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Gregg L. Semenza, M.D., Ph.D.
C. Michael Armstrong Professor of Medicine
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
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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
Bosch-Marce, M., Okuyama, H., Wesley, J. B., Sarkar, K., Kimura, H., Liu, Y. V., Zhang, H., Strazza, M., Rey, S., Savino, L., Zhou, Y. F., McDonald, K. R., Na, Y., Vandiver, S., Rabi, A., Shaked, Y., Kerbel, R., LaVallee, T., and Semenza, G. L. Effects of aging and HIF-1 activity on angiogenic cell mobilization and recovery of perfusion following limb ischemia. Circ. Res. 101:1310-1318 (2007).
Semenza, G. L. Regulation of tissue perfusion in mammals by hypoxia-inducible factor 1. Exp. Physiol. 92: 988-991 (2007).
Cai, Z., Zhong, H., Bosch-Marce, M., Fox-Talbot, K., Wang, L. Wei, C., Trush, M. A., and Semenza, G. L. Complete loss of ischemic preconditioning-induced cardioprotection in mice with partial deficiency of HIF-1a. Cardiovasc. Res. 77:463-470 (2008).
Liu, L., Marti, G., Wei, X., Zhang, X., Zhang, H., Liu, Y., Nastai, M., Semenza, G. L., and Harmon, J. Age-dependent impairment of HIF-1a expression in diabetic mice: correction with electroporation-facilitated gene therapy increases wound healing, angiogenesis, and circulating angiogenic cells. J. Cell. Physiol. 217:319-327 (2008).
Zhang, H., Qian, D. Z., Tan, Y. S., Lee, K., Gao, P., Ren, Y. R., Rey, S., Hammers, H., Chang, D., Pili, R., Dang, C. V., Liu, J. O., and Semenza, G. L. Digoxin and other cardiac glycosides inhibit HIF-1a synthesis and block tumor growth. Proc. Natl. Acad. Sci. USA 105:19579-19586 (2008).
Lee, K., Qian, D. Z., Rey, S., Wei, H., Liu, J. O., and Semenza, G. L. Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc. Natl. Acad. Sci. USA 106:2353-2358 (2009).
Semenza, G. L. Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin. Cancer Biol. 19:12-16 (2009).
Semenza, G. L. Regulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda) 24:97-106 (2009).
Lee, K., Zhang, H., Qian, D. Z., Rey, S., Liu, J. O., and Semenza, G. L. Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization. Proc. Natl. Acad. Sci. USA, in press.
Zhang, X., Wei, X., Marti, G. P., Ghanamah, M. S., Arshad, M. J., Strom, L., Spence, R., Jeng, J., Milner, S., Harmon, J. W., and Semenza, G. L. Increasing burn severity in mice is associated with delayed mobilization of circulating angiogenic cells. Arch. Surg., in press.
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