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2013 Scientific Report

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VARI | 2013 Research Interests Our lab is interested in a family of related proteins called the mitogen-activated protein kinase kinases (MKKs). MKKs are evolutionarily conserved, regulatory protein kinases that play pivotal roles in a wide variety of developmental cellular processes, including growth, division, and differentiation. Our lab is specifically interested in the roles of these kinases in the developmental and pathologic growth of blood vessels. More than a decade ago we showed that blocking the activity of MKKs in tumors caused decreased blood flow and tumor regression. Since then we have used a variety of experimental approaches to understand how the loss of MKK activity affects the growth of blood vessels. Most recently we discovered that MKK activity was essential for the regrowth of blood vessels in a mouse model of diabetic retinopathy. Our results suggest that the inhibition of MKK activity may be a good strategy for treating eye diseases such as proliferative diabetic retinopathy or wet macular degeneration. We are currently exploring this possibility in collaboration with Grand Rapids ophthalmologist Dr. Louis Glazer. In some cases the abnormal growth of cells that form blood vessels results in cancer. These tumors, called angiosarcomas, are an extremely rare but deadly form of cancer for which there is no effective treatment. In collaboration with Dr. Barbara Kitchell at the Michigan State University College of Veterinary Medicine, Dr. Laurence Baker at the University of Michigan, and Dr. Gary Schwartz at the Memorial Sloan – Kettering Cancer Center, we have discovered that MKK activity plays an essential role in the growth of these tumors. On-going studies in our lab are using unique mouse models we have developed to identify combinatorial approaches for treating these tumors. While excessive blood vessel growth is characteristic of cancer and retinal diseases, decreased blood flow is a crucial factor in peripheral arterial disease. This disease, often associated with obesity, diabetes, and smoking, is caused by blood vessel obstruction and a diminished ability to grow or expand existing blood vessels. Together with Dr. Christopher Chambers, a cardiovascular surgeon at the Meijer Heart and Vascular Institute, we have begun an exciting new research project involving human clinical samples to investigate the molecular biology of peripheral arterial disease. The goals of the lab in the coming years are to • Define the key roles of MKKs in developmental and pathologic growth of blood vessels, using models of retinal disease and peripheral arterial disease • Identify novel anti-angiogenic targets • Discover and validate genetic and biochemical drivers of site-specific disease in angiosarcoma • Translate these findings to improve the clinical care of patients. 17

Van Andel Research Institute | Scientific Report Figure 1 Figure 1: MKK activity is essential for blood vessel growth. In a model that mimics diabetic retinopathy, blood vessels in these mouse retina whole mounts show regrowth following oxygen deprivation (left panel). Such regrowth is prevented (right panel) in retinas treated with anthrax lethal toxin, an MKK inhibitor. Such inhibitors may have utility in treating human eye diseases such as proliferative diabetic retinopathy. Photographs by Jennifer Bromberg-White (Bromberg-White et al., 2011, Investigative Ophthalmology and Visual Science 52: 8979); ©Association for Research in Vision and Ophthalmology. Recent Publications Bromberg-White, Jennifer L., Nicholas J. Andersen, and Nicholas S. Duesbery. 2012. MEK genomics in development and disease. Briefings in Functional Genomics 11(4): 300–310. Andersen, Nicholas, Roe Froman, B. Ketchell, and Nicholas S. Duesbery. 2011. Angiosarcoma: clinical and molecular aspects. In Soft Tissue Sarcoma, Austria: I-Tech Education and Publishing, pp. 149–174. Bromberg-White, Jennifer L., Elissa Boguslawski, Daniel Hekman, Eric J. Kort, and Nicholas S. Duesbery. 2011. Persistent inhibition of oxygen-induced retinal neovascularization by anthrax lethal toxin. Investigative Ophthalmology and Visual Science 52(12): 8979–8992. Lee, Chih-Shia, Karl J. Dykema, Danielle M. Hawkins, David M. Cherba, Craig P. Webb, Kyle A. Furge, and Nicholas S. Duesbery. 2011. MEK2 is sufficient but not necessary for proliferation and anchorage-independent growth of SK-MEL-28 melanoma cells. PLoS One 6(2): e17165. 18

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