William A. Frazier, Ph.D.
Professor
Biochemistry and Molecular Biophysics
Cell Biology and Physiology
Biomedical Engineering
Molecular Cell Biology Program
Biochemistry Program
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Office Phone: 314-362-3348
Lab Phone: 314-362-3347
Other Phone:
FAX: 314-362-7183
Box: 8231
Lab Address: Rm. 1902, South Building
Email: frazier@wustl.edu
Website: http://www.biochem.wustl.edu/~frazier
Keywords: apoptosis; mitochondria; nitric oxide; protein-protein interaction; receptors; vascular biology
Short Research Description: Thrombospondin-1/CD47 regulation of mitochondria, nitric oxide and cardiovascular function |
Research Abstract:
Thrombospondin-1 (TSP1) and its receptor, CD47 (integrin-associated protein) are expressed by all vascular cells and regulate many aspects of vascular system function including thombosis (platelet activation/adhesion), inflammation (endothelial cell activation, leukocyte adhesion/transmigration) and tissue ischemia and blood pressure (smooth muscle cell contraction/relaxation). Very recently, we have discovered a unifying mechanism of action for TSP1-CD47 function in vascular biology. Through CD47, TSP1 opposes the actions of nitric oxide (NO) and cycic GMP in vascular cells. This system was selected during vertebrate evolution to promote rapid hemostasis, prevent shock and fight infection. However, in ischemic and reperfusion pathologies such as vascular occlusion, surgical interventions, infarction and stroke, organ transplantaion and others, TSP1-CD47 signaling exacerbates injury and delays or prevents healing. The TSP1-CD47 system is also prothrombotic and proinflammatory, both effects being maladaptive in the context of modern diet, life style and longevity. We are currently studying the molecular mechanisms of the CD47 inhibition of NO signaling in cell culture and knockout mice. We are designing inhibitors of the TSP1-CD47 system and testing their therapeutic potential in animal models of ischemia, thrombosis and vascular disease in preparation for future clinical trials. One of the most exciting aspects of this new paradigm for TSP1-CD47 action is that knocking out or inhibiting CD47 overcomes the effects of age-dependent endothelial dysfunction and may actually delay the aging process through effects on mitochondrial biogenesis coupled with improved mitochondrial efficiency (decreased production of reactive oxygen species). Experimental approaches include mutational analysis of protein function, signaling pathway studies, physiological profiling of knockout mice and transcriptional regulation of mitogenesis and profiling of gene expression in mouse tissues. |
Selected Publications:
Isenberg JS, Qin Y, Maxhimer JB et al. Thrombospondin-1 and CD47 regulate blood pressure and cardiac responses to vasoactive stress. Matrix Biol 2009 28:110-119.
Uluckan O, Becker SN, Deng H et al. CD47 regulates bone mass and tumor metastasis to bone. Cancer Res 2009 69:3196-3204.
Isenberg JS, Maxhimer JB, Powers P et al. Treatment of liver ischemia-reperfusion injury by limiting thrombospondin-1/CD47 signaling. Surgery 2008 144:752-761.
Vomund AN, Stuhlsatz-Krouper S, Dimitry J et al. A naturally occurring extracellular alpha-beta clasp contributes to stabilization of beta3 integrins in a bent, resting conformation. Biochemistry 2008 47:11616-11624.
Isenberg JS, Roberts DD, Frazier WA. CD47: A new target in cardiovascular therapy. Arterioscler Thromb Vasc Biol 2008 28:615-621. |