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2015 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report 2015 Detection of preinvasive pancreatic cysts Another class of pancreatic disease we are working on is pancreatic cysts. These cysts develop from a variety of causes; some that are not cancerous arise through inflammatory events, and others arise through the growth of neoplastic, pre-malignant cells. The latter type could be life threatening if the cysts develop into cancer, so the removal of cysts with high malignant potential is crucial. Surgery can remove the threat, but physicians do not have accurate methods for distinguishing dangerous cysts from benign ones. Furthermore, surgeons do not want to remove cysts unnecessarily because pancreatic surgery carries significant risks and physical stress. We are developing molecular biomarkers that help distinguish between life-threatening cysts and nonmalignant ones. As we found in our studies on pancreatic adenocarcinoma, certain glycans produced by the cysts are valuable biomarkers. One protein, MUC5AC, is particularly informative. Like most other proteins secreted by the cells of epithelial layers, MUC5AC has several different glycans attached to it. The informative feature is that the glycans on MUC5AC from pre-malignant cells differ from those produced by nonmalignant cells. We can use this difference to our advantage: the detection of the specific glycoform of MUC5AC produced by pre-malignant cells forms the basis of an accurate molecular test. We have also identified glycoforms of two proteins called MUC3A and endorepellin that contribute to promising biomarker panels. We have performed two blinded validation studies that have confirmed initial results, and we are performing further validation, optimization, and characterization of the markers. We hope to develop a clinical assay useful to doctors and patients, ultimately leading to more accurate diagnosis of the pre-malignant cysts and improved outcomes for patients. Novel tools and methods that advance biomarker and glycobiology research Our work required the development of several novel approaches and tools. One such tool is a database and analysis program, GlycoSearch, which was built by our collaborators at the Palo Alto Research Center and houses analyzed data and metadata from glycan array experiments. Researchers can use the software to find lectins or glycan-binding antibodies that bind specific targets, to delve into the details of specific proteins, or to explore biological relationships. We foresee significant value of this system for many research applications, especially in combination with microarray methods for the molecular profiling of clinical samples. Recent Publications Kletter, Doron, Bryan Curnutte, Kevin Maupin, Marshall Bern, and Brian B. Haab. In press. Exploring the specificities of glycan-binding proteins using glycan array data and the GlycoSearch software. Methods in Molecular Biology. Sinha, Arkadeep, David Cherba, Heather Bartlam, Elizabeth Lenkiewicz, Lisa Evers, Michael T. Barrett, and Brian B. Haab. In press. Mesenchymal-like pancreatic cancer cells harbor specific genomic alterations more frequently than their epithelial-like counterparts. Molecular Oncology. Gbormittah, Francisca Owusu, Brian B. Haab, Katie Partyka, Carolina Garcia-Ott, Marina Hincapie, and William S. Hancock. 2014. Characterization of glycoproteins in pancreatic cyst fluid using a high performance multiple lectin affinity chromatography platform. Journal of Proteome Research 13(1): 289–299. Partyka, Katie, Shuangshuang Wang, Ping Zhao, Brian Cao, and Brian B. Haab. 2014. Array-based immunoassays with rolling-circle amplification detection. In Molecular Toxicology Protocols, Phouthone Keohavong and Stephen G. Grant, eds. Methods in Molecular Biology series, Vol. 1105. New York: Humana Press, pp. 3–15. 14

Yuanzheng (Ajian) He, Ph.D. Structural Science and Molecular Signaling After graduating from the Chinese Academy of Sciences’ Shanghai Institute of Biochemistry in 2000, Dr. He worked as a postdoctoral fellow in Stoney Simons’ lab at the National Institute of Diabetes and Digestive and Kidney Diseases in Maryland. While there, he studied the mechanism of steroid hormone receptor–regulated gene expression, focusing on the glucocorticoid receptor. In 2008, Dr. He was recruited to Van Andel Research Institute to work on drug discovery for the glucocorticoid receptor and the structural relationship between ligand recognition and receptor function. He is currently a Research Assistant Professor. Research Interests Glucocorticoids play important roles in regulating many essential processes of the human body, including energy metabolism, immune modulation, stress responses, cell proliferation and differentiation, the circadian clock, and memory functions. Glucocorticoids are also the most effective and widely used anti-inflammatory agents for the treatment of diseases such as asthma and arthritis. However, long-term use of glucocorticoids can cause side effects such as obesity, diabetes, and bone loss. My research goals are to understand the structural mechanism of glucocorticoids in regulating cellular pathways and to use the knowledge to develop novel “dissociated glucocorticoids” that retain only the beneficial anti-inflammatory effects. Over the past year, we have made the following progress toward our goals. • We developed dissociated glucocorticoids based on the findings that the dissociation of transrepression from transactivation can be achieved through interfering with the dimerization interface of the glucocorticoid receptor (GR). • We solved the structure of the cortisol-bound and the mometasone furoate-bound GR ligand-binding domain (LBD), discovering that the high potency of glucocorticoids can be achieved through a lipophilic group such as a furoate ester in the C-17a position to fully occupy the hydrophobic cavity in the GR ligand-binding pocket. • We have designed and developed several highly potent glucocorticoids based on our structure of the mometasone furoate-bound LBD. These are ideal for the treatment of asthma, as they can be used at low dose to minimize unwanted systemic effects. Recent Publications He, Yuanzheng, Wei Yi, Kelly Suino-Powell, X. Edward Zhou, W. David Tolbert, Xiaobo Tang, Jing Yang, Huaiyu Yang, Jingjing Shi, et al. 2014. Structures and mechanism for the design of highly potent glucocorticoids. Cell Research 24(6): 713–726. Zhi, Xiaoyong, X. Edward Zhou, Yuanzheng He, Christoph Zechner, Kelly M. Suino-Powell, Steven A. Kliewer, Karsten Melcher, David J. Mangelsdorf, and H. Eric Xu. 2014. Structural insights into gene repression by the orphan nuclear receptor SHP. Proceedings of the National Academy of Sciences U.S.A. 111(2): 839–844. 15

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