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Van Andel Research Institute Scientific Report 2018


Cover image: The yeast Mcm2-7 double hexamer, the core of the DNA replication helicase. A complete view of this cryo-EM structure is found on p. 35.


Van Andel Research Institute Scientific Report 2018

VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | i


Published March 2018. Copyright 2018 by Van Andel Institute: all rights reserved. Van Andel Institute, 333 Bostwick Avenue, N.E. Grand Rapids, Michigan 49503, U.S.A.

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In Memoriam

Arthur S. Alberts, Ph.D. 1964–2016 Art Alberts passed away in December 2016 after a courageous eight-year battle with brain cancer. He was a passionate, deeply inquisitive scientist who joined VARI in 2000 as one of its first scientific investigators. Art was brought up in Southern California, but he never seemed to allow Michigan winters to intimidate him into forgoing flip-flops and shorts. He was a friend, mentor, and collaborator, a man who loved the purity of science, the thrills of a dangerous mountain bike trail, and a good IPA. He is deeply missed.

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Table of Contents 2017 At-A-Glance vi Introduction 1

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Center for Cancer and Cell Biology

4

JUAN DU, Ph.D.

6

PATRICK J. GROHAR, M.D., Ph.D.

7

BRIAN B. HAAB, Ph.D.

8

XIAOHONG LI, Ph.D.

9

WEI LÜ, Ph.D.

10

KARSTEN MELCHER, Ph.D.

11

LORENZO F. SEMPERE, Ph.D.

12

MATTHEW STEENSMA, M.D.

13

BART O. WILLIAMS, Ph.D.

14

NING WU, Ph.D.

15

H. ERIC XU, Ph.D.

16

TAO YANG, Ph.D.

17

Center for Epigenetics

20

STEPHEN B. BAYLIN, M.D.

22

PETER A. JONES, Ph.D., D.Sc.

23

STEFAN JOVINGE, M.D., Ph.D.

24

PETER W. LAIRD, Ph.D.

25

HUILIN LI, Ph.D.

26

GERD PFEIFER, Ph.D.

27

SCOTT ROTHBART, Ph.D.

28

HUI SHEN, Ph.D.

29

PIROSKA E. SZABÓ, Ph.D.

30

TIMOTHY J. TRICHE, JR., Ph.D.

31

STEVEN J. TRIEZENBERG, Ph.D.

32


Center for Neurodegenerative Science 36

Educational and Training Programs

62

LENA BRUNDIN, M.D., Ph.D.

38

VAIGS GRADUATE STUDENTS

64

PATRIK BRUNDIN, M.D., Ph.D.

39

SUMMER INTERNSHIP PROGRAM

65

GERHARD (Gerry) A. COETZEE, Ph.D.

40

POSTDOCTORAL FELLOWSHIP PROGRAM

66

JEFFREY H. KORDOWER, Ph.D.

41

VIVIANE LABRIE, Ph.D.

42

Organization

68

JIYAN MA, Ph.D.

43

DARREN J. MOORE, Ph.D.

44

Core Technologies and Services

48

MARIE ADAMS, M.S. Genomics

50

MEGAN BOWMAN, Ph.D. Bioinformatics and Biostatistics

51

BRYN EAGLESON, M.S., LATG Vivarium and Transgenics

52

CORINNE ESQUIBEL, Ph.D. Confocal Microscopy and Quantitative Imaging

53

SCOTT D. JEWELL, Ph.D. Pathology and Biorepository

54

RACHAEL SHERIDAN, Ph.D. Flow Cytometry

55

GONGPU ZHAO, Ph.D. Cryo-Electron Microscopy

56

Awards for Scientific Achievement

58

JAY VAN ANDEL AWARD FOR OUTSTANDING ACHIEVEMENT IN PARKINSON’S DISEASE RESEARCH

59

HAN-MO KOO MEMORIAL AWARD

60

TOM ISAACS AWARD

61

MANAGEMENT 70 ADMINISTRATIVE DEPARTMENTS

72

ORGANIZATIONAL CHART

74

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2017 At-A-Glance Record-breaking funding

115 total active awards totaling $97 million 32 new awards in 2017 totaling $33 million Of those, 13 awards, for $25 million, are federal grants

A growing scientific impact 145 2017 publications, 132 peer-reviewed

Prestigious faculty In 2017, the Institute celebrated Chief Scientific Officer Dr. Peter Jones’s election to the American Academy of Arts and Sciences, placing him in the elite company of more than 250 Nobel Laureates and 60 Pulitzer Prize winners. Director’s Scholar Dr. Stephen Baylin also earned the honor of being elected to the National Academy of Sciences, an independent and nonpartisan advisor to the federal government on matters related to science and technology. In all, VARI is home to

2 fellows of the American Academy of Arts & Sciences 2 members of the National Academy of Sciences 3 fellows of the American Association for the Advancement of Science 3 fellows of the American Association for Cancer Research Academy

A collaborative effort

383 collaborating organizations 32 countries in which VARI collaborates

A growing team

384 total employees 223 total research employees 31 faculty 43 postdoctoral fellows 27 Van Andel Institute Graduate School Ph.D. students vi | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Introduction In many ways, 2017 was a record-breaking year for Van Andel Research We continue to build critical

Institute. We experienced incredible growth in all aspects of our

mass, thanks to an ambitious

scientific enterprise, from an all-time high in scientific publications to

recruiting effort conducted

an incredible increase in peer-reviewed federal funding, the most ever

in accordance with our

awarded in our 21-year history. Several new faculty have arrived and

Strategic Plan.

more will be joining us soon, which will bolster our existing research programs and support the establishment of new ones. And, we continue our collaborations with other leading institutions both in the U.S.A. and abroad to translate lab discoveries into the clinic. STRATEGIC GROWTH We continue to build critical mass, thanks to an ambitious recruiting effort conducted in accordance with our Strategic Plan. The Center for Cancer and Cell Biology added two new faculty in 2017, Wei Lü in March and Juan Du in October. The Lü lab uses single-particle cryo-electron microscopy and other methods to study the structures and mechanisms of ion channels and transmembrane receptors. The Du lab focuses on excitatory neuronal receptors, studying their structure and function via cryo-EM, electrophysiology, and X-ray crystallography. The Center for Neurodegenerative Science welcomed Wouter Peelaerts, who joined Patrik Brundin’s lab in 2017, becoming the first Fulbright Scholar to join the Institute. In September 2017, the Center for Epigenetics welcomed Timothy J. Triche, Jr., whose lab develops statistical and mathematical methods to better understand pediatric and adult cancers, with a special focus on cancers of the blood in children. We look forward to the arrival of two more faculty in early 2018—Drs. Xiaobing Shi and Hong Wen, both experts in cancer epigenetics. A major milestone was the establishment of the Institute’s David Van Andel Advanced Cryo-Electron Microscopy Suite in early 2017. This state-of-the-art facility places VARI in elite company: the suite’s most powerful microscope, the Titan Krios, is one of fewer than 120 in the world and can visualize structures down to the atomic level. The investment, made possible by CEO David Van Andel, is already bearing fruit. Two new structures that were solved using its instruments were published in the last quarter of 2017. Huilin Li’s lab and collaborators published the paper “Cryo-EM structure of Mcm2-7 double hexamer on DNA suggests a lagging-strand DNA extrusion model” in the Proceedings of the National Academy of Sciences USA, and Wei Lü’s lab published “Electron cryo-microscopy structure of a human TRPM4 channel” in Nature. These were among the 132 peer-reviewed articles from VARI in 2017, a new annual high for the Institute. Selected publications are listed for each Center and the Cores.

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Introduction (cont.) FUNDING GROWTH

Grant funding hit an all-time high in 2017 with 32 new awards totaling over $33 million.

Our growth also is reflected in grant funding, which hit an all-time high in 2017 with 32 new awards totaling over $33 million. Of these, 13 were peer-reviewed federal awards accounting for over $25 million. These funds will support a plethora of basic and translational research endeavors aimed at making life-changing advances. Of note, VARI had the second highest growth in grant funding over 20162017 among 72 comparable independent research institutes. On the clinical front, we are thrilled that Van Andel Research Institute–Stand Up To Cancer Epigenetics Dream Team scientists received two of the ten inaugural SU2C Catalyst awards, which pair Dream Teams with industry support. Totaling nearly $5.5 million, these funds will fuel new, collaborative clinical trials designed to evaluate powerful epigenetic and immunotherapy drug combinations as potential cancer treatments. One grant is funded by Merck & Co. against non-small-cell lung cancer, one of the most common and deadly types of cancer, and the second is funded by Genentech against bladder cancer, a disease that claims thousands of lives annually. Among the major National Institutes of Health awards were a seven-year R35/ Outstanding Investigator Award from NIH/NCI to Peter Jones; to Patrik Brundin, an R01 from NIH/NIDCD, an R21 from NIH/NINDS, and a Department of Defense award; to Scott Rothbart, an R35/Maximizing Investigators’ Research Award from NIH/ NIGMS; to Peter Laird, an R01 from NIH/NCI; to Darren Moore, an R01 from NIH/ NINDS; to Ning Wu, an R01 from NIH/NCI; to Huilin Li, an R01 from NIH/NIGMS; and to Jiyan Ma, an R21 from NIH/NINDS. Several of VARI’s postdoctoral fellows and graduate students also received funding in 2017. Xi Chen, of the Moore laboratory, now has a fellowship from the Parkinson’s Foundation supporting her studies into a new model for familial Parkinson’s disease. An Phu Tran Nguyen and Md Shariful Islam, also in the Moore Lab, received grants from the American Parkinson’s Disease Association. VARI Fellow Xiaotian Zhang was the recipient of an American Society of Hematology Fellow Scholar Award in basic and translational research—the first ASH fellowship to a VARI scientist—and Rochelle Tiedemann, of the Jones and Rothbart labs, received the Institute’s first American Cancer Society fellowship. Nicole Vander Schaaf, a graduate student in the Laird lab, received an F31 predoctoral training fellowship from the National Institutes of Health for her project, “The role of polycomb target gene DNA methylation in intestinal tumorigenesis.” F31 grants are highly competitive fellowships that support promising graduate students as they work on their dissertations. Nicole is our first graduate student to be awarded an F31.

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AWARDS AND SYMPOSIA

By harnessing new knowledge born out of revolutionary scientific innovation and technology and working together against disease, we can—and will—change human health for the better.

VARI’s Chief Scientific Officer Peter Jones was elected to the American Academy of Arts and Sciences in April, and Stephen Baylin was elected to the National Academy of Sciences in May. Congratulations to both! In May, the Institute presented U.S. Rep. Fred Upton with a Legislative Champion Award on behalf of the Association for Independent Research Institutes (AIRI). Upton, along with U.S. Rep. Diana DeGette, spearheaded the 21st Century Cures Act, which passed with bipartisan support and infused more than $6 billion in new funding to the National Institutes of Health. VARI hosted several scientific symposia in 2017. Among those events were “Osteoporosis: An Impending Public Health Crisis”; “New Frontiers in Cancer Metabolism”; “Frontiers in Reproductive Epigenetics”; “Origins of Cancer”; “A Celebration of the Cryo-EM Revolution"; and “Grand Challenges in Parkinson’s Disease” and its parallel patient meeting, “Rallying to the Challenge”. We also held the second “Epigenomics at VARI” graduate student workshop during the summer.

A BRIGHT TOMORROW As we move into the future, we do so with a renewed commitment to improving human health through rigorous science. This mission is an urgent one: as the world’s population continues to grow and age, the incidence of cancer and neurodegenerative diseases also are slated to rise. Improved preventative strategies, diagnostic techniques, treatments, and—ultimately—cures are desperately needed for the millions around the world who face these diseases today or who will face them tomorrow. The past decade has encompassed a scientific renaissance of sorts, one that can be seen in research organizations around the world, including VARI. By harnessing new knowledge born out of revolutionary scientific innovation and technology and working together against disease, we can—and will—change human health for the better.

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Center for Cancer and Cell Biology Bart O. Williams, Ph.D. Director The Center’s scientists study the basic mechanisms and molecular biology of cancer and other diseases, with the goal of developing better diagnostics and therapies.

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A depiction of arrestin binding by a phosphorylated and active rhodopsin. The cell membrane lipids are shown as cream colored, rhodopsin is blue, and arrestin is red. The phosphorylated C-terminal tail of rhodopsin binds to the N-domain (left) of the arrestin molecule. In the main contact region between the two molecules (central), arrestin accommodates the ICL2 helix of rhodopsin. In this fully activated state, the tip of arrestin’s C-domain contacts the membrane (right). Image by Parker de Waal of the Xu lab.


Center for Cancer and Cell Biology

JUAN DU, Ph.D. Dr. Du earned her Ph.D. at the University of Freiburg. She joined the VARI faculty in October 2017 as an Assistant Professor.

RESEARCH INTERESTS The lab is focused on understanding the mechanism and pharmacology of excitatory neuronal receptors, which are crucially involved in numerous neurological diseases. A combined approach of single-particle cryo-EM, patch-clamp electrophysiology, and X-ray crystallography is employed to study the atomic structures and biological functions of these ion channel receptors.

STAFF Chen Fan, Ph.D. Michelle Martin, A.A.

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PATRICK J. GROHAR, M.D., Ph.D. Dr. Grohar earned his Ph.D. in chemistry and his M.D. from Wayne State University. He joined VARI in 2015 as an Associate Professor, and he has clinical and research responsibilities at Spectrum Health and Michigan State University, respectively.

RESEARCH INTERESTS Our laboratory studies pediatric sarcomas, and our goal is to develop novel, molecularly targeted therapies and to translate those therapies into the clinic. Most pediatric sarcomas are characterized by oncogenic transcription factors that are required for cell survival. We are developing new approaches to target those molecules.

STAFF Elissa Boguslawski, R.L.A.T. Jenna Gedminas, M.D. Susan Goosen, B.S., M.B.A. Mitchell McBrairty, B.S. Michelle Minard, B.S. Brandon Oswald, B.S. Erik Peterson, B.S., M.S. Katie Sorensen, B.S.

STUDENTS Maggie Chasse, M.S. Guillermo Flores, B.S.

Trabectedin is a natural product originally isolated from the sea squirt, Ecteinascidia turbinata. Our recent work has focused on characterizing the mechanism of trabectedin’s suppression of the EWS-FLI1 transcription factor in Ewing sarcoma, identifying second-generation trabectedin analogs, and developing new combination therapies. We showed that the drug works by redistributing EWS-FLI1 within the nucleus to the nucleolus. This mechanism provides justification for using a secondgeneration compound, lurbinectedin, which maintains the nuclear redistribution of EWS-FLI1 but accumulates to higher serum concentrations. Over the past year, we have shown convincingly that a targeted combination therapy of trabectedin plus irinotecan provides cooperative suppression of EWS-FLI1. Irinotecan augments and sustains suppression of EWS-FLI1 in vivo, leading to the differentiation of Ewing sarcoma cells into benign tissue. We have also shown that lurbinectedin maintains both this synergy with irinotecan and the mechanism of synergy. We have a number of anecdotal responses to treatment with trabectedin plus irinotecan, and responses to lurbinectedin have been seen in patients in two independent studies. We are working to formally evaluate these combinations in phase II studies in the United States. We have also extensively studied mithramycin, which reverses EWS-FLI1 activity and blocks the expression of key EWS-FLI1 downstream targets. In a phase I/II trial at the National Cancer Institute, we found that mithramycin did not achieve serum levels high enough to block EWS-FLI1 activity. We have now identified secondgeneration compounds with improved properties that show excellent activity in Ewing sarcoma cells. We are extending these findings to other tumor types. We have shown that cells deficient in components of the SWI/SNF chromatin remodeling complex are hypersensitive to mithramycin. Work is in progress to understand the mechanism of this hypersensitivity. We are also exploring the interface of epigenetics and transcription as a drug target.

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Center for Cancer and Cell Biology

BRIAN B. HAAB, Ph.D. Dr. Haab obtained his Ph.D. in chemistry from the University of California at Berkeley in 1998. He joined VARI as a Special Program Investigator in 2000, became a Scientific Investigator in 2004, and is now a Professor.

RESEARCH INTERESTS

STAFF ChongFeng Gao, Ph.D. Zachary Klamer, B.S. Ying Liu, Ph.D. Katie Partyka, B.S. Ben Staal, M.S. Jeanie Wedberg, A.S. Luke Wisniewski, B.S.

STUDENTS

Patients facing a possible diagnosis of cancer need answers to such fundamental questions as whether a lesion is cancerous and, if so, which treatment will work best, yet getting the answers can be difficult. The heterogeneity of cancers of a particular organ is a major source of the difficulty. For example, for pancreatic cancer, physicians do not have tests that reliably distinguish cancerous from noncancerous lesions or that group the cancers into specific subtypes. To address this need, we are 1) seeking molecular markers to identify the subtypes of pancreatic cancer cells; 2) determining the behavioral and biological differences between the subtypes; and 3) developing assays to detect the subtypes in a clinical setting. With such assays, we hope to improve the ability to detect and diagnose pancreatic cancers, to enable prediction of the behavior of each cancer, and to guide studies aimed at treating each subtype. We found that a carbohydrate structure, which we named the sTRA antigen, is produced by a subtype of pancreatic cancer cell that is different from typical cancer cells. We also found that another carbohydrate, the well-known CA19-9 antigen, identifies a separate type of pancreatic cancer cell. Individual tumors may have cancer cells producing one, both, or neither of the antigens. Our research is revealing that the sTRA-producing cancer cells are more resistant to death and more aggressive than the CA19-9-producing cells. We are seeking to clarify the nature and mechanisms of the differences between the subtypes and to determine optimal treatments for each. Both antigens are secreted into the blood, so we are investigating the use of blood tests for sTRA and CA19-9 to identify more pancreatic cancers than previously possible and to determine their subtype. We are also using new methods of carbohydrate analysis developed in our lab to find markers for additional subtypes of pancreatic cancer cells.

David Ayala-Talavera Daniel Barnett, B.A., B.S. Anna Barry, B.S. Johnathan Hall Peter Hsueh, B.S. Hannah Kalee 8 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


XIAOHONG LI, Ph.D. Dr. Li received her Ph.D. from the Institute of Zoology, Chinese Academy of Sciences, in Beijing in 2001. She joined VARI as an Assistant Professor in September 2012.

RESEARCH INTERESTS Our laboratory is committed to understanding tumor dormancy and cancer bone metastasis. Our long-term goals are to develop better therapeutic approaches for bone metastasis and to prolong a dormancy-permissive bone microenvironment so that cancer cells can be killed while they are in that state.

STAFF Sourik Ganguly, Ph.D. Alexandra Vander Ark, M.S. Jeanie Wedberg, A.S. Erica Woodford, B.S.

Project 1. Influence of the bone microenvironment on drug resistance in prostate cancer bone metastasis. Second-line hormonal therapies such as enzalutamide improve overall patient survival by only a few months in about 50% of patients, and almost all patients develop drug resistance. Thus, we need to determine the mechanisms of drug resistance and to develop new approaches for overcoming it. Based on our studies, the goals of this project are to determine how enzalutamide decreases TGFBR2 in osteoblasts, to investigate how loss of TGFBR2 in osteoblasts promotes the progression of prostate cancer bone metastases, and to target the underlying mechanism as a novel therapeutic approach to overcoming enzalutamide resistance. Project 2. Influence of the bone microenvironment on prostate cancer dormancy. The majority of cancer patients die of metastases that begin years or decades after primary diagnosis and treatment. Up to 70% of prostate cancer patients have disseminated tumor cells in the bone marrow at the time of initial diagnosis, and these cells can remain dormant and reactivate later. Understanding the underlying mechanism will provide novel avenues for early preventive and therapeutic approaches to eradicating metastatic recurrence. We have created a mouse model in which prostate cancer bone metastasis development is delayed by four weeks, which is equivalent to three years in humans. Based on our studies, we are proposing to test the effect of blocking CTHRC1 or of vitamin C treatment on prostate cancer dormancy and bone metastasis.

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Center for Cancer and Cell Biology

WEI LÜ, Ph.D. Wei Lü earned his Ph.D. from the University of Freiburg in the laboratory of Oliver Einsle. He then was a postoctoral fellow in the laboratory of Eric Gouaux (HHMI/Vollum Institute) before joining VARI as an Assistant Professor in 2017.

RESEARCH INTERESTS We use single-particle cryo-electron microscopy and other biophysical/biochemical methods to study the structure and mechanism of ion channels and transmembrane receptors that are linked to neurological diseases and cancers. We recently determined the cryo-EM structure of the human TRPM4 channel.

STAFF Yihe Huang, Ph.D. Michelle Martin, A.A. Paige Winkler, Ph.D.

STUDENT Wooyoung Choi

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KARSTEN MELCHER, Ph.D. Dr. Melcher earned his master's degree in biology and his Ph.D. in biochemistry from the Eberhard Karls Universität in Tübingen, Germany. He was recruited to VARI in 2007, and in 2013 he was promoted to Associate Professor.

RESEARCH INTERESTS Our laboratory studies the structure and function of proteins that have central roles in cellular signaling. To do so, we employ X-ray crystallography and cryoelectron microscopy in combination with biochemical and cellular methods to identify mechanisms of signaling and frameworks for the rational design of new and improved drugs against diseases such as cancer, diabetes, and neurological disorders.

STAFF Xin Gu, M.S. Michelle Martin, A.A.

STUDENTS Zachary DeBruine, B.S. Yan Yan, B.S.

VISITING SCIENTIST Feng Zhang, Ph.D.

AMP-activated protein kinase (AMPK) AMPK is a central regulator of energy homeostasis and important drug target for the treatment of metabolic diseases, including diabetes, obesity, and cancer. AMPK senses the energy state of the cell by competitive binding of AMP, ADP, and ATP to three sites in its γ subunit. We are determining the structural mechanisms of AMPK regulation by direct binding of AMP, ADP, ATP, and various drugs, as well as by post-translational modifications. Plant hormone signaling We are studying perception, signal transduction, and target gene regulation for hormones that reprogram plants in response to drought and other abiotic stresses (abscisic acid), to herbivorous insects and microbial pathogens (jasmonates), and to mineral nutrient stresses (strigolactones). These stresses are responsible for major crop losses worldwide and have a large impact on human malnutrition. WNT reception and signaling WNTs are morphogens that have key roles in human development and stem cell maintenance; components of the WNT signaling pathway are frequently mutated in cancers, as well as in bone and retinal diseases. This pathway is therefore an important therapeutic target. Yet, how to therapeutically target the docking of a WNT to its cell surface receptor complex, and the molecular mechanism of how such docking transduces signals to the inside of the cell, have remained elusive. We are using a combination of structural and live-cell analysis to determine the structure of the intact receptor complex and the mechanism of WNT transmembrane signaling.

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Center for Cancer and Cell Biology

LORENZO F. SEMPERE, Ph.D. Dr. Sempere obtained his B.S. in biochemistry at Universidad Miguel Hernández, Elche, Spain, and earned his Ph.D. at Dartmouth under Victor Ambros. He joined VARI in January 2014 as an Assistant Professor.

RESEARCH INTERESTS

STAFF Josh Schipper, Ph.D. Jeanie Wedberg, A.S. Jenni Westerhuis, M.S.Ed., M.S.

STUDENTS Sudakshina Chakrabarty Joyce Goodluck

Our laboratory pursues complementary lines of translational research to explain the etiological role of microRNAs and to unravel microRNA regulatory networks during carcinogenesis. We investigate these questions in clinical samples and preclinical models of breast cancer and pancreatic cancer. MicroRNAs can regulate and modulate the expression of hundreds of target genes, some of which are components of the same signaling pathways or biological processes. Thus, functional modulation of a single microRNA can affect multiple target mRNAs (i.e., one drug, multiple hits), unlike therapies based on small interfering RNAs, antibodies, or small-molecule inhibitors. The laboratory has active projects in the areas of cancer biology and tumor microenvironment, with a translational focus toward improving diagnostic applications and therapeutic strategies. Because tissue samples are the direct connection between cancer research and cancer medicine, detailed molecular and cellular characterization of tumors provides the opportunity to translate scientific knowledge into useful clinical information. We use innovative multiplexed immunohistochemical and in situ hybridization assays to implement diagnostic applications of microRNA biomarkers. Molecular biology and cell biology studies help to identify microRNA targets and regulatory networks. Recent projects include the following. • Clinically validating tumor compartment-specific expression of miR-21 as a prognostic marker for breast cancer. There is focused interest in the stromal expression of miR-21 in triple-negative breast cancer, for which prognostic markers and effective targeted therapies are lacking. • Developing integrative diagnostics for pancreatic cancer using information from cancer-associated microRNAs and protein glycosylation. Integrative marker analysis should enhance diagnostic power and interpretation. • Developing methods for isolating microRNA/target mRNA interactions in in vitro and in vivo systems. • Evaluating the miR-21 activity required in cancer cell and tumor stromal compartments to support aggressive and metastatic features in animal models of breast and pancreatic cancer.

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MATTHEW STEENSMA, M.D. Dr. Steensma received his B.A. from Hope College and his M.D. from Wayne State University School of Medicine in Detroit. He is a practicing surgeon in the Spectrum Health Medical Group, and he joined VARI as an Assistant Professor in 2010.

RESEARCH INTERESTS

STAFF Patrick Dischinger, B.S., MB(ASCP)CM Curt Essenburg, B.S., LATG Carrie Graveel, Ph.D. Michelle Minard, B.S. Elizabeth Tovar, Ph.D.

Our laboratory conducts research into new treatment strategies for sarcomas. Specifically, we are interested in determining the mechanisms underlying tumor formation in sporadic bone and soft-tissue sarcomas and in neurofibromatosis type 1, a hereditary disorder caused by mutations in the neurofibromin 1 (NF1) gene. Neurofibromin is considered a tumor suppressor that suppresses Ras activity by promoting Ras GTP hydrolysis to GDP. People with mutations in the NF1 gene develop benign tumors called neurofibromas and have an elevated risk of malignancies ranging from solid tumors (including sarcomas) to leukemia. The disease affects 1 in 3000 people in the United States, of whom 8–13% will ultimately develop a neurofibromatosis-related sarcoma in their lifetime. These aggressive tumors typically arise from benign neurofibromas, but the process of benign-tomalignant transformation is not well understood, and treatment options are limited, leading to poor five-year survival rates. Our current research efforts include the development of genetically engineered mouse models of neurofibromatosis type 1 tumor progression, most notably NF1related MPNSTs and breast cancer; the identification of targetable patterns of intratumoral and intertumoral heterogeneity through next-generation sequencing; genotype–phenotype correlations in neurofibromatosis type 1 and related diseases; and mechanisms of chemotherapy resistance in bone and soft-tissue sarcomas.

STUDENTS Eve Gardner Jamie Grit, B.S. Candace King, M.A. Courtney Schmidt

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Center for Cancer and Cell Biology

BART O. WILLIAMS, Ph.D. Dr. Williams received his Ph.D. in biology from Massachusetts Institute of Technology in 1996, where he trained with Tyler Jacks. Following postdoctoral study with Harold Varmus, he joined VARI in July 1999. He is now a Professor and the Director of the Center for Cancer and Cell Biology.

RESEARCH INTERESTS

STAFF Cassie Diegel, B.S. Gabrielle Foxa, B.S. Mitch McDonald, B.S. Megan Michalski, D.D.S, Ph.D. Michelle Minard, B.S. Alex Zhong, Ph.D.

STUDENTS Isaac Izaguirre Katie Krajnak, M.S. Adam Racette

We are studying how alterations in the WNT signaling pathway cause human disease. Given that WNT signaling functions in the growth and differentiation of most tissues, it is not surprising that changes in this pathway are among the most common events in human cancer. Other diseases, including osteoporosis, cardiovascular disease, and diabetes, have also been linked to it. Our work includes studying the role of WNT signaling in normal bone formation and in the metastasis of cancer to the bone. We are also interested in identifying the genes that play key roles in skeletal development and maintenance of bone mass. Mutations in LRP5, a WNT receptor, have been causally linked to alterations in human bone development. We have characterized a mouse strain deficient in LRP5 and have shown that it recapitulates the low-bone-density phenotype seen in human patients who have that deficiency. We have further shown that mice carrying mutations in both LRP5 and the related LRP6 protein have even more-severe defects in bone density. We are also examining the effects on normal bone development and homeostasis of chemical inhibitors of the enzyme Porcupine, which is required for the secretion and activity of all WNTs. Because such inhibitors are currently in human clinical trials for treatment of several tumor types, their side effects related to the lowering of bone mass must be evaluated. We are addressing the relative roles of LRP5 and LRP6 in WNT1-induced mammary carcinogenesis. A deficiency in LRP5 dramatically inhibits the development of mammary tumors, and a germline deficiency in LRP5 or LRP6 results in delayed mammary development. We are particularly interested in the pathways that may regulate the proliferation of normal mammary progenitor cells, as well as of tumorinitiating cells. In another project, we are studying the development of skeletal osteoblastic metastasis from prostate cancer and the ability of the tumor cells to become independent of androgen for survival. Finally, part of our work focuses on developing genetically engineered mouse models, for example, models of osteoarthritis.

Nolan Redetzke

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NING WU, Ph.D. Dr. Wu received her Ph.D. from the Department of Biochemistry of the University of Toronto in 2002. She joined VARI in 2013 as an Assistant Professor.

RESEARCH INTERESTS Many human diseases, such as diabetes, neurodegeneration, cancer, and heart problems, come with old age. Our laboratory studies the interface between cellular metabolism and signal transduction, focusing on key steps in glucose and lipid metabolism in order to understand the ways that nutrients can delay aging effects and thus postpone the onset of disease.

STAFF Holly Dykstra, B.S. Althea Waldhart, B.S. Jeanie Wedberg, A.S.

Glucose is a vital, highly regulated metabolite in the human body. Its concentration is tightly controlled within a narrow range by factors secreted from several tissues. Too much glucose uptake leads to systemic problems that partly stem from oxidative stress generated by the mitochondria. Our lab examines the mechanism by which cells control glucose uptake, what regulates the flux from glucose to unwanted lipid accumulation, and how mitochondrial function is affected by glucose concentration. At the atomic scale, we employ cryo-electron microscopy to solve the structures of transporter proteins and their regulators. At the cellular level, we investigate how cells respond to metabolic stress. At the organism level, we integrate the cellular response with systemic response to understand how diet can modify and curb unwanted oxidative damage. This research will provide better insight into the relationship between diet and health and open the possibility of individualized diet recommendations to delay aging effects.

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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.

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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.

RESEARCH INTERESTS

STAFF Jianshuang Li, B.S.

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.

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Center for Cancer and Cell Biology RECENT CENTER PUBLICATIONS Barnett, Daniel, Ying Liu, Katie Partyka, Ying Huang, Huiyuan Tang, Galen Hostetter, Randall E. Brand, Aatur D. Singhi, Richard R. Drake, and Brian B. Haab. 2017. The CA19-9 and sialyl-TRA antigens define separate subpopulations of pancreatic cancer cells. Scientific Reports 7: 4020. DeBruine, Zachary J., Jiyuan Ke, Kaleeckal G. Harikumar, Xin Gu, Peter Borowsky, Bart O. Williams, Wenqing Xu, Laurence J. Miller, H. Eric Xu, and Karsten Melcher. 2017. Wnt5a promotes frizzled-4 signalosome assembly by stabilizing cysteine-rich domain dimerization. Genes and Development 31(9): 916–926. Droscha, Casey J., Cassandra R. Diegel, Nicole J. Ethen, Travis A. Burgers, Mitchell J. McDonald, Kevin A. Maupin, Agni S. Naidu, PengFei Wang, Bin T. Teh, and Bart O. Williams. 2017.  Osteoblast-specific deletion of Hprt2/Cdc73 results in high bone mass and increased bone turnover.  Bone 98: 68–78. Grohar, Patrick J., John Glod, Cody J. Peer, Tristan M. Sissung, Fernanda I. Arnaldez, Lauren Long, William D. Figg, Patricia Whitcomb, Lee J. Helman, and Brigitte C. Widemann. 2017. A phase I/II trial and pharmacokinetic study of mithramycin in children and adults with refractory Ewing sarcoma and EWS-FLI1 fusion transcript. Cancer Chemotherapy and Pharmacology 80(3): 645–652. Grohar, Patrick J., Katherine A. Janeway, Luke D. Mase, and Joshua D. Schiffman. 2017. Advances in the treatment of pediatric bone sarcomas. In 2017 Educational Book, Alexandria, Virginia: American Society of Clinical Oncology. He, Yuanzheng, Xiang Gao, Devrishi Goswami, Li Hou, Kuntal Pal, Yanting Yin, Gongpu Zhao, Oliver P. Ernst, Patrick Griffin, Karsten Melcher, and H. Eric Xu. 2017. Molecular assembly of rhodopsin with G protein–coupled receptor kinases. Cell Research 27(6): 728–747. Klamer, Zachary, Ben Staal, Anthony R. Prudden, Lin Liu, David F. Smith, Geert-Jan Boons, and Brian Haab. 2017. Mining highcomplexity motifs in glycans: a new language to uncover the fine specificities of lectins and glycosidases. Analytical Chemistry 89(22): 12342–12350. Lee, Ho-Joon, Mark P. Jedrychowski, Arunachalam Vinayagam, Ning Wu, Ng Shyh-Chang, Yanhui Hu, Chua Min-Wen, Jodene K. Moore, John M. Asara, Costas A. Lyssiotis, Norbert Perrimon, Steven P. Gygi, Lewis C. Cantley, and Marc W. Kirschner. 2017. Proteomic and metabolomic characterization of a mammalian cellular transition from quiescence to proliferation. Cell Reports 20(3): 721–736. Li, Jianshuang, Di Lu, Huadie Liu, Bart O. Williams, Paul A. Overbeek, Brendan Lee, Ling Zheng, and Tao Yang. 2017. Sclt1 deficiency causes cystic kidney by activating ERK and STAT3 signaling. Human Molecular Genetics 26(15): 2949–2960. Ma, Honglei, Jingbo Duan, Jiyuan Ke, Yuanzheng He, Xin Gu, Ting-Hai Xu, Hong Yu, Yonghong Wang, Joseph S. Brunzelle, Yi Jiang, Scott B. Rothbart, H. Eric Xu, Jiayang Li, and Karsten Melcher. 2017. A D53 repression motif induces oligomerization of TOPLESS corepressors and promotes assembly of a corepressor-nucleosome complex. Science Advances 3(6): e1601217. Minciacchi, Valentina R., Cristiana Spinelli, Mariana Reis-Sobreiro, Lorenzo Cavallini, Sungyong You, Mandana Zandian, Xiaohong Li, Paola Chiarugi, Rosalyn M. Adam, Edwin M. Posadas, Giuseppe Viglietto, Michael R. Freeman, Emanuele Cocucci, Neil A. Bhowmick, and Dolores Di Vizio. 2017. MYC mediates large oncosome-induced fibroblast reprogramming in prostate cancer. Cancer Research 77(9): 2306–2317. Pridgeon, Matthew G., Patrick J. Grohar, Matthew R. Steensma, and Bart O. Williams. 2017. Wnt signaling in Ewing sarcoma, osteosarcoma, and malignant peripheral nerve sheath tumors. Current Osteoporosis Reports 15(4): 239–246. Sempere, Lorenzo F., Jessica Keto, and Muller Fabbri. 2017. Exosomal microRNAs in breast cancer towards diagnostic and therapeutic applications. Cancers 9(7): 71.

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Valkenburg, Kenneth C., Angelo M. De Marzo, and Bart O. Williams. 2017.  Deletion of tumor suppressors adenomatous polyposis coli and Smad4 in murine luminal epithelial cells causes invasive prostate cancer and loss of androgen receptor expression.  Oncotarget 8(46): 80265–80277. Waldhart, Althea N., Holly Dykstra, Anderson S. Peck, Elissa A. Boguslawski, Zachary B. Madaj, Jennifer Wen, Kelsey Veldkamp, Matthew Hollowell, Bin Zheng, Lewis C. Cantley, Timothy E. McGraw, and Ning Wu. 2017. Phosphorylation of TXNIP by AKT mediates acute influx of glucose in response to insulin. Cell Reports 19(10): 2005–2013. Winkler, Paige A., Yihe Huang, Weinan Sun, Juan Du, and Wei Lü. 2017. Electron cryo-microscopy structure of a human TRPM4 channel. Nature 552(7684): 200–204. Yan, Yan, Ting-Hai Xu, Kaleeckal G. Marikumar, Laurence J. Miller, Karsten Melcher, and H. Eric Xu. 2017. Dimerization of the transmembrane domain of amyloid precursor protein is determined by residues around the gamma-secretase cleavage sites. Journal of Biological Chemistry 292(38): 15826–15837. Yang, Tao, and Bart O. Williams. 2017. Low-density lipoprotein receptor-related proteins in skeletal development and disease. Physiological Reviews 97(3): 1211–128. Yin, Yanting, Parker W. De Waal, Yuanzheng He, Li-Hua Zhao, Dehua Yang, Xiaoqing Cai, Yi Jiang, Karsten Melcher, Ming-Wei Wang, and H. Eric Xu. 2017. Rearrangement of a polar core provides a conserved mechanism for constitutive activation of class B G protein–coupled receptors. Journal of Biological Chemistry 292(24): 9865–9881. Zhang, Feng, Jiyuan Ke, Li Zhang, Rongzhi Chen, Koichi Sugimoto, Gregg A. Howe, H. Eric Xu, Mingguo Zhou, Sheng Yang He, and Karsten Melcher. 2017. Structural insights into alternative splicing-mediated desensitization of jasmonate signaling. Proceedings of the National Academy of Sciences U.S.A. 114(7): 1720–1725. Zhou, X. Edward, Yuanzheng He, Parker W. de Waal, Xiang Gao, Yanyong Kang, Ned Van Eps, Yanting Yin, Kuntal Pal, Devrishi Goswami, Thomas A. White, Anton Barty, Naomi R. Latorraca, Henry N. Chapman, Wayne L. Hubbell, Ron O. Dror, Raymond C. Stevens, Vadim Cherezov, Vsevolod V. Gurevich, Patrick R. Griffin, Oliver P. Ernst, Karsten Melcher, and H. Eric Xu. 2017. Identification of phosphorylation codes for arrestin recruitment by G protein–coupled receptors. Cell 170(3): 457–469.e13.

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Center for Epigenetics Peter A. Jones, Ph.D., D.Sc. Director The Center’s researchers study epigenetics and epigenomics in health and disease, with the ultimate goal of developing novel therapies to treat cancer and neurodegenerative diseases. The Center collaborates extensively with other VARI research groups and with external partners to maximize its efforts to develop therapies that target epigenetic mechanisms.

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Methyl (red) and acetyl (light blue) groups as epigenetic marks on nucleosomes and DNA. Image by Nicole Ethen, formerly of the Williams lab.


Center for Epigenetics

STEPHEN B. BAYLIN, M.D. Dr. Baylin joined VARI as a Professor and Director's Scholar in the Center for Epigenetics in January 2015. He is co-leader of the VARI-SU2C Epigenetics Dream Team, and he devotes a portion of his time to VARI. His primary appointment is at Johns Hopkins University as the Virginia and D.K. Ludwig Professor of Oncology and Medicine and as co-head of Cancer Biology at the Sidney Kimmel Comprehensive Cancer Center. RESEARCH INTERESTS The Van Andel Research Institute–Stand Up To Cancer (VARI-SU2C) Epigenetics Dream Team is a multi-institutional effort to develop new epigenetic therapies against cancer and to move promising therapies to clinical trials. As co-leader, Dr. Baylin oversees the team’s research, which leverages the combined expertise of its members. Epigenetics is the study of how the packaging and modification of DNA influences the genes that are active or kept silent in a particular cell, and it holds untold potential for treating cancer and other diseases. Through a detailed understanding of how normal epigenetic processes work, scientists can identify erroneous epigenetic modifications that may contribute to the development and progression of cancer. Epigenetic therapies, which work by correcting these errors, have the potential to directly treat cancer and to sensitize patients to traditional treatments such as chemotherapy and promising new immunotherapy approaches. The VARI-SU2C Epigenetics Dream Team is headquartered at VARI in Grand Rapids, Michigan. It includes members from Fox Chase Cancer Center, Garvan Institute of Medical Research, Indiana University, Johns Hopkins University, Memorial Sloan Kettering Cancer Center, Rigshospitalet/University of Copenhagen, Temple University, University of Maryland, and University of Southern California. The American Association for Cancer Research, as SU2C’s scientific partner, reviews projects and provides objective scientific oversight.

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PETER A. JONES, Ph.D., D.Sc. Dr. Jones received his Ph.D. from the University of London. He joined the University of Southern California in 1977 and served as Director of the USC Norris Comprehensive Cancer Center between 1993 and 2011. Dr. Jones joined VARI in 2014 as its Chief Scientific Officer and Director of the Center for Epigenetics.

RESEARCH INTERESTS Our laboratory uses a holistic approach to determine how DNA methylation, nucleosome positioning, and histone modifications influence each other to bring about epigenetic changes that contribute to cancer. Some current and recent projects are summarized here.

STAFF Brittany Carpenter, Ph.D. Ashley DeWitt, M.S. Minmin Liu, Ph.D. Amy Nelson Hitoshi Otani, Ph.D. Stacey Thomas, Ph.D. Rochelle Tiedemann, Ph.D. Tinghai (Peter) Xu, Ph.D. Wanding Zhou, Ph.D.

Both DNA and histone modifications play important roles in suppressing endogenous retrovirus (ERV) expression in mammalian cells. ERVs, which have populated the human genome for more than 100 million years, are CpG-rich at the time of infection, but they have lost CpG content over such long time periods. We are currently examining ERVs of different ages to determine their mechanism of silencing and their ability to induce the expression of viral defense genes. The data suggest that there is an epigenetic switch in the silencing mechanism, such that older ERVs are predominately silenced by histone modification rather than DNA methylation. Following up our finding that DNA methylation inhibitors induce a state of “viral mimicry” in cancer cells, we have found that treatment of cells with a low dose of 5-azanucleoside plus vitamin C enhanced immune signals, including the increased expression of ERVs. Because many patients with hematological neoplasia are vitamin C–deficient, correction of this deficiency may improve patient response to epigenetic therapy. This work has led to an ongoing VARI-SU2C pilot clinical trial in adult patients who have MDS or AML, to assess whether vitamin C supplements can increase patient response to DNA methylation inhibitors. Another focus of the lab is the noncoding RNA nc886 (vtRNA2-1), which is variably imprinted by methylation from the mother during development and is strongly associated with the risk of both obesity and cancer. We will define the mechanism of this variable imprinting, examine the role of nc886 in normal cell physiology, and determine how chromatin structure and DNA methylation silence nc886. Taking advantage of VARI’s latest cryo-EM instrument, the Titan Krios G2, we have begun work to solve the structures of the DNA methyltransferases DNMT3A and DNMT3B bound to nucleosomes. This information will increase our understanding of how DNA methylation patterns are established and maintained by these enzymes.

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Center for Epigenetics

STEFAN JOVINGE, M.D., Ph.D. Dr. Jovinge received his M.D. (1991) and his Ph.D. (1997) at Karolinska Institute in Stockholm. Since December 2013 he has been a Professor at VARI and the Medical Director of Research at the Frederik Meijer Heart and Vascular Institute. He also directs the DeVos Cardiovascular Research Program, is a Professor at the MSU College of Human Medicine, and is a Consulting Professor at Stanford University. RESEARCH INTERESTS The DeVos Cardiovascular Research Program is a joint effort between VARI and Spectrum Health. The basic science lab is the Jovinge laboratory at VARI, and a corresponding clinical research unit resides within the Fred Meijer Heart and Vascular Institute.

STAFF Lucas Chan, Ph.D. Shelby Compton Paula Davidson, M.S. Lisa DeCamp, M.A., MB(ASCP), RLAT Ellen Ellis Emily Eugster, M.S. Joseph Faski, B.S. Jens Forsberg, Ph.D. Eric Kort, M.D. Olivia Licari Hsiao-Yun Yeh (Christy) Milliron, Ph.D. Matthew Weiland, M.S.

To regenerate myocardium after disease or damage is one of the major challenges in medicine. We have shown that endogenous generation of heart muscle cells in humans is continuous throughout life. However, it declines rapidly with age and is far too insufficient to compensate for the large loss of muscle cells seen in most diseased hearts. Our preliminary data support the concept that preexisting cardiomyocytes are the source of this endogenous generation. We have now been able to isolate dividing cardiomyocytes based on their gene expression pattern. Thus, we are working our way toward control of the endogenous generation of cardiomyocytes and thereby toward the possibility of developing strategies to enable the heart to heal itself. “Rare diseases� affect fewer than 200,00 individuals in the USA; while each patient group is small, together rare diseases encompass some 30 million individuals. The generation of drugs for such small populations is very costly, so those who have such diseases are often left without specific treatment. With the use of the NIH database LINCS, which screens all FDA-approved drugs for off-target effects, we have identified a drug that specifically targets the deficiency in patients who have a rare mutation that causes a severe heart muscle disease. By reprogramming blood cells and deriving heart muscle cells from these patients, we have been able to verify the database predictions for the drug, thereby making possible the availability of new drugs for patients with this rare disease at a reasonable cost. Using a sophisticated technology, we have been able to reprogram and derive cardiac pacemaker cells. This year, we were able to use pacemaker cells to create a biological pacemaker in a culture dish. In another study, we have created a large database that allows us to optimize treatment for patients who have severe heart failure and are on mechanical support. We can also create advanced algorithms for predicting the outcome of support selection and for preventing complications.

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PETER W. LAIRD, Ph.D. Dr. Laird earned his Ph.D. in 1988 from the University of Amsterdam with Piet Borst. He was a faculty member at the University of Southern California from 1996 to 2014, where he was Skirball-Kenis Professor of Cancer Research and directed the USC Epigenome Center. He joined VARI as a Professor in September 2014.

RESEARCH INTERESTS

STAFF Kelly Foy, B.S. Walid Habib, Ph.D. Toshinori Hinoue, Ph.D. Manpreet Kalkat, Ph.D. Liang Kang, A.S. KwangHo Lee, Ph.D. Amy Nelson Wanding Zhou, Ph.D.

STUDENTS Zack Jansen

Our goal is to develop a detailed understanding of the molecular basis of human disease, with a particular emphasis on the role of epigenetics in cancer. Cancer is often considered to have a primarily genetic basis, with contributions from germline variations in risk and somatically acquired mutations, rearrangements, and copy number alterations. However, it is clear that nongenetic mechanisms can exert a powerful influence on cellular phenotype, as evidenced by the marked diversity of cell types within our bodies, which virtually all contain an identical genetic code. This differential gene expression is controlled by tissue-specific transcription factors and variations in chromatin packaging and modification, which can provide stable phenotypic states governed by epigenetic, not genetic, mechanisms. It seems likely that an intrinsically opportunistic disease such as cancer would take advantage of such a potent mediator of cellular phenotype. Our laboratory is dedicated to understanding how epigenetic mechanisms contribute to the origins of cancer and how to translate this knowledge into more-effective cancer prevention, detection, treatment, and monitoring. We use a multidisciplinary approach in our research, relying on mechanistic studies in model organisms and cell cultures, clinical and translational collaborations, genome-scale and bioinformatic analyses, and epidemiological studies to advance our understanding of cancer epigenetics. In recent years, we participated in the generation and analysis of high-dimensional epigenetic data sets, including the production of all epigenomic data for The Cancer Genome Atlas (TCGA) and the application of next-generation sequencing technology to whole-genome DNA methylation analysis at single-base-pair resolution. We are leveraging this epigenomic data for translational applications and hypothesis testing in animal models. A major focus of our laboratory is to develop mouse models for investigating epigenetic mechanisms and drivers of cancer and to develop novel strategies for single-cell epigenomic analysis.

Nicole Vander Schaaf, B.S.

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Center for Epigenetics

HUILIN LI, Ph.D. Dr. Li earned his Ph.D. in electron crystallography from the University of Science and Technology Beijing, where he trained with the late K. H. Kuo. He joined VARI in 2016 from Stony Brook University, New York.

RESEARCH INTERESTS The work of our lab focuses on the structural basis of DNA replication, the bacterial proteasome system, and the regulation and modification of the Notch receptor.

STAFF Lin Bai, Ph.D. Xiang Feng, Ph.D. Hao-Chi Hsu, Ph.D. Amanda Kovach, B.S. Hua Li, Ph.D. Michelle Martin, A.A. Yanting Yin, Ph.D. Hongjun Yu, Ph.D.

Eukaryotic DNA replication Replication initiation is tightly regulated, because failure to ensure once-only initiation per cell cycle can result in uncontrolled proliferation and genomic instability, which are hallmarks of tumorigenesis. We use structural and biochemical approaches to uncover the molecular mechanisms underlying eukaryotic chromosomal replication. Work in our lab over the past year has revealed how ORC, with the help of Cdc6, loads the Mcm2-7 hexamer and how the Mcm2-7 double-hexamer binds the origin DNA. In the S phase of the cell cycle, the active Cdc45–Mcm2-7–GINS helicase (CMG) works with the leading strand polymerase epsilon, the lagging strand polymerase delta, and the primase-polymerase alpha to synthesize new DNA. We also determined the structure of the 11-protein yeast CMG helicase and have shown how the helicase interacts with the replication fork DNA. Proteostasis in Mycobacterium tuberculosis Tuberculosis kills some 1.5 million people globally every year. Mycobacterium tuberculosis can be killed by nitric oxide (NO) of the host immune system. The Mtb proteasome is a key to the organism’s resistance to such attack and thus is a promising target for the development of anti-TB chemotherapeutics. In the past year, we have solved the structure of the ATPase-dependent proteasomal activator Mpa and the ATP-independent proteasomal activator PafE. We also uncovered the structural basis for the species-selective binding of six N,C-capped dipeptides to the Mtb proteasome. Our work illuminates the bacterial proteasome system and facilitates anti-TB chemotherapeutic development efforts.

STUDENTS Minge Du, M.S. Ruda Santos, M.S. Zuanning Yuan, M.S.

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GERD PFEIFER, Ph.D. Dr. Pfeifer earned his M.S. in pharmacology in 1981 and his Ph.D. in biochemistry in 1984 from Goethe University in Frankfurt, Germany. He most recently held the Lester M. and Irene C. Finkelstein Chair in Biology at the City of Hope in Duarte, California, before joining VARI in 2014 as a Professor. RESEARCH OVERVIEW The laboratory studies epigenetic mechanisms of human diseases, with a focus on DNA methylation and the role of 5-methylcytosine oxidation by the TET protein family.

STAFF Zhijun Huang, Ph.D. Seung-Gi Jin, Ph.D. Jennifer Johnson, M.S. Amy Nelson Zhi-Qiang (Ken) Wang, Ph.D.

DNA methylation in cancer This work centers on the hypothesis that CpG islands are protected from methylation in normal cells by a set of specific proteins, such as 5-methylcytosine oxidases, CXXC proteins, and the polycomb complex. The protection breaks down during early stages of malignancy. We investigate mechanisms of DNA hypermethylation using DNA-methylation mapping and chromatin mapping in both normal and malignant cells, as well as bioinformatic approaches and functional studies employing gene inactivation in tissue culture. TET3 and related proteins in basic biology and human disease The removal of methyl groups from DNA has been recognized as an important pathway in cancer and possibly in other diseases. Our lab studies mechanisms of 5-methylcytosine oxidation. We have identified three isoforms of the TET3 5-methylcytosine oxidase and characterized them using biochemical, functional, and genetic approaches. We observed that one isoform of TET3 specifically binds to 5-carboxylcytosine, thus establishing an anchoring mechanism of TET3 to its reaction product, which may aid in localized 5-methylcytosine oxidation and removal. We also study several TET3-associated proteins, trying to understand their biological roles. TET3 has a rather limited genomic distribution and is targeted to the transcription start sites of defined sets of genes, many of which function within the lysosome and autophagy pathways. We are exploring the mechanistic consequences of 5-methylcytosine oxidation in these genes, with the long-term goal of determining whether neurodegeneration has an epigenetic origin. In another project, we are exploring the function of a TET3-binding protein and its effect on TET-mediated processes in embryonic stem cells and in myoblasts. This work has implications for understanding the mechanisms underlying muscular dystrophy.

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Center for Epigenetics

SCOTT ROTHBART, Ph.D. Dr. Rothbart earned a Ph.D. in pharmacology and toxicology from Virginia Commonwealth University in 2010. He joined VARI in April 2015 as an Assistant Professor.

RESEARCH INTERESTS The long-term goal of my research program is to define molecular mechanisms regulating chromatin modification signaling. Through a multidisciplinary and collaborative research program, we hope to translate basic knowledge of epigenetic mechanisms into therapeutic benefits.

STAFF Evan Cornett, Ph.D. Bradley Dickson, Ph.D. Alison Lanctot, Ph.D. Amy Nelson Kevin Shaw, B.S. Rochelle Tiedemann, Ph.D.

STUDENTS

We are keen on understanding the complex relationship between DNA methylation and histone post-translational modifications (PTMs); these are two key epigenetic regulators of genome accessibility, interaction, and function. Within this broad framework, we ask 1) how are the writers and erasers of chromatin modifications regulated? 2) how do nuclear proteins and their complexes interface with (i.e., read) epigenetic marks to perform their chromatin regulatory functions? and 3) how does deregulation of chromatin signaling contribute to human diseases like cancer? We fabricate histone peptide microarrays in my lab as an integral part of our effort to characterize the complex interactions of proteins with the DNA and histone components of chromatin. We use this platform extensively to characterize the reader, writer, and eraser activities of chromatin regulators and also the behavior of antibodies that recognize histones and their PTMs. We are also developing new functional proteomics techniques to study the writers, erasers, and readers of lysine methylation signaling. Our studies are providing crucial systems-level information for the construction of lysine methylation signaling networks, are aiding drug discovery and development efforts, and are improving our understanding of lysine methylation function in human health and disease.

Christine Ausherman Robert Vaughan, B.S. Philip Versluis

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HUI SHEN, Ph.D. Dr. Shen earned her Ph.D. at the University of Southern California in genetic, molecular, and cellular biology. She joined VARI in September 2014 as an Assistant Professor.

RESEARCH INTERESTS

STAFF Huihui Fan, Ph.D. Hongbo Liu, Ph.D. Amy Nelson Wanding Zhou, Ph.D.

The laboratory focuses on the epigenome and its interaction with the genome in various diseases, with a specific emphasis on cancers of women and cross-cancer comparisons. We use bioinformatics as a tool to understand the etiology, cell of origin, and epigenetic mechanisms of disease and to devise better approaches for cancer prevention, detection, therapy, and monitoring. We have extensive experience with genome-scale DNA methylation profiles in primary human samples, and we have made major contributions to epigenetic analysis within The Cancer Genome Atlas (TCGA). DNA methylation is ideally suited for deconstructing heterogeneity among cell types within a tissue sample. In cancer research, this approach can be used for cancer cell clonal evolution studies or for quantifying normal cell infiltration and stromal composition. The latter can provide insights into the tumor microenvironment, and in noncancer studies it can be a useful tool for accurately estimating cell populations and providing insights into lineage structures and population shifts in disease. In addition, we are interested in translational applications of epigenomic technology. To this end, we bring markers emerging from our bioinformatics analysis into clinical assay development, marker panel assembly, and optimization, with the ultimate goal of clinical testing and validation.

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Center for Epigenetics

PIROSKA E. SZABร“, Ph.D. Dr. Szabรณ earned an M.Sc. in biology and a Ph.D. in molecular biology from Jรณzsef Attila University, Szeged, Hungary. She joined VARI in 2014 as an Associate Professor.

RESEARCH INTERESTS Our laboratory studies the molecular mechanisms responsible for resetting the mammalian epigenome between generations, globally and specifically in the context of genomic imprinting. We focus on how DNA methylation patterns are established in germ cells and how some of those are protected in the zygote and in the embryo.

STAFF Brianna Bixler, B.S. Ji Liao, Ph.D. Amy Nelson Tie-Bo Zeng, Ph.D.

STUDENTS Brianna Busscher Yingying Meng, M.S.

The role of broad transcription and dynamic chromatin changes in the germline Correctly setting up male or female gamete-specific methylation patterns is vitally important for fertility, development, and health. Our genome-wide mapping results have revealed that DNA methylation in fetal male germ cells (prospermatogonia) occurs by default along a profile of broad, low-level transcription. We have also found that dynamically increasing or diminishing H3K4 methylation at specific sequences is predictive of escaping or attaining DNA methylation, respectively, in the male germline. We hypothesize that transcription run-through is required for establishing default, broad DNA methylation in the prospermatogonia genome, including paternal imprinted differentially methylated regions (DMRs). Dynamic changes in H3K4me by H3K4 demethylases (KDMs) and H3K4 methyltransferases (HMTs), on the other hand, provide a pattern for de novo DNA methylation. We are addressing these questions using experimental approaches of mouse genetics and epigenomics. Maternal effects of histone methyltransferases Crucial events in the early embryo, such as reaching totipotency and embryonic genome activation, depend on accurate levels of epigenetic modifiers deposited in the egg. We are only beginning to understand the underlying epigenetic mechanisms in these events. We and others have shown that genome-wide DNA demethylation in the zygote involves sequential TET-mediated oxidation of 5mC to 5hmC, 5fC, and 5caC in the paternal pronucleus. Specific loci and the entire maternal pronucleus, however, are protected from TET-initiated DNA demethylation; this protection involves histone H3K9 methylation. Using mouse genetics and epigenomics, we will genetically identify the mechanistic connections between maternally deposited HMTs, DNA methylation, and the developmental potential of the embryo.

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TIMOTHY J. TRICHE, JR., Ph.D. Dr. Triche earned his Ph.D. from the University of Southern California in 2013. He joined VARI in the autumn of 2017 as an Assistant Professor in the Center for Epigenetics.

RESEARCH INTERESTS Our laboratory develops statistical and mathematical methods to dissect pediatric and adult diseases, with a focus on cancers of the blood in children. We study interactions between genetic factors and environmental factors (deficiencies and exposures), particularly where epigenetic mediation plays a major role, such as in immune response and evasion.

STAFF Amy Nelson

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Center for Epigenetics

STEVEN J. TRIEZENBERG, Ph.D. Dr. Triezenberg earned his Ph.D. at the University of Michigan. He was a faculty member at Michigan State University for more than 18 years before joining VARI in 2006 as the founding Dean of Van Andel Institute Graduate School and as a VARI Professor.

RESEARCH INTERESTS Our research explores the mechanisms that control how genes are expressed inside cells, with a special interest in the processes that activate transcription of genetic information from DNA into RNA. We study those mechanisms in the context of infection by herpes simplex virus type 1 (HSV-1), the cause of cold sores.

STAFF Glen Alberts, B.S. Susanne Miller-Schachinger, B.B.A. .

STUDENT Nikki Thellman, D.V.M. (Ph.D., May 2017)

Some of our work looks at early stages of lytic or productive infection by HSV-1, which results in the obvious (and painful) cold-sore symptoms near the mouth. We have explored how a particular viral protein, VP16, activates the first viral genes that are expressed during lytic infection. We are now looking at proteins of the host cell that affect the early stages of infection, some of which control how the virus gets into a cell and some that control how the VP16 protein performs its functions. This approach may yield new ideas for antiviral drugs that can block HSV infections. After the initial infection resolves, HSV-1 finds its way into nerve cells, where the virus can remain in a latent mode for the entire life of the host. Occasionally, some stressful event will cause the latent virus to reactivate, producing new viruses in the nerve cell and sending them back to the skin to cause a recurrence of the cold sore. We are investigating the role that VP16 might play during this reactivation. We are especially interested in the epigenetic regulators that might be involved in unpacking the chromatin that silences the latent viral DNA. Our present hypothesis is that epigenetic coactivators recruited by VP16 are required to open up chromatin as an early step in reactivating the viral genes from latency. We are currently testing this hypothesis in quiescent infections of cultured human nerve cells.

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RECENT CENTER PUBLICATIONS Azad, Nilofer S., Anthony el-Khoueiry, Jun Yin, Ann L. Oberg, Patrick Flynn, Douglas Adkins, Anup Sharma, Daniel J. Weisenberger, Thomas Brown, Prakriti Medvari, Peter A. Jones, Hariharan Easwaran, Ihab Kamel, Nathan Bahary, George Kim, Joel Picus, Henry C. Pitot, Charles Erilichman, Ross Donehower, Hui Shen, Peter W. Laird, Richard Piekarz, Stephen Baylin, and Nita Ahuja. 2017. Combination epigenetic therapy in metastatic colorectal cancer (mCRC) with subcutaneous 5-azacitidine and entinostat: a phase 2 consortium/Stand Up 2 Cancer study. Oncotarget 8(21): 35326–35338. Cancer Genome Atlas Research Network, The. 2017. Integrated genomic characterization of oesophageal carcinoma. Nature 541(7636): 169–175. Cherniack, Andrew D., Hui Shen, Vonn Walter, Chip Stewart, Bradley A. Murray, Reanne Bowlby, Xin Hu, Shiyun Ling, Robert A. Soslow, Russell R. Broaddus, Rosemary E. Zuna, Gordon Robertson, Peter W. Laird, Raju Kucherlapati, Gordon B. Mills, The Cancer Genome Atlas Research Network, John N. Weinstein, Jiashan Zhang, Rehan Akbani, and Douglas A. Levine. 2017. Integrated molecular characterization of uterine carcinosarcoma. Cancer Cell 31(3): 411–423. Connolly, Roisin M., Huili Li, Rachel C. Jankowitz, Zhe Zhang, Michelle A. Rudek, Stacie C. Jeeter, Shannon A. Slater, Penny Powers, Antonio C. Wolff, John H. Fetting, Adam Burufsky, Richard Piekarz, Nita Ahuja, Peter W. Laird, Hui Shen, Daniel J. Weisenberger, Leslie Cope, James G. Herman, George Somlo, Garcia Agustin A., Peter A. Jones, Stephen B. Baylin, Nancy E. Davidson, Cynthia A. Zahnow, and Vered Stearns. 2017. Combination epigenetic therapy in advanced breast cancer with 5-azacitidine and entinostat: a Phase II National Cancer Institute/Stand Up to Cancer study. Clinical Cancer Research 23(11): 2691–2701. Cornett, Evan M., Bradley M. Dickson, and Scott B. Rothbart. 2017. Analysis of histone antibody specificity with peptide microarrays. Journal of Visualized Experiments 126: e55912. Georgescu, Roxana, Zuanning Yuan, Lin Bai, Ruda de Luna Almeida Santos, Jingchuan Sun, Dan Zhang, Olga Yurieva, Huilin Li, and Michael E. O’Donnell. 2017. Structure of eukaryotic CMG helicase at a replication fork and implications to replisome architecture and origin initiation. Proceedings of the National Academy of Sciences U.S.A. 114(5): D697–E706. Hanley, M.P., M.A. Hahn, A.X. Li, X. Wu, J. Lin, A.H. Choi, Z. Ouyang, Y. Fong, G.P. Pfeifer, T.J. Devers, and D.W. Rosenberg. 2017. Genome-wide DNA methylation profiling reveals cancer-associated changes within early colonic neoplasia. Oncogene 36(35): 5035–5044. Helbo, Alexandra Søgaard, Fides D. Lay, Peter A. Jones, Gangning Liang, and Kirsten Grønbaek. 2017. Nucleosome positioning and NDR structure at RNA polymerase III promoters. Scientific Reports 7: 41947 Lakshminarasimhan, Ranjani, Claudia Andreu-Vieyra, Kate Lawrenson, Christopher E. Duymich, Simon A. Gayther, Gangning Liang, and Peter A. Jones. 2017. Down-regulation of ARID1A is sufficient to initiate neoplastic transformation along with epigenetic reprogramming in non-tumorigenic endometriotic cells. Cancer Letters 401: 11–19. Lee, Kwang-Ho, Shirley Oghamian, Jin-A Park, Liang Kang, and Peter W. Laird. 2017. The REMOTE-control system: a system for reversible and tunable control of endogenous gene expression in mice. Nucleic Acids Research 45(21): 12256–12269. Ma, Honglei, Jingbo Duan, Jiyuan Ke, Yuanzheng He, Xin Gu, Ting-Hai Xu, Hong Yu, Yonghong Wang, Joseph S. Brunzelle, Yi Jiang, Scott B. Rothbart, H. Eric Xu, Jiayang Li, and Karsten Melcher. 2017. A D53 repression motif induces oligomerization of TOPLESS corepressors and promotes assembly of a corepressor-nucleosome complex. Science Advances 3(6): e1601217. Noguchi, Yasunori, Auanning Yuan, Lin Bai, Sarah Schneider, Gongpu Zhao, Bruce Stillman, Christian Speck, and Huilin Li. 2017. Cryo-EM structure of Mcm2-7 double hexamer on DNA suggests a lagging-strand DNA extrusion model. Proceedings of the National Academy of Sciences U.S.A. 114(45): E9529–E9538.

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Center for Epigenetics RECENT CENTER PUBLICATIONS (cont.) Olsson, P., E. Theander, U. Bergström, S. Jovinge, L.T.H. Jacobsson, and C. Turesson. 2017. Multiplex cytokine analyses in patients with rheumatoid arthritis require use of agents blicking heterophilic antibody activity. Scandanavian Journal of Rheumatology 46(1): 1–10. Polak, Paz, Jaegil Kim, Lior Z. Braunstein, Rosa Karlilc, Nicholas J. Haradhavala, Grace Tiao, Daniel Rosebrock, Dimitri Livitz, Kirsten Kübler, Kent W. Mouw, Atanas Kamburov, Yosef E. Maruvka, Ignaty Leshchiner, Eric S. Lander, Todd R. Golub, Aviad Zick, Alexandre Orthwein, Michael S. Lawrence, Rajbir N. Batra, Carlos Caldas, Daniel A. Haber, Peter W. Laird, Hui Shen, Leif W. Ellisen, Alan D. D’Andrea, Stephen J. Chanock, William D. Foulkes, and Gad Getz. 2017. A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nature Genetics 49(10): 1476–1486. Robertson, A. Gordon, Jaegil Kim, Hikmat Al-Ahmadie, Joaquim Bellmunt, Guangwu Guo, Andrew D. Cherniak, Toshinori Hinoue, Peter W. Laird, Katherine A. Hoadley, Rehan Akbani, et al. 2017. Comprehensive molecular characterization of muscleinvasive bladder cancer. Cell 171(3): 540–556.e25. Shanle, Erin K., Stephen A. Shinsky, Joseph B. Bridgers, Narkhyun Bae, Cari Sagum, Krzysztof Krajewski, Scott B. Rothbart, Mark T. Bedford, and Brian D. Strahl. 2017. Histone peptide microarray screen of chromo and Tudor domains defines new histone lysine methylation interactions. Epigenetics and Chromatin 10: 12. Thellman, Nikki M., Carolyn Botting, Zachary Madaj, and Steven J. Triezenberg. 2017. An immortalized human dorsal root ganglia cell line provides a novel context to study herpes simplex virus Type-1 latency and reactivation. Journal of Virology 91(12): 00080-17. Thellman, Nikki M., and Steven J. Triezenberg. 2017. Herpes simplex virus establishment, maintenance, and reactivation: in vitro modeling of latency. Pathogens 6(3): 28. Veland, Nicolas, Swanand Hardikar, Yi Zhong, Sitaram Sayatri, Jiameng Dan, Brian D. Strahl, Scott B. Rothbart, Mark T. Bedford, and Taiping Chen. 2017. The arginine methyltransferase PRMT6 regulates DNA methylation and contributes to global DNA hypomethylation in cancer. Cell Reports 21(12): 3390–3397. Weng, Xi-Lan, Ran An, Jessica Cassin, Jessica Joseph, Ruifa Mi, Chen Wang, Chun Zhong, Seung-Gi Jin, Gerd P. Pfeifer, Alfonso Bellacosa, Xinzhong Dong, Ahmet Hoke, Zhigang He, Hongjun Song, and Guo-li Ming. 2017. An intrinsic epigenetic barrier for functional axon regeneration. Neuron 94(2): 337–346. Wu, Yujie, Kuan Hu, Defeng Li, Lin Bai, Shaoqing Yang, Jordan B. Jastrab, Shuhao Xiao, Yonglin Hu, Susan Zhang, K. Heran Darwin, Tao Wang, and Huilin Li. 2017. Mycobacterium tuberculosis proteasomal ATPase Mpa has a β-grasp domain that hinders docking with the proteasome core protease. Molecular Microbiology 105(2): 227–241. Yuan, Zuanning, Alberto Riera, Lin Bai, Jingchuan Sun, Saikat Nandi, Christos Spanos, Zhuo Angel Chen, Marta Barbon, Juri Rappsilber, Bruce Stillman, Christian Speck, and Huilin Li. 2017. Structural basis of Mcm2–7 replicative helicase loading by ORC–Cdc6 and Cdt1. Nature Structural & Molecular Biology 24(3): 316–324. Zhou, Wanding, Peter W. Laird, and Hui Shen. 2017. Comprehensive characterization, annotation and innovative use of Infinium DNA methylation BeadChip probes. Nucleic Acids Research 45(4): e22.

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A side view of the cryo-EM density map of the S. cerevisiae Mcm2-7 double hexamer, with individual subunits labeled. The two hexamers are stacked at a tilt angle of 14°. Image from Huilin Li’s laboratory. VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 35


Center for Neurodegenerative Science Patrik Brundin, M.D., Ph.D. Director The Center's laboratories focus on developing novel treatments that slow or halt the progression of neurodegenerative disease, in particular Parkinson’s disease. The work involves three main goals: disease modification, biomarker discovery, and brain repair.

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Neurons from the brain of a mouse model of Parkinson’s disease. The neurons are stained green, cell nuclei are stained blue with DAPI, and pathological inclusions of ι-synuclein are stained red. Image by Nolwen Rey of the Patrik Brundin lab.


Center for Neurodegenerative Science

LENA BRUNDIN, M.D., Ph.D. Dr. Brundin earned her Ph.D. in neurobiology and her M.D. from Lund University, Sweden. She joined VARI in 2012 and is an Associate Professor.

RESEARCH INTERESTS We hypothesize that inflammation in the brain causes psychiatric symptoms such as depression and thoughts of suicide, and we study how inflammation can damage nerve cells and be involved in neurological conditions such as Parkinson’s disease. We are conducting clinical studies on patients in the Grand Rapids area and translational experiments in the laboratory at VARI, trying to understand the mechanisms by which inflammation affects the brain.

STAFF Elena Bryleva, Ph.D. Nils Eastburg, B.S. Emily Glidden, B.S. Stan Krzyzanowski, B.A. Keerthi Rajamani, Ph.D.

STUDENT Sarah Keaton, M.S.

Infections may play a role in triggering inflammation and subsequent symptoms in patients. In collaboration with Pine Rest Christian Mental Health, we are assessing the role of herpes simplex virus infection in triggering psychiatric symptoms. Our hypothesis is that patients with depression are more vulnerable to developing mood symptoms upon reactivation of HSV infection and that the infection could trigger depressive episodes. We have found that infection with the parasite Toxoplasma gondii is associated with a sevenfold risk of attempted suicide. Some 10-20% of all Americans are infected with this parasite, which may cause subtle behavioral changes, perhaps due to low-grade chronic brain inflammation. Toxoplasma infection may be treatable using current medications, but clinical trials are needed to prove that such treatment has a beneficial effect on depressive and suicidal behavior. We are conducting a study of perinatal depression together with Pine Rest Christian Mental Health, Spectrum Health, and Michigan State University. This NIH-funded effort, led by Dr. Brundin, investigates the role of placental inflammation in the development of perinatal depression. The goals of the study are to understand the cause of depression during pregnancy and to find biomarkers to identify women who are at risk for such depression. We have successfully enrolled 199 women and evaluated them in pregnancy and post partum over the past three years, and we are now analyzing the data. We have identified an enzyme, aminocarboxymuconate semialdehyde decarboxylase (ACMSD), that may regulate the vulnerability to developing psychiatric and neurological symptoms upon infection or inflammation. A person having low activity of ACMSD might have difficulties in controlling inflammation. The by-products of inflammation may cause nerve cell damage and neurological and psychiatric symptoms. We are studying whether increased amounts of ACMSD can be protective and prevent symptoms of Parkinson’s disease and depression.

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PATRIK BRUNDIN, M.D., Ph.D. Dr. Brundin earned his M.D. and Ph.D. at Lund University, Sweden. He was a professor of neuroscience at Lund before becoming a Professor and Associate Research Director of VARI in 2012.

RESEARCH INTERESTS Our research mission is to understand why Parkinson’s disease (PD) develops. We use cellular and animal PD models to discover new treatments that we hope can slow disease progression.

STAFF Kim Cousineau, M.P.A. Sonia George, Ph.D. Lindsay Meyerdirk, M.S. Wouter Peelaerts, Ph.D. Emmanuel Quansah, Ph.D. Keerthi Rajamani, Ph.D. Nolwen Rey, Ph.D. Emily Schulz, B.S. Jennifer Steiner, Ph.D.

Misfolded variants of the protein α-synuclein (α-syn) are a main constituent of intraneuronal Lewy bodies, the protein aggregates that are the major neuropathological hallmark of PD. The mechanisms underlying α-syn pathology are poorly understood. We were one of the first groups to propose that abnormal α-syn might propagate between neurons and drive the progression of symptoms. Our interests include understanding how α-syn aggregation is triggered, how the aggregates spread, and how they cause neurological deficits. We have created a mouse model of the human disease based on injections of misfolded α-syn into the olfactory bulb. The loss of olfaction is an early change in PD, often preceding the onset of the classic motor symptoms. In our model, α-syn aggregate pathology gradually spreads along olfactory pathways, causing progressive olfactory deficits. We are now defining whether the deficits are due to neuronal death or to dysfunction in neurons that contain aggregates. The olfactory bulb model has been proposed to be a starting point of Lewy body pathology, but the initial trigger is unknown. We are currently exploring whether airborne environmental pollutants or other proinflammatory stimuli can cause α-syn aggregate pathology in the olfactory bulb. We are also examining immunotherapy and repurposed antidiabetic drugs for effects that reduce PD pathology in animal models. Given the favorable safety profile of antidiabetic agents, several are already being tested in PD clinical trials, but further animal trials are needed to understand the mechanism(s) of action. Our major funders include the National Institutes of Health, the Department of Defense, the Michael J. Fox Foundation, the Cure Parkinson’s Trust UK, and H. Lundbeck A/S.

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Center for Neurodegenerative Science

GERHARD (Gerry) A. COETZEE, Ph.D. Dr. Coetzee earned his Ph.D. in medical biochemistry from the University of Stellenbosch, South Africa, in 1977. He was a professor in the Departments of Urology, Microbiology, and Preventive Medicine at the Keck School of Medicine at USC before joining VARI as a Professor in November 2015. RESEARCH INTERESTS

STAFF Alix Booms, B.S. Kim Cousineau, M.P.A. Steve Pierce, Ph.D. Trevor Tyson, Ph.D. J.C. Vanderschans, B.S.

Our laboratory focuses on exploring genome-wide association studies (GWAS) to uncover genetic risk mechanisms in breast cancer and Parkinson’s disease (PD); we call these post-GWAS studies. GWAS of complex phenotypes such as those of breast cancer and PD have become powerful pointers to genetic predisposition. Additionally, as next-generation sequencing techniques have become more feasible and increasingly affordable, mechanisms may be explored genome-wide. A daunting and unexpected finding was that for many complex diseases, more than 90% of the risk single nucleotide polymorphisms (SNPs) are located in noncoding DNA. To address these issues, we and others have used chromatin biofeatures to explore potential functionality. Specifically, our laboratory uses cell culture models to probe mechanisms of risk. Our main hypothesis is that risk resides in enhancers scattered through our genome that are identifiable within chromatin biofeatures (nucleosome occupancy and histone covalent modifications). Enhancers are cell type–specific and mediate risk by specific gene expression control. For example, in one of our projects we used differentiating dopaminergic neurons (Lund human mesencephalic [LUHMES] cells) to probe PD risk enhancers. We matched the differention-specific appearance or disappearance of enhancers with changes in gene expression. We thus identified 22,057 enhancers paired with 6,388 differentially expressed genes by proximity. These enhancers are enriched with 14 transcription factor response elements driving a cluster of genes involved in neurogenesis. We found that differentiated LUHMES cells, but not undifferentiated cells, showed enrichment for PD risk SNPs. Candidate genes for these loci were associated with the processes of synaptic vesicle cycling and transport, which implies that PD-related disruption of these pathways is intrinsic to dopaminergic neurons. We are using gene-editing tools to delve deeply into how they affect genetic predisposition. Understanding of this kind may lead to the identification of preventive strategies against PD.

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JEFFREY H. KORDOWER, Ph.D. Dr. Kordower earned his Ph.D. at City University of New York in 1984. He joined Rush University Medical Center in 1990, where he currently is the Alla V. and Solomon Jesmer Professor of Neurological Sciences and the director of the Rush Research Center for Brain Repair, among other positions. He joined VARI in January 2016 as a Professor and Director's Scholar while continuing his primary appointment at Rush. RESEARCH INTERESTS There is a close collaboration between the Kordower lab and the scientists in the Center for Neurodegenerative Science in trying to understand Parkinson’s disease pathogenesis and to develop novel therapies for the disease. Recently, the lab has been investigating the prion-like transfer of abnormal α-synuclein from cell to cell within the brain. The Kordower lab’s collaborative research program, based at Rush University Medical Center in Chicago, uses insights garnered from this work to design and carry out crucial preclinical studies, a vital step in translating potential therapies into clinical trials for Parkinson’s patients.

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Center for Neurodegenerative Science

VIVIANE LABRIE, Ph.D. Dr. Labrie received her Ph.D. in genetics and neuroscience from the University of Toronto. She was an assistant professor at University of Toronto before joining VARI in early 2016.

RESEARCH INTERESTS

STAFF Emily Glidden, B.S. Bryan Killinger, Ph.D. Peipei Li, Ph.D. Lee Marshall, Ph.D.

Our goal is to gain an in-depth understanding of the primary molecular causes of Alzheimer’s disease and Parkinson’s disease in order to help develop new treatments. Specifically, we study epigenetic involvement in these neurodegenerative illnesses. Epigenetic marks such as methyl or acetyl groups control gene activities without changing the DNA sequence. Such marks are partially stable, that is, they can change in response to environmental signals and over time. This dynamic aspect is highly relevant, because advanced age is the best-known risk factor for both Alzheimer’s and Parkinson’s disease. It takes years before symptoms arise in patients, and after disease onset, the pathological features and symptoms worsen with time. We propose that aberrant epigenetic changes, accumulating with age at key genomic regions, contribute to the etiology of these diseases. We perform genome-wide searches for epigenetic abnormalities in genomic regulatory elements such as enhancers, which affect the complex spatial and temporal expression of genes. Under the influence of regulatory elements, genes can be highly expressed in certain tissues or cell types but weakly or not at all in others. By activating or repressing regulatory elements, epigenetic marks can modify the abundance, timing, and cell-specific patterns of gene expression, which are central to healthy brain function. By applying epigenomic and next generation sequencing–based techniques to human samples, we aim to identify epigenetically misregulated regulatory elements in Alzheimer’s and Parkinson’s disease. We also study the interaction between DNA sequence factors (SNPs) and epigenetic marks to determine whether certain disease-risk variants help coordinate such misregulation. Once we identify disturbed regulatory elements, functional studies will help us understand how they contribute to disease susceptibility. We look for changes in 3D chromatin conformation and in gene transcripts to identify the genes and pathways affected. We also use CRISPR-Cas9 genome editing in cell lines and mice to determine the contribution of epigenetically disrupted regulatory elements to disease pathology and symptoms. Through this research, we can uncover new genomic regions causally involved in Alzheimer’s and Parkinson’s disease.

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JIYAN MA, Ph.D. Dr. Ma earned his Ph.D. in biochemistry and molecular biology from the University of Illinois at Chicago. He was at Ohio State University from 2002 until he joined VARI in November 2013 as a Professor.

RESEARCH INTERESTS

STAFF Romany Abskharon, Ph.D. Katelyn Becker, M.S. Emily Glidden, B.S. Amandine Roux, Ph.D. Juxin Ruan, Ph.D. Fei Wang, Ph.D. Xinhe Wang, Ph.D.

Protein aggregation is a key pathological feature of a large group of late-onset neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. Our overall goals are to uncover the molecular events leading to protein misfolding in the aging central nervous system; to understand the relationship between misfolded protein aggregates and neurodegeneration; and to develop approaches to prevent, halt, or reverse protein aggregation and neurodegeneration in these devastating diseases. We study protein aggregates in prion diseases (transmissible spongiform encephalopathies). These are true infectious diseases that can spread from individual to individual and cause outbreaks. We have established an in vitro system to reconstitute prion infectivity with bacterially expressed prion protein plus defined cofactors. We use this system to dissect the essential components and the structural features of an infectious prion and to uncover the molecular mechanisms responsible for the prion strain and species barrier. Recently, the concept of prions has expanded to Parkinson’s and Alzheimer’s diseases. α-Synuclein has been suggested to spread the disease pathology in a prion-like manner from a sick cell to healthy ones. We want to understand the similarities and differences between prions and amyloidogenic proteins such as α-synuclein. We are investigating cellular factors that affect α-synuclein aggregation and the connections between various α-synuclein aggregated forms, their prion-like spread, and dopaminergic neuron degeneration.

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Center for Neurodegenerative Science

DARREN J. MOORE, Ph.D. Dr. Moore earned a Ph.D. in molecular neuroscience from the University of Cambridge, U.K., in 2001 in the laboratory of Piers Emson. He was at Johns Hopkins University and the Swiss Federal Institute of Technology (EPFL) in Lausanne before joining the VARI faculty as an Associate Professor in early 2014. He was promoted to Professor in 2017. RESEARCH INTERESTS

STAFF Xi Chen, Ph.D. Madalynn Erb, Ph.D. Emily Glidden, B.S. Md Shariful Islam, Ph.D. Jennifer Kordich, M.S. Nate Levine, B.S. An Phu Tran Nguyen, Ph.D.

STUDENTS Lindsey Cunningham, B.S. Allie Weber, B.S. Erin Williams, B.A.

Our laboratory studies the molecular pathogenesis of Parkinson’s disease, with the long-term goal of developing novel, targeted, disease-modifying therapies and neuroprotective strategies. Although most cases of PD are sporadic, 5–10% of cases are inherited, with causative mutations identified in at least 13 genes. We focus on the cell biology and pathophysiology of several proteins that cause inherited PD, including the dominantly inherited LRRK2 (leucine-rich repeat kinase 2, a multidomain protein with GTPase and kinase activity) and VPS35 (vacuolar protein sorting 35 ortholog, a component of the retromer complex), and the recessive proteins parkin (an E3 ubiquitin ligase), synaptojanin-1 (an endosomal lipid phosphatase), and ATP13A2 (a lysosomal P5B-type ATPase). We seek to explain the normal biological function of these proteins in the mammalian brain and the molecular mechanisms through which disease-associated variants produce neuronal dysfunction and eventual neurodegeneration in inherited forms of Parkinson’s. We employ a multidisciplinary approach that combines molecular, cellular, and biochemical techniques in experimental model systems such as human cell lines, primary neuronal cultures, Saccharomyces cerevisiae, nematodes, fruit flies, rodents, and human brain tissue. We have developed several unique rodent models (transgenic, knock-out, knock-in) for mechanistic studies of proteins. Some of our current projects focus on • the contribution of enzymatic activity and protein aggregation to neurodegeneration in novel, adenoviral-based, LRRK2 rodent models of PD; • neuroprotective effects of pharmacological kinase inhibition in LRRK2 rodent models; • genome-wide identification of genetic modifiers of LRRK2 toxicity in S. cerevisiae; • identification of novel GTPase effector proteins and kinase substrates for LRRK2; • the role of ArfGAP1 in mediating LRRK2-induced neurotoxic pathways; • the functional interaction of LRRK2 with other PD-linked proteins (ATP13A2 and synaptojanin-1); and • the development of novel rodent models of VPS35-linked PD and the pathological interactions of VPS35 with α-synuclein and LRRK2.

Leslie Wyman, B.S.

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RECENT CENTER PUBLICATIONS Amos, Christopher I., Joe Dennis, Zhaoming Wang, Jinyoung Byun, Frederick R. Schumacher, Simon A. Gayther, Graham Casey, David J. Hunter, Thomas A. Sellers, Stephen B. Gruber, Alison M. Dunning, . . . , Gerhard A. Coetzee, Dennis J. Hazelett, . . ., and Douglas F. Easton. 2017. The OncoArray Consortium: a network for understanding the genetic architecture of common cancers. Cancer, Epidemiology, Biomarkers & Prevention 26(1): 126–135. Brundin, Patrik, Kuldip D. Dave, and Jeffrey H. Kordower. 2017. Therapeutic approaches to target alpha-synuclein pathology. Experimental Neurology 298 (Pt. B): 225–235. Bryleva, E.Y., S.A. Keaton, J. Grit, Z. Madaj, A. Sauro-Nagendra, L. Smart, S. Halstead, E. Achtyes, and L. Brundin. 2017. The acute-phase mediator serum amyloid A is associated with symptoms of depression and fatigue. Acta Psychiatrica Scandinavica 135(5): 409–418. Espay, Alberto, Patrik Brundin, and Anthony E. Lang. 2017. Precision medicine for disease modification in Parkinson disease. Nature Reviews Neurology 13(2): 119–126. Fernström, Johan, Åsa Westrin, Cécile Grudet, Lil Träskman-Bendz, Lena Brundin, and Daniel Lindqvist. 2017. Six autoantibodies associated with autoimmune encephalitis are not detectable in the cerebrospinal fluid of suicide attempters. PLoS One 12(4): e0176358. Islam, Md. Shariful, and Darren J. Moore. 2017. Mechanisms of LRRK2-dependent neurodegeneration: role of enzymatic activity and protein aggregation. Biochemical Society Transactions 45(1): 163–172. Jakubowski, Jennifer L., and Viviane Labrie. 2017. Epigenetic biomarkers for Parkinson’s disease: from diagnostics to therapeutics. Journal of Parkinson’s Disease 7(1): 1-12. Killinger, Bryan Andrew, and Viviane Labrie. 2017. Vertebrate food products as a potential source of prion-like α-synuclein. npj Parkinson’s Disease 3: 33. Labrie, Viviane, and Patrik Brundin. 2017. Alpha-synuclein to the rescue: immune cell recruitment by alpha-synuclein during gastrointestinal infection. Journal of Innate Immunity 9(5): 437–440. Nguyen, An Phu Tran, Guillaume Daniel, Pamela Valdés, Md Shariful Islam, Bernard L. Schneider, and Darren J. Moore. In press. G2019S LRRK2 enhances the neuronal transmission of tau in the mouse brain. Human Molecular Genetics. Nguyen, An Phu Tran, and Darren J. Moore. 2017. Understanding the GTPase activity of LRRK2: regulation, function, and neurotoxicity. In Leucine-rich Repeat Kinase 2 (LRRK2), Hardy J. Rideout, ed. Advances in Neurobiology series, Vol. 14. Cham, Switzerland: Springer, pp. 71-88. Oh, Edward, Richie Jeremian, Gabriel Oh, Daniel Groot, Miki Susic, KwangHo Lee, Kelly Foy, Peter W. Laird, Arturas Petronis, and Viviane Labrie. 2017. Transcriptional heterogeneity in the lactase gene within cell-type is linked to the epigenome. Scientific Reports 7: 41843. Pierce, Steven, and Gerhard A. Coetzee. 2017. Parkinson's disease-associated genetic variation is linked to quantitative expression of inflammatory genes. PLoS One 12(4): e0175882. Rey, Nolwen L., Sonia George, Jennifer A. Steiner, Zachary Madaj, Kelvin C. Luk, John Q. Trojanowski, Virginia M.-Y. Lee, and Patrik Brundin. In press. Spread of aggregates after olfactory bulb injection of α-synuclein fibrils is associated with early neuronal loss and is reduced long term. Acta Neuropathologica.

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Center for Neurodegenerative Science RECENT CENTER PUBLICATIONS (cont.) Tyson, Trevor, Megan Senchuk, Jason F. Cooper, Sonia George, Jeremy M. Van Raamsdonk, and Patrik Brundin. 2017. Novel animal model defines genetic contributions for neuron-to-neuron transfer of α-synuclein. Scientific Reports 7: 7506. Ventorp, Filip, Cecillie Bay-Richter, Analise Sauro Nagendra, Shorena Janelidze, Viktor Sjödahl Matsson, Jack Lipton, Ulrika Nordström, Åsa Westrin, Patrik Brundin, and Lena Brundin. 2017. Exendin-4 treatment improves LPS-induced depressive-like behavior without affecting pro-inflammatory cytokines. Journal of Parkinson’s Disease 7(2): 263–273. Wang, Fei, Xinhe Wang, Christina D. Orrú, Bradley R. Groveman, Krystyna Surewicz, Romany Abskharon, Morikazu Imamura, Takashi Yokoyama, Yong-Sun Kim, Kayla J. Vander Stel, Kumar Sinniah, Suzette A. Priola, Witold K. Surewicz, Byron Caughey, and Jiyan Ma. 2017. Self-propagating, protease-resistant, recombinant prion protein conformers with or without in vivo pathogenicity. PLoS Pathogens 13(7): e1006491. Williams, Erin T., Xi Chen, and Darren J. Moore. 2017. VPS35, the retromer complex and Parkinson’s disease. Journal of Parkinson’s Disease 7(2): 219–233. Zamponi, Emiliano, Fiamma Buratti, Gabriel Cataldi, Hector Hugo Caicedo, Yuyu Song, Lisa M. Jungbauer, Mary J. LaDu, Mariano Bisbal, Alfredo Lorenzo, Jiyan Ma, Pablo R. Helguera, Gerardo A. Morfini, Scott T. Brady, and Gustavo F. Pigino. 2017. Prion protein inhibits fast axonal transport through a mechanism involving casein kinase 2. PLoS One 12(12): E0188340.

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Differentiation of LUHMES cells as a model of human substantia nigra neurons. These human neural precursor cells were immortalized using a Myc oncogene in a Tet-off system; adding tetracycline suppresses the expression of the Myc gene and allows differentiation to occur. Differential interference contrast (DIC) micrographs (100X) of A) undifferentiated LUHMES cells and B) LUHMES cells after 6 days of differentiation. Images by Trevor Tyson of the Coetzee laboratory. VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 47


Core Technologies and Services Van Andel Research Institute’s Core Technologies and Services offer a comprehensive range of advanced technologies and expertise to support and enhance the research done at the Institute and with collaborating organizations.

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Staining of mouse bone to visualize bone marrow (red cells), solid bone with embedded osteocytes (tan areas), and regions of actively growing new bone (blue-green). Image by Alexis Bergsma.


Genomics Core

MARIE ADAMS, M.S. Ms. Adams earned an M.S. in genetics from Iowa State University and is an expert in the latest next-generation sequencing techniques. She joined VARI in September 2016 from the University of Wisconsin Biotechnology Center, where she managed the next-generation sequencing core.

SERVICES The Genomics Core provides a comprehensive catalog of sequencing, genotyping, and cytogenetic services to support research into the genomic, transcriptomic, and epigenomic bases of diseases such as cancer and neurodegenerative disorders. Core staff collaborate with over 45 VARI and external investigators to design and implement robust protocols and experimental design.

STAFF Julie Koeman, B.S., C.G.(ASCP)CM Lori Moon, E.M.B.A. Mary Rhodes, B.S.

STUDENT Sarah Harrie

Sequencing services offered include whole-genome, exome, and targeted DNA sequencing; mRNA expression, total RNA transcriptome, translatome, and targeted RNA sequencing; and ChIP-seq, methyl-seq, whole-genome bisulfite sequencing, and targeted bisulfite sequencing, all using Illumina sequencing platforms. Additionally, single-cell and long-read sequencing are facilitated through the 10X Genomics Chromium system. We constantly evaluate new assays to provide the most up-to-date service in this evolving field. High-throughput genotyping services are performed using the Illumina iScan system and include the MethylationEPIC Array, Omni-series genome and exome arrays, Neuro Consortium array, and QC array. Other arrays are easily accommodated on request. We are also available for qPCR and SNP assays. Cytogenetic capabilities include FISH probe creation, validation, and analysis; chromosome breakage studies; transgene localization; and trisomy 8 and 11 mouse embryonic stem cell screens.

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Bioinformatics and Biostatistics Core

MEGAN BOWMAN, Ph.D. Dr. Bowman earned her Ph.D. from the University of Wisconsin – Madison. She completed postdoctoral research in genomics and bioinformatics with the United States Department of Agriculture and Michigan State University prior to joining VARI in 2016.

SERVICES Established in April 2013, the Bioinformatics and Biostatistics Core serves the analytical needs of VARI by providing high-quality computational and statistical support to the research laboratories. The broader mission of the BBC is to strengthen and advance bioinformatics and biostatistics at VARI through collaboration, education, and methods development.

STAFF Benjamin Johnson, Ph.D. Zachary Madaj, M.S. Lori Moon, E.M.B.A. * Mary E. Winn, Ph.D. Emily Wolfrum, M.P.H.

The BBC provides statistical consulting and experimental design, including sample size determination and randomization procedures, and we analyze a wide variety of data related to next-generation sequencing, such as genomic variant detection and annotation, differential expression, DNA copy number determination, and differential methylation analyses. We offer expertise in systems-level analysis, including gene-set and network-based analyses, time-series data, tumor growth, drug response, and other small or large data sets using appropriate statistical and computational methods. We also assist in the preparation of research grants, manuscripts, and data deposition. The Core focuses on reproducibility and rigor via robust statistical design, analysis, and the maintenance of version-controlled source code. We support the greater educational mission of the Institute, helping students and staff develop an analytic approach and skills in experimental design through seminars, lectures, and workshops.

* Formerly manager of the BBC, now Program Manager in the Office of the Cores.

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Vivarium and Transgenics Core

BRYN EAGLESON, M.S., LATG Ms. Eagleson earned an M.S. degree in laboratory animal science from Drexel University’s College of Medicine. She worked for many years at the National Cancer Institute’s Frederick Cancer Research and Development Center in Maryland before joining VARI as the Director of Vivarium and Transgenics in 1999. SERVICES The goal of the VARI Vivarium and Transgenics Core is to develop, provide, and maintain high-quality mouse modeling services. The vivarium is a state-of-the-art facility that includes a high-level containment barrier. Van Andel Research Institute is an AAALAC-accredited institution, most recently reaccredited in November 2016. All procedures are conducted according to the Guide for the Care and Use of Laboratory Animals. The staff provides rederivation, surgery, dissection, necropsy, breeding, weaning, tail biopsies, sperm and embryo cryopreservation, animal data management, project management, and health-status monitoring. Transgenic mouse models are produced on request for project-specific needs. The creation of gene-targeted mice using the CRISPR/Cas9 system has been implemented. We also provide therapeutic testing and preclinical model development services. Projects include pharmacological testing, target validation testing, patient-derived xenograft (PDX) development, orthotopic engraftment model development, and subcutaneous xenograft/allograft model development. The Small-Animal Imaging Facility provides preclinical imaging technologies that offer anatomic and functional information to biomedical investigators. Currently available technologies include high-resolution microCT, micro-ultrasound, and optical imaging.

STAFF Megan Briggs, B.S.

Sara Greenwald, B.S.

Mathew Rackham

Brandon Bonnema, B.S.

Audra Guikema, B.S., LVT

Lisa Ramsey, A.S., LVT

Stephen Bowman, M.S.

Tristan Kempston, B.S.

Adam Rapp, B.S.

Charles Bradfield, B.S.

Tina Meringa, A.A.

Yanli Su, A.M.A.T.

Rita Burdette

David Monsma, Ph.D.

Aurora Thoms, A.S.

Thomas Dingman, B.S.

Lori Moon, E.M.B.A.

Collin Tidd, A.S.

Nicholas Getz, B.S.

Malista Powers, A.S., LVT

William Weaver, B.S.

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Confocal Microscopy and Quantitative Imaging Core

CORINNE ESQUIBEL, Ph.D. Dr. Esquibel has a B.S. in biology from Truman State University and a Ph.D. in molecular and cellular pharmacology from the University of Wisconsin–Madison. She joined Van Andel Research Institute as the Core manager in 2017.

SERVICES Established in October 2013, the Core provides optical imaging services for Van Andel Research Institute and collaborating institutions. We focus on comprehensive training of users for every aspect of imaging: experimental design and optimization, data acquisition, and image analysis. This helps users of all experience levels to perform quantitative research at or exceeding the professional standards of their field. To do this, we maintain multiple instruments with a range of imaging capabilities.

STAFF Kristin Feenstra, B.S. Lori Moon, E.M.B.A.

A Nikon A1plus laser scanning confocal is an essential instrument within the Core, designed to generate high-resolution images in multiple dimensions. It is equipped for imaging in both galvanometric and resonant scanning modes with four solid state lasers, four high-sensitivity detectors, and a multi-anode spectral detector. The confocal can achieve optical sectioning of cells and tissue and can image live samples over time. The computer-coded stage allows for imaging large areas of the sample. The PerkinElmer Vectra 3.0 Automated Quantitative Pathology Imaging system is capable of imaging up to 200 slides per session, using a sophisticated multispectral camera to mathematically unmix up to seven fluorophores in each slide. Trainable algorithms in the PerkinElmer inForm software allow for automated segmentation and quantitative phenotyping of slides. Image analysis is supported not only through consultation and training of users, but also through the availability of a powerful Silicon Mechanics PC workstation that contains a suite of commercial and open-source image analysis programs. Analysis options include 3D-5D visualization (FIJI, Nikon Elements, Imaris), deconvolution (Huygens Professional), neuron tracing (Imaris), segmentation (Imaris, MATLAB), machine learning (CellProfiler and CPAnalyst), and figure preparation (FIJI/Image J, Illustrator, Photoshop). When out-of-the-box solutions are not available, additional sophisticated mathematical analysis can be written for case-specific applications (MATLAB).

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Pathology and Biorepository Core

SCOTT D. JEWELL, Ph.D. Dr. Jewell earned his Ph.D. degree from The Ohio State University. He joined VARI in 2010 as a Professor, Director of the Program for Technologies and Cores, and Director of the Pathology and Biorepository Core. SERVICES

STAFF Bree Berghuis, B.S., HTL(ASCP), QIHC Alex Blanski, B.S. Melissa Dehollander, M.B.A., B.S. Brianne Docter, M.S. Kristin Feenstra, B.S. Phil Harbach, M.S. Meghan Hodges, B.S. Galen Hostetter, M.D. Eric Hudson, B.S. Carrie Joynt, B.S., HT Rob Montroy, B.S. Lori Moon, E.M.B.A. Chelsea Peterson, B.S. Daniel Rohrer, B.S., M.B.A. Lisa Turner, B.S., HT, QIHC(ASCP)

The Pathology and Biorepository Core integrates anatomic pathology expertise with biorepository and biospecimen science in order to assist in VARI’s research. We build upon historical strengths in standard histology, microscopy, and biobanking, and we apply best practices in biospecimen science. The pathology discipline provides complementary emphasis on high-quality biospecimens and interpretable results with which to validate experimental models and extend them to clinical samples, thereby advancing our common translational mission. The VARI Biorepository has been accredited by the College of American Pathologists (CAP) since 2012. Dr. Jewell serves as a committee member for the CAP Biorepository Accreditation Program. Dr. Jewell, with his experience in clinical trials and biobanking, and Dr. Hostetter, who is board-certified in anatomic pathology, are currently studying the effects of preanalytical variables in tissue collection and transport on the integrity of downstream analytes. The Core provides assessment of tumor suppressors and immunomodulators in tumor tissues and the application of genomic and epigenomic assays for biospecimens. The VARI biorepository is nationally and internationally recognized, serving as the NCI Comprehensive Biospecimen Resource for the Genotype-Tissue Expression Program (GTEX). In 2015, it was designated as the Biorepository Core Resource for the NCI Clinical Proteomic and Tumor Analysis Consortium (CPTAC) and as the biorepository for the Tuberous Sclerosis Alliance. In addition, we are moving into our seventh year of providing biorepository services for the Multiple Myeloma Research Foundation’s CoMMpass Study. The biorepository is serving the VARI-SU2C consortium for epigenetics clinical trials biobanking, collaborating with Drs. Jones and Baylin. Pathology Core services • Histology and diagnostic tissue services, including morphology, immunohistochemistry, in situ hybridization, and multiplex fluorescent IHC assays • Pathology review and annotation of clinical samples from VARI’s prospective and retrospective tissue collections • Design and construction of tissue microarrays • Digital imaging and spectral microscopy coupled with image analysis tools • Cell fractionation and biospecimen processing • Laser capture microdissection Biorepository Core services • Biospecimen kit construction, shipping, and tracking • Clinical trials biobanking coordination • Quality management program

Dana Valley, B.A., ASQ CMQ/OE, CSSGB Anthony Watkins, A.S. 54 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


Flow Cytometry Core

RACHAEL SHERIDAN, Ph.D. Rachael Sheridan earned her Ph.D. in biochemistry from the University of Wisconsin–Madison and also holds a professional cytometry certification, SCYM(ASCP). Prior to joining Van Andel Research Institute in October 2016, she was an instrumentation specialist in the University of Wisconsin Comprehensive Cancer Center Flow Cytometry Laboratory. SERVICES

STAFF Lori Moon, E.M.B.A.

The Core provides comprehensive flow cytometry analysis and sorting services in support of VARI research. Additional services include assistance with protocol development and training in data analysis. Flow cytometry services are provided using a Beckman Coulter MoFlo Astrios and Beckman Coulter CytoFLEX S. Available hematology equipment includes a VetScan instrument, a VetScan HMII, and a Shandon Cytospin 3.

Kellie Sisson, B.S.

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Cryo-Electron Microscopy Core

GONGPU ZHAO, Ph.D. Dr. Zhao earned his Ph.D. in physics at the University of North Carolina at Chapel Hill. He joined Van Andel Research Institute in 2016 as manager of the Cryo-EM Core.

SERVICES

Project 1. During replication initiation, the core component of the helicase—the Mcm2-7 hexamer—is loaded on the origin DNA as a double hexamer. Determining how the origin DNA interacts with the axial channel could provide key insights into Mcm2-7 function and regulation. We worked with Huilin Li’s lab to solve a 3.9-Å cryo-EM structure of the Mcm2-7 double hexamer on DNA, which suggests a laggingstrand DNA extrusion model.

STAFF Xing Meng, Ph.D. Lori Moon, E.M.B.A.

Project 2. G protein–coupled receptor (GPCR) kinases (GRKs) play key roles in the desensitization of GPCR signaling. Dysregulation of this process has been associated with a broad spectrum of diseases. The overall goal of this project is to use rhodopsin– GRK1 as a model in order to gain structural insight into the GPCR/GRK complex and its mechanism of GRK-mediated GPCR signaling. We have worked with the Xu lab to reveal the overall architecture of the rhodopsin–GRK1 complex via negative-stain EM. Our plans are to use cryo-EM to solve the structure of the complex at high resolution. Project 3. G protein–coupled receptors are a superfamily of integral membrane proteins that turn extracellular signals into intracellular responses. The selective coupling of GPCRs to specific G proteins is crucial for activating the appropriate physiological response. With the help of state-of-the-art electron microscopy at VARI, the Core has worked with the Xu lab to determine a 4-Å structure of the rhodopsin–Gi complex, giving the first insights into Gi-mediated GPCR activation. This research also established a general method for studying GPCR structures in an active confirmation and will provide guidance for new-generation, biased drug designs that can specifically trigger beneficial effects and avoid side effects. This work has significant influence on both basic biological research and translational studies.

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RECENT CORE PUBLICATIONS Barnett, Daniel, Ying Liu, Katie Partyka, Ying Huang, Huiyuan Tang, Galen Hostetter, Randall E. Brand, Aatur D. Singhi, Richard R. Drake, and Brian B. Haab. 2017. The CA19-9 and sialyl-TRA antigens define separate subpopulations of pancreatic cancer cells. Scientific Reports 7: 4020. Berger, Penny L., Mary E. Winn, and Cindy K. Miranti. 2017. Miz1, a novel target of ING4, can drive prostate luminal epithelial cell differentiation. Prostate 77(1): 45–59. Dues, Dylan J., Claire E. Schaar, Benjamin K. Johnson, Megan J. Bowman, Mary E. Winn, Megan M. Senchuk, and Jeremy M. Van Raamsdonk. 2017. Uncoupling of oxidative stress resistance and lifespan in long-lived isp-1 mitochondrial mutants in Caenorhabditis elegans. Free Radical Biology and Medicine 108: 362–373. He, Yuanzheng, Xiang Gao, Devrishi Goswami, Li Hou, Kuntal Pal, Yanting Yin, Gongpu Zhao, Oliver P. Ernst, Patrick Griffin, Karsten Melcher, and H. Eric Xu. 2017. Molecular assembly of rhodopsin with G protein–coupled receptor kinases. Cell Research 27(6): 728–747. Manojlovic, Zarko, Austin Christofferson, Winnie S. Liang, Jessica Aldrich, Megan Washington, Shukmei Wong, Daniel Rohrer, Scott Jewell, Rick A. Kittles, Mary Derome, Daniel Auclair, David Wesley Craig, Jonathan Keats, and John D. Carpten. 2017. Comprehensive molecular profiling of 718 multiple myelomas reveals significant differences in mutation frequencies between African and European descent cases. PLoS Genetics 13(11): e1007087. Martin, Katie R., Wanding Zhou, Megan J. Bowman, Juliann Shih, Kit Sing Au, Kristin E. Dittenhafer-Reed, Kellie A. Sisson, Julie Koeman, Daniel J. Weisenberger, Sandra L. Cottingham, Steven T. DeRoos, Orrin Devinsky, Mary E. Winn, Andrew D. Cherniack, Hui Shen, Hope Northrup, Darcy A. Krueger, and Jeffrey P. MacKeigan. 2017. The genomic landscape of tuberous sclerosis complex. Nature Communications 8: 15816. Noguchi, Yasunori, Auanning Yuan, Lin Bai, Sarah Schneider, Gongpu Zhao, Bruce Stillman, Christian Speck, and Huilin Li. 2017. Cryo-EM structure of Mcm2-7 double hexamer on DNA suggests a lagging-strand DNA extrusion model. Proceedings of the National Academy of Sciences U.S.A. 114(45): E9529–E9538. Westrick, Randal J., Kärt Tomberg, Amy E. Siebert, Guojing Zhu, Mary E. Winn, Sarah L. Dobies, Sara L. Manning, Marisa A. Brake, Audrey C. Cleuren, Linzi M. Hobbs, Lena M. Mishack, Alexander J. Johnston, Emilee Kotnik, David R. Siemieniak, Jishu Xu, Jun Z. Li, Thomas L. Sauders, and David Ginsburg. 2017. Sensitized mutagenesis screen in Factor V Leiden mice identifies thrombosis suppressor loci. Proceedings of the National Academy of Sciences U.S.A. 114(36): 9659–9664.

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Awards for Scientific Achievement

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Jay Van Andel Award for Outstanding Achievement in Parkinson’s Disease Research The Jay Van Andel Award for Outstanding Achievement in Parkinson’s Disease Research was established in 2012 in memory of Van Andel Institute founder Jay Van Andel, who battled Parkinson’s disease for a decade before his death in 2004. The award is given to scientists who have made outstanding contributions to Parkinson’s disease research and who have positively impacted human health.

2017 RECIPIENT J. William Langston, M.D.

Dr. J. William Langston is the Scientific Director, Chief Scientific Officer, and Founder of the Parkinson’s Institute in Sunnyvale, California. Dr. Langston gained international recognition in 1980s for the discovery of the link between a tainted synthetic heroin and parkinsonism. The discovery of the biologic effects of that compound led to a renaissance of basic and clinical research into Parkinson’s disease. Dr. Langston’s current research includes the study of mechanisms of neuronal degeneration, the etiology of Parkinson’s disease, the development of new strategies to slow or halt disease progression, and ways to identify the disease in its earliest “pre-motor” stages.

PRIOR RECIPIENTS 2016—Stanley Fahn, M.D. 2015—Robert Nussbaum, M.D., and Maria Grazia Spillantini, Ph.D., FMedSci, FRS 2014—Andrew John Lees, M.D., FRCP, FMedSci 2013—Alim-Louis Benabid, M.D., Ph.D. 2012—Andrew Singleton, Ph.D.

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Awards for Scientific Achievement Han-Mo Koo Memorial Award Dr. Han-Mo Koo joined Van Andel Research Institute in 1999 as one of its founding investigators, focusing on the identification of genetic targets for anti-cancer drug development against melanoma and pancreatic cancer. In May 2004, Dr. Koo passed away following a six-month battle with cancer. To honor his memory and scientific contributions, the Han-Mo Koo Memorial Award was established in 2010. Awardees are selected based on scientific achievements, peer recognition, and that their contributions to human health and research align with the scientific legacy of Han-Mo Koo.

2017 RECIPIENT James P. Allison, Ph.D.

Dr. Allison is a professor and the chair of the Department of Immunology at the University of Texas MD Anderson Cancer Center. His fundamental discoveries include the definition of the structure of the T cell antigen receptor and the demonstration that CTLA-4 is an inhibitory checkpoint that inhibits activated T cells. He proposed that immune checkpoint blockade might be a powerful strategy against many cancer types and conducted preclinical experiments showing its potential. His development of the concept of immune checkpoint blockade has transformed cancer therapy and saved thousands of lives.

PRIOR RECIPIENTS 2016—Matthew L. Meyerson, M.D., Ph.D. 2015—Eric Lander, Ph.D. 2013—Frank P. McCormick, Ph.D., F.R.S. 2012—Phillip A. Sharp, Ph.D.

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Tom Isaacs Award The Tom Isaacs Award is given jointly by Van Andel Research Institute and The Cure Parkinson’s Trust. The award was established in memory of Trust co-founder and champion of the Parkinson’s community Tom Isaacs, who passed away in May 2017. This award recognizes his vision that a cure for Parkinson’s can and will be found, but that greater value will be gained from working with people who have Parkinson’s in this quest. In that spirit, recipients of the award must have had a significant impact on the lives of people with Parkinson’s or have involved people with Parkinson’s in a participatory way in their work.

Inaugural Recipient Thomas Foltynie, B.Sc., MBBS, MRCP, Ph.D.

Dr. Foltynie is a consultant neurologist at University College London. He trained in medicine at UCL, and he undertook his Ph.D. in Cambridge where he studied the heterogeneity of Parkinson's disease. He is the senior author of a groundbreaking study that shows the diabetes drug exenatide may interfere with Parkinson’s progression, something no current medication can do.

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Educational and Training Programs

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Van Andel Institute Graduate School STEVEN J. TRIEZENBERG, Ph.D. President and Dean Van Andel Institute Graduate School develops future leaders in biomedical research through an intense, problem-focused Ph.D. degree in cellular, molecular, and genetic biology. VAIGS has created an innovative curriculum that guides doctoral students to think and act like research leaders through problem-based learning. In doing so, students develop key skills of finding and evaluating scientific knowledge and of designing experimental approaches to newly arising questions. We also foster the development of leadership skills and professional behavior, and we seek to integrate graduate students into the professional networks and culture of science. VAIGS currently has 27 students. The most recent cohort of seven includes two international students. In the past year, five students defended their dissertations and completed their Ph.D. degrees. VAIGS alumni have gone on to postdoctoral and professional positions at leading biomedical research institutions and companies throughout the United States. VAIGS is accredited by the Higher Learning Commission (www.hlcommission.org; 1-800-621-7440).

Julie Davis Turner, Ph.D., Associate Dean Kathy Bentley, B.S. Patty Farrell-Cole, Ph.D. Michelle Love, M.A. Christy Mayo, M.A. Susanne Miller-Schachinger, B.B.A. Nancy Schaperkotter, A.M., LCSW, CEAP

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VAIGS Graduate Students The following students were enrolled in VAIGS in 2017. Menusha Arumugam

Guillermo Flores

Abbey Solitro

University of Michigan–Flint First-year student

Hope College, Holland, Michigan Grohar lab

Ferris State University, Big Rapids, Michigan MacKeigan lab

Aditi Bagchi, M.D.

Jamie Grit

Kasturba Medical College, Mangalore, India MacKeigan/Jewell labs

Hope College, Holland, Michigan Steensma lab

Nicole Thellman, D.V.M. Louisiana State University, Baton Rouge Triezenberg lab (Ph.D., 2017)

Emily Haley Alexis Bergsma University of Michigan, Ann Arbor Miranti/Williams labs

University of Alabama at Birmingham First-year student

Bailey Tibben University of Arizona, Tucson First-year student

Candace King Maggie Chassé Colorado State University, Fort Collins Grohar lab

Tougaloo College, Mississippi Steensma lab

Katie Krajnak Wooyoung Choi Tsinghua University, Beijing, China Lü lab

Purdue University Calumet, Hammond, Indiana Williams lab

Jason Cooper

Emily Machiela

University of Texas at Austin Van Raamsdonk lab (Ph.D., 2017)

Grand Valley State University, Allendale, Michigan Van Raamsdonk lab

Eric Cordeiro-Spinetti Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro, Brazil First-year student

Lauren McGee

Lindsey Cunningham

Kevin Maupin

Northern Arizona University, Flagstaff Moore lab

Grand Valley State University, Allendale, Michigan Williams lab (Ph.D., 2017)

Hanover College, Indiana First-year student

Zachary DeBruine Hope College, Holland, Michigan Melcher lab

Nathan Merrill University of Michigan, Ann Arbor MacKeigan lab (Ph.D., 2107)

Parker de Waal Kalamazoo College, Michigan Xu lab

Eric Nollett

Minge Du

Calvin College, Grand Rapids, Michigan Miranti lab (Ph.D., 2017)

Ludong University, Yantai, China H. Li lab

Jordan Prahl

Jamie Endicott Michigan State University, East Lansing First-year student

Grand Valley State University, Allendale, Michigan First-year student

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Nicole Vander Schaaf Indiana Wesleyan University, Marion, Indiana Laird lab

Robert Vaughan Grand Valley State University, Allendale, Michigan Rothbart lab

Allie Weber Michigan State University, East Lansing Moore lab

Erin Williams Anderson University, Indiana Moore lab

Leslie Wyman Grand Valley State University, Allendale, Michigan Moore lab


Summer Internship Program The VARI summer internships are designed to provide undergraduate students to opportunities be mentored by professionals in biomedical research, to use state-of-the-art scientific equipment, and to learn valuable interpersonal, workplace, and presentation skills. The goal of this program is to expose aspiring researchers and clinicians to exciting advances in biomedical science that will help them define their career paths. Internships last 10 weeks, with two cohorts per summer. Van Andel Education Institute partners with the United Negro College Fund to match students interested in biomedical research careers with summer internships at VARI. Since 2001, hundreds of VARI internships have been generously supported through the Frederik and Lena Meijer Summer Internship Program. Meijer interns are noted in the listing below by an asterisk (*). Calvin College, Grand Rapids, Michigan *Brianna Busscher (Szabo) *Rachel House (Wu) *Lucas VanLaar (Melcher) *Mark Wolf (MacKeigan)

Grand Valley State University, Allendale, Michigan

Michigan Technological University, Houghton

Sudakshina Chakrabarty (Sempere) Jessica DeWyse (Finance) Johnathan Hall (Haab) Delaney McCarrey (Purple Community)

*Carly Joseph (Van Raamsdonk)

Boston College, Massachusetts Catherine VanderWoude (Business Development)

Central Michigan University, Mt. Pleasant *Matthew Fini (Li) Cheyann Oliver (Purple Community)

Hillsdale College, Michigan *Christine Ausherman (Rothbart) *Madison Frame (Triezenberg) *Taylor Zimmer (Ma)

*Sean Zhou Morash (Xu)

Jessica (Jess) Guillaume (MacKeigan) Philip Versluis (Rothbart)

University of Chicago, Illinois

Indiana Wesleyan University, Marion *Hannah VanDusen (Haab)

Lowell High School, Michigan

Innovation High School, Grand Rapids, Michigan

Michelle Zhang (Moore)

Angelica Velasquez (Jovinge)

Drew Eder (Facilities) Sarah Harrie (Genomics) *Courtney Wernette (Grohar) Maria Winquest (VAIGS)

Calvin Li (Information Technology)

University of Alabama - Huntsville

Ricardo Burke (Haab)

Ferris State University, Big Rapids, Michigan

Stony Brook University, New York

Hope College, Holland, Michigan

Claflin University, Orangeburg, South Carolina

Corah Kaufman (Van Raamsdonk)

Rosalind Franklin University, Chicago, Illinois Marie Mustert (Jewell)

Michigan State University, East Lansing *Joyce Goodluck (Sempere) *Brandt Gruizinga (Labrie) *Zachary Jansen (Laird) *Yamini Vepa (Labrie) *Yuk Kei Wan (Yang)

University of Michigan, Ann Arbor Schyler Bennett (Haab) Adrienne (Denise) Bilbao (Yang) *Kate Blumenstein (Li) *Nolan Klunder (Jovinge) *Adam Racette (Williams) *Nolan Redetzke (Williams)

Western Michigan University, Kalamazoo *Megan Callaghan (Steensma)

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Postdoctoral Fellowship Program Van Andel Research Institute provides postdoctoral training opportunities to advance the knowledge and research experience of new Ph.D.s while at the same time supporting our research endeavors. Each fellow is assigned to a scientific investigator who oversees the progress and direction of research. Fellows who worked in VARI laboratories in 2017 are listed here. Walid Abi Habib

Yihe Huang

Université Pierre et Marie Curie, Paris, France Laird lab

Peking University, China Lü lab

Hongbo Liu Harbin Institute of Technology, China Shen lab

Zhijun Huang Romany Abskharon Vrije Universitiet Brussel, Belgium Ma lab

Harbin Institute of Technology, China Pfeifer lab

Md Shariful Islam Brittany Carpenter

Lee Marshall Garvan Institute of Medical Research, Sydney, Australia Labrie lab

University of Kentucky, Lexington Jones lab

Max Planck Institute for Heart and Lung Research, Bad Neuheim, Germany Moore lab

Xi Chen

Manpreet Kalkat

Sun Yat-sen University Cancer Center, Guangzhou, China X. Li lab

University of Liverpool, United Kingdom Moore lab

University of Toronto, Canada Laird lab

Megan Michalski

Evan Cornett

Bryan Killinger

University of Michigan, Ann Arbor Williams lab

University of Central Florida, Orlando Rothbart lab

Wayne State University, Detroit, Michigan Labrie lab

Madalynn Erb Oregon Health and Science University, Portland Moore lab

Xiangqi Meng

John Murdoch Yale University, New Haven, Connecticut Labrie lab

Alison Lanctot Northwestern University, Evanston, Illinois Rothbart lab

An Phu Tran Nguyen

Hua Li

Hitoshi Otani

Guangzhou Institutes of Biomedicine and Health, China H. Li lab

Tokyo Medical and Dental University, Japan Jones lab

Jianshuang Li

Kuntal Pal

Wuhan University, China Yang lab

National University of Singapore, Singapore Xu lab

University of Tübingen, Germany Moore lab

Chen Fan Institute for Nutritional Sciences, Shanghai, China Du lab

Huihui Fan Harbin Medical University, China Shen lab

Xiang Feng Baylor College of Medicine, Waco, Texas H. Li lab

Sourik Ganguly

Peipei Li Chungbuk National University, Cheongju, South Korea Labrie lab

University of Kentucky, Lexington X. Li lab

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Wouter Peelaerts Katholieke Universiteit Leuve, Belgium P. Brundin lab


Steven Pierce

Tinghai Xu

Columbia University, New York, New York Coetzee lab

Shanghai Institute of Materia Medica, China Jones lab

Emmanuel Quansah

Yanting Yin

De Montfort University, Leicester, United Kingdom P. Brundin lab

Shanghai Institute of Materia Medica, China H. Li lab

Nolwen Rey

Tie-bo Zeng

University of Lyon, France P. Brundin lab

Harbin Institute of Technology, China SzabĂł lab

Amandine Roux

Wanding Zhou

University Pierre and Marie Curie, Paris, France Ma lab

Rice University, Houston, Texas Shen lab

Juxin Ruan Shanghai Institute for Biological Sciences, China Ma lab

Rajamani Keerthi Thirtamara Ohio State University, Columbus L. Brundin lab

Rochelle Tiedemann Georgia Regents University, Augusta Rothbart lab

Elizabeth Tovar Wayne State University, Detroit, Michigan Steensma lab

Zhi-Qiang Wang Laval University, Quebec City, Canada Pfeifer lab

Laura Winkler University of Wisconsin, Madison Jovinge lab

Paige Winkler Michigan State University, East Lansing LĂź lab

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Organization

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Primary cortical neurons of a rat. Staining is for Map2 (red), a protein found in neural dendrites, and sortilin (green), a neural receptor typically found in endosomes. DAPI stains the cell nuclei blue. The large cell to the upper left that has no dendrites is likely an astrocyte. Image by Erin Williams of the Moore laboratory. Copyright MBF Bioscience; used with permission.


Management VARI Board of Trustees David L. Van Andel, Chairman Tom R. DeMeester, M.D. James B. Fahner, M.D. Michelle M. Le Beau, Ph.D. George F. Vande Woude, Ph.D. Ralph Weichselbaum, M.D. Max S. Wicha, M.D.

DAVID L. VAN ANDEL Chairman and CEO Van Andel Institute

Board of Scientific Advisors The Board of Scientific Advisors advises the CEO and the Board of Trustees, providing recommendations and suggestions regarding the overall goals and scientific direction of VARI. The members are Michael S. Brown, M.D., Chairman Richard Axel, M.D. Joseph L. Goldstein, M.D. Tony Hunter, Ph.D. Phillip A. Sharp, Ph.D.

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PETER A. JONES, Ph.D., D.Sc.

PATRIK BRUNDIN, M.D., Ph.D.

Chief Scientific Officer

Associate Director

Office of the Chief Scientific Officer

External Scientific Advisory Board

Aubrie Bruinsma, B.A., Events and Meetings Coordinator

Tony Hunter, Ph.D.

Ryan Burgos, B.S., Clinical Research Analyst

Marie-Franรงoise Chesselet, M.D., Ph.D.

David Cabrera, M.S., Chief of Staff

Sharon Y.R. Dent, Ph.D.

Kayla Habermehl, B.A., B.S., Science Communications Specialist

Howard J. Federoff, M.D., Ph.D.

Jennifer Holtrop, B.S., Research Operations Coordinator

Theresa Ann Guise, M.D.

Chelsea John, B.S., Research Department Administrator

Kristian Helin, Ph.D.

David Nadziejka, M.S., E.L.S., Science Editor

Rudolf Jaenisch, Ph.D.

Aaron Patrick, B.S., Research Operations Supervisor

Max S. Wicha, M.D.

Bonnie Petersen, Executive Assistant Beth Resau, B.A., M.B.A., Scientific Events and Meetings Supervisor Daniel Rogers, B.S., CCRC, CIP, Clinical Research Manager Veronique Schulz, B.S., Research Operations Coordinator Stephanie Stewart, B.S., Senior Administrative Assistant

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Administrative Departments The departments listed below provide administrative support to both the Van Andel Research Institute and the Van Andel Education Institute. Executive

Facilities

Finance

David Van Andel, Chairman and CEO Christy Goss, Senior Executive Assistant

Samuel Pinto, Director Beau Burnett, Chef Jeff Cooling, Manager Jeff Wilbourn, Manager Tim Bachinski Maria Becerra-Mota Dedefo Bedaso Nuritu Bedaso Rob Cairns Hebib Chakeri Jessica Copley Deb Dale Jason Dawes Lupe Delgado Ken DeYoung Art Dorsey Kristi Gentry Tammy Humphreys Hodilia Jimenez Matthew Jump Todd Katerburg Tracy Lewis Lewis Lipsey Micah McNeil Dave Marvin Kristina Mason Jeannette Mendez Amanda Miller Joan Morrison Jamison Pate Karen Pittman Amber Ritsema Tyler Rosel-Pieper Kristina Schaner Amber TenBrink Dalu Tibesso Rich Ulrich Pete Van Conant

Timothy Myers, Vice President and Chief Financial Officer Katie Helder, Controller Rich Herrick, VARI Finance Director Kathryn Bishop Mark Denhof Sandi Dulmes Nate Gras Rami Ibrahim Tess Kittridge Angie Lawrence Leah Postema Susan Raymond Cindy Turner

Operations Jana Hall, Ph.D., M.B.A., Chief Operations Officer Ann Schoen, Senior Executive Assistant

Business Development and Extramural Administration Thomas DeKoning, Director Robert Garces, Ph.D. Andrea Poma, M.P.A. Christine Timbol, B.A., M.A.

Compliance Gwenn Oki, Director Jessica Austin Angie Jason Laura Kersjies Dave Lutkenhoff

Communications and Marketing Beth Hinshaw Hall, Director Frank Brenner Alex Edema Rachel Harden Caitlin Smith

Development Brett Holleman, Chief Development Officer Patrick Placzkowski, Director Hannah Acosta Betty Alexander Maddie Eaton Allyson Huttenga Ashley Owen Teresa Reid Sarah Rollman Lawrence Rush Angie Stumpo

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Human Resources Linda Zarzecki, Vice President Ryan DeCaire Deirdre Griffin Eric Miller Pamela Murray John Shereda Erica Siebrasse Darlene Walz


Information Technology

Innovation and Collaboration

Security

Bryon Campbell, Ph.D., Chief Information Officer David Drolett, Manager Zack Ramjan, Manager Candy Wilkerson, Manager Bill Baillod Terry Ballard Tom Barney Phil Bott James Clinthorne Kim Coan Dan DeVries Sean Haak Kenneth Hoekman Matt Hoffman Jason Kotecki Diana Lewis Ben Lewitt Deb Marshall Randy Mathieu Matt McFarlane Rob Montroy David Mowry Bruce Racalla Thad Roelofs Anthony Watkins

Jerry Callahan, Ph.D., M.B.A., I&C Officer Norma Torres

Kevin Denhof, CPP, Director Shelly Adamczak Brian Nix Chelsea Sturm Ross Vander Klok Andriana Vincent

Investments Office Kathy Vogelsang, Chief Investment Officer Ted Heilman Karla Mysels Turner Novak Austin Way

Legal Thomas R. Curran, Jr., General Counsel

Sponsored Research Jeff Richardson, Director Kathy Koehler Sara O’Neal Heather Wells Barbara Wygant

Materials Management Richard M. Disbrow, C.P.M., Director Matt Donahue Tracey Farney Heather Frazee Desaray Fourman Justin Harper Cheryl Poole Shannon Rydel Bob Sadowski Kyle Sloan Kimberly Stringham John Waldon Tracey Walker

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Van Andel Institute Van Andel Institute Board of Trustees David Van Andel, Chairman John C. Kennedy Mark Meijer

Board of Scientific Advisors Michael S. Brown, M.D., Chairman Richard Axel, M.D. Joseph L. Goldstein, M.D. Tony Hunter, Ph.D. Phillip A. Sharp, Ph.D.

Van Andel Research Institute Board of Trustees

Chief Executive Officer David Van Andel

Van Andel Education Institute Board of Trustees

David Van Andel, Chairman Tom R. DeMeester, M.D. James B. Fahner, M.D. Michelle Le Beau, Ph.D. George F. Vande Woude, Ph.D. Ralph Weichselbaum, M.D. Max Wicha, M.D.

David Van Andel, Chairman James E. Bultman, Ed.D. Donald W. Maine Juan R. Olivarez, Ph.D. Gordon L. Van Harn, Ph.D.

Van Andel Research Institute Chief Scientific Officer

Van Andel Education Institute Director

Peter A. Jones, Ph.D., D.Sc.

Terra Terrango

Chief Operations Officer Jana Hall, Ph.D., M.B.A.

Innovation & Collaboration

VP & Chief Financial Officer

Jerry Callahan, Ph.D.

Timothy Myers

VP Human Resources

General Counsel

Linda Zarzecki

Thomas R. Curran, Jr.

Communications & Marketing

Development

Beth Hinshaw Hall

Brett Holleman, CFRE, CFRM

Compliance

Security

Gwenn Oki, M.P.H.

Kevin Denhof

Facilities Samuel Pinto

74 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT


The Van Andel Institute and its affiliated organizations (collectively the “Institute�) support and comply with applicable laws prohibiting discrimination based on race, color, national origin, religion, gender, age, disability, pregnancy, height, weight, marital status, U.S. military veteran status, genetic information, or other personal characteristics covered by applicable law. The Institute also makes reasonable accommodations required by law. The Institute’s policy in this regard covers all aspects of the employment relationship, including recruiting, hiring, training, and promotion, and, if applicable, the student relationship.

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2018 Scientific Report  

2018 Scientific Report  

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