Gregg L. Semenza, M.D., Ph.D. Director, Program in Vascular Cell Engineering - Institute for Cell Engineering Professor - Department of Pediatrics and Institute of Genetic Medicine Johns Hopkins University School of Medicine 733 N. Broadway Broadway Research Building, Suite 671 Baltimore, MD 21205 Phone: (410)-955-1619 Fax: (443)-287-4868 Email: gsemenz1@jhem.jhmi.edu

Research

We are studying molecular mechanisms underlying angiogenesis and vascular remodeling in ischemic cardiovascular disease and cancer.  The transcription factor HIF-1 (hypoxia-inducible factor 1) controls the production of multiple angiogenic cytokines/growth factors in response to hypoxia/ischemia.  These factors serve many functions, including the mobilization and homing of bone marrow-derived progenitor cells and the activation of resident endothelial and smooth muscle cells. These angiogenic responses are impaired by aging and diabetes, leading to myocardial infarction and critical limb ischemia in which cells die due to lack of oxygen. We are attempting to augment angiogenic responses in animal models of ischemia by utilizing both gene therapy and stem cell therapy.

Angiogenesis has become a major therapeutic target in cancer and HIF-1 plays an important role in tumor vascularization. In addition to angiogenesis, HIF-1 plays important roles in other critical aspects of cancer biology, including glucose/energy metabolism and invasion/metastasis. We have recently performed a screening assay to identify drugs that inhibit HIF-1 and may have therapeutic utility as novel anti-cancer agents. We are characterizing their mechanism of action and ability to prevent tumor growth in mice.

Selected Recent Publications

Fukuda R, Zhang H, Kim J-w, Shimoda L, Dang CV, Semenza GL. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell 129: 111-122, 2007.

Hirota K, Semenza GL.  Regulation of angiogenesis by hypoxia-inducible factor 1.  Crit Rev Oncol Hematol  59: 15-26, 2006.

Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH, Semenza GL. Hypoxia-inducible factor-1-dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A, and ZFHX1B.  Cancer Res 66: 2725-2731, 2006.

Liu YV, Baek JH, Zhang H, Diez R, Cole RN, Semenza GL. RACK1 competes with HSP90 for binding to HIF-1a and is required for O2-independent and HSP90 inhibitor-induced degradation of HIF-1a. Mol. Cell  25: 207-217, 2007.

Okuyama H, Krishnamachary B, Zhou YF, Nagasawa H, Bosch-Marce M, Semenza  GL. Expression of vascular endothelial growth factor receptor 1 in bone marrow-derived mesenchymal cells is dependent on hypoxia-inducible factor 1.  J. Biol. Chem. 281: 15554-15563, 2006.

Patel TH, Kimura H, Weiss CR, Semenza GL, Hofmann LV. Constitutively active HIF-1a improves perfusion and arterial remodeling in an endovascular model of limb ischemia.   Cardiovasc Res 68: 144-154, 2005.

Zhang H, Gao P, Fukuda R, Kumar G, Krishnamachary B, Zeller KI, Dang CV, Semenza GL. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity.  Cancer Cell  11: 407-420, 2007.