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.
Dr. Semenza’s lab is currently investigating:
- 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.
- 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.
- 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.
- 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
HIF-1 Regulated Endothelial Progenitor Cell (EPC) Recruitment in Burn Wound Healing
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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.