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2013 Scientific Report

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VARI | 2013 Research Interests I apply a classical genetic perspective and genomic discovery platforms to a unique animal model. Dogs suffer the same inherited disorders as humans, including cancers and neurodegenerative diseases. In veterinary medicine, canine disorders are detected with human diagnostics and treated with human medicines, so it stands to reason that naturally occurring diseases in the dog are models of human disease counterparts. Genetic analysis can identify, in an unbiased way and owing to the strengths of breed isolates, the causal mechanisms underlying complex disease susceptibilities. DNA risk signatures enable predictive genetic epidemiology with corresponding clinical benefits—early intervention and prevention—and they inform on aberrant biological processes. Clinical trials can be performed more rapidly, more powerfully, and more economically in veterinary medicine owing to lesser regulatory constraints and accelerated patient time frames. Pet dogs also serve as a model for lifestyle management (e.g., exercise, appetite, and behavioral modification), creating the opportunity to offset inherited risks. The dog is arguably the best patient model for evidence-based, personalized, and preventive medicine. Over the years, our group has developed the subject recruitment, genomic, and statistical analysis pipelines needed for advancing robust, informative, and efficient experiments in canine genetics research. Just as importantly, we have developed strong relationships with the dog owner and breeder community, without which research in this field would not be possible. Our lab studies naturally occurring diseases in the dog. We apply the perspective of genetics and the tools of genomics to tie complex phenotypes to causal genotypes. We exploit the strengths of breeds as genetic isolates to identify identicalby-descent mutations from within large ancestral haplotype blocks. These mutations can then be functionally characterized in model organisms or cell culture. Our collaborations over the past two years have included projects on osteosarcoma, hemangiosarcoma, essential head tremor, obsessive-compulsive disorder, agoraphobic-like behavior, cervical spondylopathy, adult onset hearing loss, and idiopathic pulmonary fibrosis. Recent Publications Wong, A.K., A.L. Ruhe, K.R. Robertson, E.R. Loew, D.C. Williams, and M.W. Neff. In press. A de novo mutation in KIT causes white spotting in a subpopulation of German Shepherd dogs. Animal Genetics. Neff, Mark W., John S. Beck, Julie M. Koeman, Elissa Boguslawski, Lisa Kefene, Andrew Borgman, and Alison L. Ruhe. 2012. Partial deletion of the sulfate transporter SLC13A1 is associated with an osteochondrodysplasia in the miniature poodle breed. PLoS One 7(12): e51917. Wong, Aaron K., Alison L. Ruhe, Shameek Biswas, Kathryn R. Robertson, Ammar Ali, Joshua M. Akey, and Mark W. Neff. 2012. Marker panels for genealogy-based mapping, breed demographics, and inference-of-ancestry in the dog. Animal Biotechnology 23(4): 241–252. Yokoyama, Jennifer S., Ernest T. Lam, Alison L. Ruhe, Carolyn A. Erdmann, Kathryn R. Robertson, Aubrey A. Webb, D. Colette Williams, Melanie L. Chang, Marjo K. Hytönen, Hannes Lohi, et al. 2012. Variations in genes related to cochlear biology is strongly associated with adult-onset deafness in Border collies. PLoS Genetics 8(9): e1002898. 45

Brian J. Nickoloff, M.D., Ph.D. Laboratory of Cutaneous Oncology Dr. Nickoloff received his M.D. and Ph.D. (biochemistry) from Wayne State University, and he completed an internship in Internal Medicine at Harbor General – UCLA Hospital. He is the former director of the Skin Disease Research Laboratory at Loyola University Chicago Medical Center. In 2003, he became the director of Loyola’s Oncology Institute and deputy director of the Cardinal Bernardin Cancer Center. In 2011, he relocated to Grand Rapids to become Professor and Division Director of Dermatology at the College of Human Medicine, Michigan State University. He also holds an appointment as Professor and head of the Laboratory of Cutaneous Oncology at the Van Andel Research Institute. Most recently he became the Medical Director of Dermatopathology at St. Mary’s Hospital in the Skin Cancer Clinic. Research Interests Our primary interest is in finding new and better methods for diagnosing melanoma using genomics and treatment options in the setting of personalized medicine. Current efforts focus on overcoming treatment resistance and relapse in melanoma patients treated with targeted therapy. We are using human metastatic melanoma xenografts in immunodeficient mice. We have established a vemurafenib-resistant model system and also combination therapies to overcome this resistance. Another project is exploring the altered metabolomics in melanoma, using PET/CT imaging to develop novel approaches for targeting BRAF mutant and wild-type tumors. Recent Publications Monsma, David J., Noel R. Monks, David M. Cherba, Dawna Dylewski, Emily Eugster, Jahn Hailey, Sujata Srikanth, Stephanie B. Scott, Patrick J. Richardson, Robin E. Everts, et al. 2012. Genomic characterization of explant tumorgraft models derived from fresh patient tumor tissue. Journal of Translational Medicine 10: 125. Nickoloff, Brian J., and George Vande Woude. 2012. Hepatocyte growth factor in the neighborhood reverses resistance to BRAF inhibitor in melanoma. Pigment Cell & Melanoma Research 25(6): 758–761. Qin, Jianzhong, Hong Xin, and Brian J. Nickoloff. 2012. Specifically targeting ERK1 or ERK2 kills melanoma cells. Journal of Translational Medicine 10: 15. 46

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