinical Investigation, 2012
  • Canada Gairdner Award, 2010
  • Member, National Academy of Sciences USA, 2008
  • Member, Association of American Physicians, 2008
  • E. Mead Johnson Award for Research in Pediatrics, Society for Pediatric Research, 2000
  • Jean and Nicholas Leone Award, Children''s Brain Tumor Foundation, 1999
  • Member, American Society for Clinical Investigation, 1995
  • Established Investigator Award, American Heart Association, 1994
  • Member, Society for Pediatric Research, 1991
  • Lucille P. Markey Scholar Award in Biomedical Science, Markey Trust, 1989
  • Alpha Omega Alpha Honor Medical Society, 1981

Videos & Media

The Vascular Biology Program at Johns Hopkins' Institute for Cell Engineering

Researcher Gregg Semenza introduces the Vascular Biology Program, where scientists trace cells as they move through the body and study the relationship between low-oxygen conditions, blood vessel growth, and cancer.

Gregg Semenza of Johns Hopkins Medicine on Science

Gregg Semenza, M.D., Ph.D., of the Johns Hopkins McKusick-Nathans Institute of Genetic Medicine on the excitement and unpredictability of being a scientist.

Gregg Semenza of Johns Hopkins Medicine on HIF 1

Gregg Semenza, M.D., Ph.D., of the Johns Hopkins McKusick-Nathans Institute of Genetic Medicine on hypoxia inducible factor.

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