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2018 Scientific Report

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Center for Cancer and

Center for Cancer and Cell Biology H. ERIC XU, Ph.D. Dr. Xu went to Duke University and the University of Texas Southwestern Medical Center, earning his Ph.D. in molecular biology and biochemistry. He joined VARI in July 2002 and is now a Professor. Dr. Xu is also the Primary Investigator and Distinguished Director of the VARI–SIMM Research Center in Shanghai, China. RESEARCH INTERESTS Hormone signaling is essential to eukaryotic life. Our research focuses on the signaling mechanisms of physiologically important hormones, striving to answer fundamental questions that have a broad impact on human health and disease. We are studying two families of proteins, the nuclear hormone receptors and the G protein–coupled receptors (GPCRs), because these receptors are fundamentally important for treating major human diseases. STAFF Xiang Gao, Ph.D. Yanyong Kang, Ph.D. Michelle Martin, A.A. Kelly Powell, B.S. Xiaoyin (Edward) Zhou, Ph.D. STUDENTS Parker de Waal, B.S. Yan Yan, B.S. VISITING SCIENTIST Ross Reynolds, Ph.D. Nuclear hormone receptors The nuclear hormone receptors form a large family comprising ligand-regulated and DNA-binding transcription factors, which include receptors for the classic steroid hormones such as estrogen, androgens, and glucocorticoids, as well as receptors for peroxisome proliferator activators, vitamin D, vitamin A, and thyroid hormones. These receptors are among the most successful targets in the history of drug discovery: every receptor has one or more synthetic ligands being used as medicines. In the last five years, we have developed projects centering on the peroxisome proliferator–activated receptors (PPARα, β, and γ), the human glucocorticoid receptor, the androgen receptor, and a number of orphan nuclear receptors including CAR, SHP, SF-1, COUP-TFII, and LRH-1. We have solved many of their structures and identified small-molecule ligands for several of them, including potent ligands for GR, AR, PPARs, and COUP-TFII, which could be developed into therapeutics against diabetes, cancer, and inflammatory disease. G protein–coupled receptors The GPCRs form the largest family of cell-surface receptors (over 800 members) and account for over 40% of drug targets. There are only a few dozen solved GPCR structures because they are seven-transmembrane receptors. Many important questions regarding GPCR ligand binding and activation remain unanswered, including pressing questions about the assembly of GPCR signaling complexes that have downstream effects, such as G protein, arrestin, and GPCR kinases. Our group aims to use rhodopsin, the prototypical GPCR, as a model system for understanding how an activated GPCR is assembled with the GPCR downstream signaling effectors. Answering these basic questions could help in the design of pathway-selective GPCR ligands as drugs. 16 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT

TAO YANG, Ph.D. Dr. Yang received his Ph.D. in biochemistry at the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, in 2001. He joined VARI as an Assistant Professor in February 2013. STAFF Jianshuang Li, B.S. RESEARCH INTERESTS Our long-term interest is to investigate the signals and cellular processes orchestrating the activities of mesenchymal stem cells (MSCs) and MSC-derived cells during skeletal development, homeostasis, regeneration, and degeneration. The skeletal system develops from mesenchymal cells and is an important reservoir of MSCs in postnatal life. MSCs play pivotal roles in skeletal tissue growth, homeostasis, and repair, while dysregulations in MSC renewal, linage specification, and pool maintenance are common causes of skeletal disorders. Currently, our lab is focusing on understanding the role of the sumoylation pathway in skeletal degeneration, aging, and malignancy. We are also studying the role of LRP1 signaling in osteoporosis, inflammatory bone loss, and skeletal aging. Huadie Liu, M.S. Di Lu, M.S. Jeanie Wedberg, A.S. VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 17

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