2019-10-10T10:02:15-05:00 2018-11-30 861065772 DELOITTE TAX LLP 200 RENAISSANCE CENTER STE 3900 DETROIT MI 48243 990 2017-12-01 522000823 VAN ANDEL RESEARCH INSTITUTE VANA 6162345000 333 BOSTWICK AVENUE NE GRAND RAPIDS MI 49503 TIMOTHY J MYERS VICE PRESIDENT & CFO 6162345368 2019-10-10 1 ANNE FULTON P00941863 3133963000 155.130.133.20 2019-10-10 10:52:49 ED P F78548749BD4E13989256802F10A02C0F91D1746 F78548749BD4E13989256802F10A02C0F91D1746 2017 2019-02-21 02:37:17Z TIMOTHY J MYERS 333 BOSTWICK AVENUE NE GRAND RAPIDS MI 49503 86638273 0 X WWW.VAI.ORG X 1996 MI MEDICAL RESEARCH ORGANIZATION 5 4 449 16 409670 104762 71484792 76050595 1122867 1206439 993632 683062 9465550 8528787 83066841 86468883 1012021 1095983 0 0 36040459 39942174 0 0 967682 38499186 45167491 75551666 86205648 7515175 263235 247321206 229968935 329139789 299912525 -81818583 -69943590 X MEDICAL RESEARCH ORGANIZATION VAN ANDEL RESEARCH INSTITUTE IS AN INDEPENDENT BIOMEDICAL RESEARCH ORGANIZATION COMMITTED TO IMPROVING THE HEALTH AND ENHANCING THE LIVES OF CURRENT AND FUTURE GENERATIONS. 0 0 9527469 123733 45447 CENTER FOR CANCER AND CELL BIOLOGY SCHEDULE O PROVIDES FURTHER INFORMATION REGARDING THIS PROGRAM'S ACCOMPLISHMENTS. 10815000 938184 188097 CENTER FOR EPIGENETICSSCHEDULE O PROVIDES FURTHER INFORMATION REGARDING THIS PROGRAM'S ACCOMPLISHMENTS. 6383212 19566 220375 CENTER FOR NEURODEGENERATIVE SCIENCESEE SCHEDULE O FOR FURTHER INFORMATION ABOUT THIS PROGRAM'S ACCOMPLISHMENTS. 32313516 14500 752520 32313516 14500 752520 59039197 1 1 0 1 0 0 0 0 0 1 1 0 0 1 1 1 0 1 0 1 1 1 0 0 1 0 0 1 1 1 1 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 1 1 1 0 0 1 161 0 449 1 1 1 0 0 0 0 1 1 0 0 0 0 X 5 4 1 0 0 0 0 1 0 1 1 0 0 1 1 1 1 1 1 1 1 0 MI X TIMOTHY J MYERS VP & CFO 6162345368 333 BOSTWICK AVENUE NE GRAND RAPIDS MI 495032518 DAVID VAN ANDEL CHAIRMAN / CEO 36.00 17.00 X X 490327 0 129226 DR JAMES FAHNER TRUSTEE 1.00 1.00 X 10000 2000 0 DR RALPH WEICHSELBAUM TRUSTEE (ENDED 09/10/18) 1.00 0.00 X 9000 0 0 DR MAX WICHA TRUSTEE 1.00 0.00 X 13000 0 0 DR MICHELLE LEBEAU TRUSTEE 1.00 0.00 X 10000 0 0 DR TOM DEMEESTER TRUSTEE 1.00 0.00 X 10000 0 0 DR JANA HALL CHIEF OPERATIONS OFFICER 50.00 3.00 X 423365 0 147856 TIMOTHY MYERS V.P. & CHIEF FINANCIAL OFFICER 50.00 3.00 X 308792 0 107081 DR PETER JONES CHIEF SCIENTIFIC OFFICER & RES. DIR. 52.00 0.00 X 712053 0 202298 KATHY VOGELSANG CHIEF INVESTMENT OFFICER 45.00 0.00 X 610494 0 371506 DR PATRIK BRUNDIN ASSOCIATE RESEARCH DIRECTOR 45.00 0.00 X 488766 0 115385 DR PETER LAIRD INVESTIGATOR 45.00 0.00 X 403258 0 58817 DR GERD PFEIFER INVESTIGATOR 45.00 0.00 X 360876 0 46218 TED HEILMAN ASSOC DIRECT-SR. PORTFOLIO MGR. 45.00 0.00 X 406010 0 229054 DR GEORGE VANDE WOUDE TRUSTEE/INVESTIGATOR 0.00 0.00 X 269298 0 28352 DAVID WHITESCARVER FORMER SECRETARY/V.P. 0.00 0.00 X 295363 0 0 4820602 2000 1435793 71 1 1 0 DK SECURITY INC 5160 FALCONVIEW AVE SE KENTWOOD MI 49512 SECURITY SERVICES 305357 LOS ALAMOS NATIONAL LABORATORY MS K710 LOS ALAMOS NM 87545 SCIENTIFIC SERVICES 242520 ANDY J EGAN COMPANY INC 2001 WALDROF NW SUITE 200 GRAND RAPIDS MI 49544 MAINTENANCE SERVICES 161534 FEDERAL EXPRESS PO BOX 371461 PITTSBURGH PA 152512125 SHIPPING SERVICE 151422 PRESIDIO NETWORK SOLUTIONS GROUP LLC PO BOX 677638 DALLAS TX 752677638 CONSULTING SERVICES 149911 10 76554 54765920 15455493 5752628 10053 76050595 RESEARCH BILLED REV 541700 1206439 796831 409608 1206439 611040 611040 769948 769948 208181 133827 74354 74354 62 74292 85282 13260 72022 72022 72022 7940 76554 22303 -14363 -14363 ALLOCATED ADMIN. EXP. 561000 7454379 7454379 REIMBURSED EXPENSES 900099 89238 89238 155231 155231 7698848 86468883 796831 409670 9211787 827751 827751 217006 217006 51226 51226 2283411 806925 1476486 29071924 17890164 10590249 591511 2661929 1587253 1025387 49289 4044566 2411691 1557985 74890 1880344 1121210 724317 34817 460633 45459 415174 71053 71053 96000 96000 2337221 1801631 514677 20913 760537 29289 586536 144712 150365 54671 95634 60 340238 162710 172387 5141 2604067 2067187 535615 1265 743796 520941 200269 22586 182155 113331 63337 5487 10760495 7999832 2760663 10976842 9408576 1568266 533115 333064 200051 FED / STATE INCOME TAX 135824 0 135824 LAB SUPPLIES & SERVICES 5162377 5162377 EQUIPMENT & SOFTWARE 3794364 2762597 1030455 1312 BAD DEBT EXPENSE (ADJUS 1572658 1572658 4485751 3664306 805746 15699 86205648 59039197 26198769 967682 8597139 8076049 3382233 4270243 6269641 3969006 42645 1697944 157198 1194778 1544611 293053446 109593147 184886459 183460299 5108311 7153585 37840000 19640000 247321206 229968935 49184301 32511690 1340635 2256713 219722640 219733588 58892213 45410534 329139789 299912525 X -85638212 -74444439 3153327 3867142 666302 633707 -81818583 -69943590 247321206 229968935 X 263235 2172 11609586 X 0 1 X 1 1 1 X SPECTRUM HEALTH GRAND RAPIDS MI 96000 96000 86109648 86205648 1000000 250000 0 0 1000000 1000000 1000000 1000000 4000000 6000000 165579 238376 96000 96000 595955 250000 250000 250000 250000 1000000 1500000 666302 10100 12604 62742 626264 612777 61326 7801 666302 596343 18408 1974 612777 1.00000 0 1 1 5288315 5288315 229359310 66890424 162468886 56798553 42644015 14154538 1607268 58708 1548560 183460299 PLEDGED SECURITIES 19640000 19640000 UNREALIZED LOSS ON INTEREST RATE SWAP 41273437 RELATED-PARTY PAYABLE 4137097 45410534 X 79172806 2172 156130 158302 79014504 7454379 7454379 86468883 67297814 -11453455 -11453455 78751269 7454379 7454379 86205648 PART X, LINE 2: PART X, LINE 1(1) AND LINE 2: THERE ARE NO UNCERTAIN TAX POSITIONS RELATED TO VARI. PART XI, LINE 2D - OTHER ADJUSTMENTS: RENTAL EXPENSES 133,827. FUNDRAISING EVENT EXPENSE 22,303. PART XI, LINE 4B - OTHER ADJUSTMENTS: NET ALLOCATED 7,454,379. PART XII, LINE 2D - OTHER ADJUSTMENTS: RENTAL EXPENSES 133,827. FUNDRAISING EVENT EXPENSE 22,303. GAIN ON INTEREST RATE SWAP -11,609,585. PART XII, LINE 4B - OTHER ADJUSTMENTS: NET ALLOCATED 7,454,379. PART V VAN ANDEL INSTITUTE (A RELATED ORGANIZATION) MAINTAINS ENDOWED FUNDS FOR THE BENEFIT OF BOTH VARI AND VAN ANDEL EDUCATION INSTITUTE (A RELATED ORGANIZATION) TO FUND OPERATING EXPENSES. PART XI AND XII, LINE 4B EXPENSE ALLOCATIONS PRESENTED WITHIN REVENUE. 1 EAST ASIA & THE PACIFIC 0 1 PROGRAM SERVICES RESEARCH COLLABORATION - RESEARCH SERVICES 232715 EUROPE 0 0 PROGRAM SERVICES RESEARCH COLLABORATION - RESEARCH SERVICES 431476 0 1 0 0 0 1 664191 0 664191 EAST ASIA AND THE PACIFIC RESEARCH COLLABORATION 50000 WIRE TRANSFER 1 0 0 0 0 0 0 PART I, LINE 2: GRANT FUNDS ARE MONITORED BY QUARTERLY EXPENDITURE REPORTS BEFORE DISBURSING INCREMENTAL FUNDING. PROGRESS REPORTS ARE REQUIRED ANNUALLY AND REVIEWED BY VAN ANDEL RESEARCH INSTITUTE AND A THIRD PARTY. SCHEDULE F, PART II, LINE 1 ORGANIZATION PROVIDED ASSISTANCE IS MONITORED WITH QUARTERLY EXPENDITURE REPORTING. 5K RACE 40343 32403 7940 6183 GRIFFINS 44151 44151 16120 84494 76554 7940 22303 22303 -14363 1 JOHNS HOPKINS UNIVERSITY 3400 N CHARLES STREET BALTIMORE MD 21218 520595110 501C3 143460 RESEARCH COLLABORATION UNIVERSITY OF MARYLAND 3112 LEE BUILDING 7809 REGENTS DR COLLEGE PARK MD 20742 526002033 501C3 50000 RESEARCH COLLABORATION TEMPLE UNIVERSITY 1852 NORTH 10TH ST PHILADELPHIA PA 19122 231365971 501C3 50000 RESEARCH COLLABORATION INSTITUTE FOR CANCER RESEARCH 333 COTTMAN AVENUE PHILADELPHIA PA 19111 236296135 501C3 54243 RESEARCH COLLABORATION FRIENDS OF CRESCENT PARK 301 BOSTWICK NE GRAND RAPIDS MI 49503 264562012 501C3 14500 SUPPORT CRESCENT PARK MAINTENANCE STAND UP TO CANCER 10880 WILSHIRE BLVD SUITE 1400 LOS ANGELES CA 90024 951644609 501C3 513432 RESEARCH COLLABORATION 6 0 GRADUATE STUDENT STIPENDS FOR MICHIGAN STATE UNIVERSITY STUDENTS 3 89338 GRADUATE STUDENT STIPENDS VAN ANDEL INSTITUTE GRADUATE SCHOOL 2 53484 FOREIGN NATIONAL STIPENDS 7 50821 GUEST STUDENT STIPENDS 2 23363 PART I, LINE 2: STUDENTS RECEIVE A STIPEND FOR LIVING EXPENSE AND INSURANCE. GRANT FUNDS TO INSTITUTIONS ARE MONITORED BY QUARTERLY EXPENDITURE REPORTS BEFORE DISBURSING INCREMENTAL FUNDING. PROGRESS REPORTS ARE REQUIRED ANNUALLY AND REVIEWED BY VAN ANDEL RESEARCH INSTITUTE AND A THIRD PARTY. X 1 1 X X X X 1 0 0 1 0 0 0 0 0 DAVID VAN ANDEL CHAIRMAN / CEO 366923 0 102000 0 21404 0 128250 0 976 0 619553 0 102000 0 DR JANA HALL CHIEF OPERATIONS OFFICER 351551 0 68250 0 3564 0 136650 0 11206 0 571221 0 68250 0 TIMOTHY MYERS V.P. & CHIEF FINANCIAL OFFICER 270346 0 37636 0 810 0 95875 0 11206 0 415873 0 37636 0 DR PETER JONES CHIEF SCIENTIFIC OFFICER & RES. DIR. 542780 0 146710 0 22563 0 191092 0 11206 0 914351 0 146710 0 KATHY VOGELSANG CHIEF INVESTMENT OFFICER 341372 0 248800 0 20322 0 360300 0 11206 0 982000 0 248800 0 DR PATRIK BRUNDIN ASSOCIATE RESEARCH DIRECTOR 435382 0 51062 0 2322 0 104179 0 11206 0 604151 0 51062 0 DR PETER LAIRD INVESTIGATOR 377688 0 23248 0 2322 0 47611 0 11206 0 462075 0 23248 0 DR GERD PFEIFER INVESTIGATOR 346680 0 10632 0 3564 0 35012 0 11206 0 407094 0 10632 0 TED HEILMAN ASSOC DIRECT-SR. PORTFOLIO MGR. 220911 0 167940 0 17159 0 217848 0 11206 0 635064 0 167940 0 DR GEORGE VANDE WOUDE TRUSTEE/INVESTIGATOR 247396 0 0 0 21902 0 26540 0 1812 0 297650 0 0 0 DAVID WHITESCARVER FORMER SECRETARY/V.P. 256837 0 0 0 38526 0 0 0 0 0 295363 0 38526 0 PART I, LINE 1A VARI ALLOWS FOR FIRST-CLASS OR CHARTER TRAVEL FOR OFFICERS AND TRUSTEES. PART I, LINE 4A INCLUDES SEVERANCE PAYMENTS TO DAVID WHITESCARVER OF $256,837 FROM VAN ANDEL RESEARCH INSTITUTE FOR CALENDER YEAR 2017. PART I, LINE 5 BONUS IS PAID BASED ON GRANT REVENUE EARNED FOR ELIGIBLE PROGRAM PARTICIPANTS. A MICHIGAN STRATEGIC FUND 521417332 000000000 2018-10-01 220000000 REFUND BOND ISSUE 4/01/13 0 0 0 A 220000000 220000000 1 0 1 1 A 0 1 1 1 1 1 0.00690 0.00690 0 0 1 A 0 1 0 0 1 0 0 0 1 A 1 X 1 10053 NYSE VALUE 0 0 0 0 PART I, COLUMN (B): VARI IS REPORTING THE NUMBER OF CONTRIBUTIONS RECEIVED DURING THE TAX YEAR. FORM 990, PART VI, SECTION A, LINE 2 VARI, VAI, VAEI, AND VAIGS SHARE COMMON MANAGEMENT. DAVID VAN ANDEL, DR. JANA HALL AND TIMOTHY MYERS ARE ALSO OFFICERS OF VAI, AND DAVID VAN ANDEL AND TIMOTHY MYERS ARE OFFICERS OF VAEI AND VAIGS. FORM 990, PART VI, SECTION A, LINE 7A THE TRUSTEES OF VAN ANDEL INSTITUTE HAVE THE AUTHORITY TO ELECT ONE OR MORE MEMBERS OF VARI'S GOVERNING BODY. FORM 990, PART VI, SECTION B, LINE 11B FOLLOWING COMPLETION OF THE FINANCIAL STATEMENT AUDIT, THE FORM 990 IS PREPARED AND REVIEWED BY MANAGEMENT. IT IS THEN CIRCULATED TO THE FULL BOARD FOR REVIEW AND COMMENTS PRIOR TO FILING WITH THE IRS. FORM 990, PART VI, SECTION B, LINE 12C VARI HAS WRITTEN CONFLICT OF INTEREST ("COI") POLICIES AND PROCEDURES WHICH ADMINISTER AND ENFORCE A PROCESS TO IDENTIFY, EVALUATE, AND MANAGE POTENTIAL CONFLICTS OF INTEREST. THESE POLICIES HAVE BEEN APPROVED BY THE BOARD OF TRUSTEES. VAI ADMINISTERS COI POLICIES AND PROCEDURES THROUGH TWO STANDING COMMITTEES: THE CONFLICTS COMMITTEE ("CC") AND THE INSTITUTIONAL COI COMMITTEE ("ICOIC"). COI POLICIES AND PROCEDURES APPLY TO AND SERVE AS A GUIDE FOR EVERYONE IN THE ORGANIZATION. IN PARTICULAR, THEY PROVIDE A USEFUL RESOURCE FOR DEVELOPING ACTIVITIES OR RELATIONSHIPS WITH OUTSIDE ENTITIES OR PERSONS, AND ESTABLISH A PROCESS FOR COMMITTEES TO REVIEW AND MANAGE POTENTIAL CONFLICTS OF INTEREST AS THEY MAY ARISE. THE CC AND ICOIC ARE CHAIRED BY THE GENERAL COUNSEL. THE CC REQUIRES ANNUAL AND UPDATED DISCLOSURES BY COVERED PERSONS AND REVIEWS AND APPROVES MANAGEMENT PLANS. ICOIC POLICIES AND PROCEDURES SERVE AS A GUIDE FOR BOARDS OF TRUSTEES AND SENIOR EXECUTIVES. IN THE EVENT A POTENTIAL COI ARISES AT THE BOARD OR SENIOR EXECUTIVE LEVEL, THE ICOIC MEETS TO REVIEW AND DETERMINE HOW TO MANAGE SUCH A POTENTIAL CONFLICT OF INTEREST IN ACCORDANCE WITH THE COI POLICIES AND PROCEDURES. FORM 990, PART VI, SECTION B, LINE 15 COMPARABILITY DATA FROM AN EXPERT THIRD PARTY IS OBTAINED AND REVIEWED BY THE INDEPENDENT, JOINT COMPENSATION COMMITTEE OF VAN ANDEL RESEARCH INSTITUTE AND RELATED ORGANIZATIONS TO DETERMINE APPROPRIATE COMPENSATION FOR THE CEO, EXECUTIVE MANAGEMENT OFFICIALS, OFFICERS, AND KEY EMPLOYEES, ON BEHALF OF VAN ANDEL RESEARCH INSTITUTE. FORM 990, PART VI, SECTION C, LINE 19 ALL DOCUMENTS REQUIRED TO BE MADE AVAILABLE TO THE PUBLIC ARE AVAILABLE FOR PUBLIC INSPECTION UPON WRITTEN REQUEST. FORM 990, PART XI, LINE 9: GAIN ON INTEREST RATE SWAP 11,609,586. FORM 990, PART III, LINE 2 VAN ANDEL RESEARCH INSTITUTE (VARI) IS DEDICATED TO DETERMINING THE EPIGENETIC, GENETIC, MOLECULAR, AND CELLULAR ORIGINS OF CANCER, PARKINSON'S DISEASE, AND OTHER ILLNESSES AND TO TRANSLATING THOSE FINDINGS INTO EFFECTIVE THERAPIES. THE INSTITUTE'S SCIENTISTS WORK IN ON-SITE LABORATORIES AND PARTICIPATE IN COLLABORATIONS THAT SPAN THE GLOBE. THE INSTITUTE IS ORGANIZED INTO THE CENTER FOR CANCER AND CELL BIOLOGY, THE CENTER FOR EPIGENETICS, AND THE CENTER FOR NEURODEGENERATIVE SCIENCE. VARI'S LABS ARE SUPPORTED BY AN OUTSTANDING CORE TECHNOLOGIES AND SERVICES GROUP, WHICH PROVIDES A VIVARIUM, A BIOREPOSITORY, AND VALUABLE ON-SITE CAPABILITIES IN IMAGING, PATHOLOGY, BIOINFORMATICS AND BIOSTATISTICS, GENOMICS, FLOW CYTOMETRY, AND CRYO-ELECTRON MICROSCOPY. VARI SCIENTISTS PUBLISHED 116 ARTICLES THIS FISCAL YEAR IN PEER-REVIEWED JOURNALS THAT INCLUDED NATURE, SCIENCE, CELL, NATURE COMMUNICATIONS, NATURE GENETICS, NATURE MEDICINE, SCIENCE TRANSLATIONAL MEDICINE, CELL REPORTS, CELL DISCOVERY, CANCER RESEARCH, CLINICAL CANCER RESEARCH, NUCLEIC ACIDS RESEARCH, GENOME RESEARCH, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES U.S.A., ACTA NEUROPATHOLOGICAL, CANCER CELL, HUMAN MOLECULAR GENETICS, MOLECULAR CELL, MOLECULAR NEURODEGENERATION, ACTA NEUROPATHOLOGICAL COMMUNICATIONS, ELIFE, BONE, JOURNAL OF BIOLOGICAL CHEMISTRY, JOURNAL OF BONE AND MINERAL RESEARCH, CELL AND TISSUE RESEARCH, SCIENTIFIC REPORTS, NJP BREAST CANCER, JOURNAL OF PARKINSON'S DISEASE, HEPATOLOGY, MOVEMENT DISORDERS, BIOCHEMISTRY, NEUROBIOLOGY OF DISEASE, JOURNAL OF NEUROSCIENCE, HUMAN MOLECULAR GENETICS, BLOOD, METABOLITES, JOURNAL OF PROTEOME RESEARCH, MOLECULAR AND CELLULAR PROTEOMICS, AND CURRENT THERAPEUTIC RESEARCH. FORM 990, PART III, LINE 4A LINE 4A - PROGRAM SERVICE ACTIVITY #1 CENTER FOR CANCER AND CELL BIOLOGY THE CENTER FOR CANCER AND CELL BIOLOGY, DIRECTED BY BART WILLIAMS, PH.D., COMPRISES 16 LABORATORIES ENGAGED IN BASIC RESEARCH IN MOLECULAR AND STRUCTURAL BIOLOGY AND IN TRANSLATIONAL RESEARCH ON CANCERS, SKELETAL DISEASES, AND METABOLISM AND NUTRITION. THE CENTER IS DIVIDED INTO PROGRAMS IN STRUCTURAL BIOLOGY, SKELETAL DISEASE AND CANCER THERAPEUTICS, AND A NEW PROGRAM IN METABOLIC AND NUTRITIONAL PROGRAMMING. NEW FACULTY MEMBERS DRS. RUSSELL JONES, CONNIE KRAWCZYK, ANDREW POSPISILIK, AND ADELHEID LEMPRADL JOINED EXISTING FACULTY DRS. BRIAN HAAB AND NING WU TO ESTABLISH THE PROGRAM. IN THIS FISCAL YEAR, RESEARCHERS AND TRAINEES WITHIN THE CENTER RECEIVED THREE NEW R01 AWARDS AND ONE RENEWAL R01, A U01 AWARD, AND AN F31 FELLOWSHIP FROM THE NATIONAL INSTITUTES OF HEALTH. OTHER NEW AWARDS RECEIVED WERE FROM THE CHILDREN'S TUMOR FOUNDATION, TWO RENEWAL AWARDS WERE RECEIVED FROM THE ARTHRITIS NATIONAL RESEARCH FOUNDATION, AND THE BREAST CANCER RESEARCH FOUNDATION. THE STEENSMA LABORATORY STUDIED THE EFFECT OF THE LOSS OF THE NF1 GENE, WHICH ENCODES THE NEUROFIBROMIN ENZYME, ON BREAST CANCER AND ON ESTROGEN RECEPTOR SIGNALING (DISCHINGER ET AL., NPJ BREAST CANCER 4: 29). THE RESULTS SHOWED A SIGNIFICANT ROLE FOR THE NF1 GENE IN BREAST CANCER AND A POSSIBLE FUNCTIONAL LINK BETWEEN NEUROFIBROMIN AND THE ESTROGEN RECEPTOR, INDICATING THAT THIS GENE MAY BE A MARKER OF PROGNOSIS AND A THERAPEUTIC TARGET FOR ENDOCRINE-RESISTANT BREAST CANCERS. IN ANOTHER STUDY BY THE LAB, SOME MALIGNANT PERIPHERAL NERVE SHEATH TUMORS (MPNSTS), FOR WHICH THERE ARE NO EFFECTIVE THERAPIES, WERE FOUND TO BE SENSITIVE TO THE MET ONCOGENE INHIBITOR CAPMATINIB (PEACOCK ET AL., CANCER RESEARCH 78(13): 3572-3687). A COMBINATION THERAPY OF CAPMATINIB AND THE MEK KINASE INHIBITOR TRAMETINIB RESULTED IN REDUCED RESPONSE VARIABILITY, SUPPRESSION OF RAS/ERK AND PI3K/AKT SIGNALING, AND ENHANCED SUPPRESSION OF TUMOR GROWTH. THE WILLIAMS AND YANG LABS TOGETHER PUBLISHED SEVERAL SKELETAL STUDIES IN 2018. ONE FOCUSED ON OSTEOCHONDROPROGENITOR CELLS, WHICH DEVELOP INTO CELLS THAT CREATE BONE OR CARTILAGE. THE ENZYME SENP6 WAS FOUND TO BE CRUCIAL IN NORMAL OSTEOCHONDROPROGENITORS FOR SKELETAL DEVELOPMENT: LOSS OF THE ENZYME CAUSED PREMATURE AGING OF CELLS AND TISSUES, AND MICE HAVING NO SENP6 HAD SMALLER SKELETONS (LI ET AL., NATURE COMMUNICATIONS 9: 143). ANOTHER STUDY FOUND THAT BONE MARROW STROMAL CELLS PREFERENTIALLY DIFFERENTIATED INTO LIPID-STORING ADIPOCYTES WHEN TREATED WITH GINKGOLIC ACID, WHICH INHIBITS THE SUMOYLATION OF PROTEINS (LIU ET AL., SCIENTIFIC REPORTS 8(1): 2545). THIS PREVIOUSLY UNKNOWN ACTION OF GINKGOLIC ACID MAY HAVE APPLICATION IN TREATING CONDITIONS INVOLVING ABNORMAL LIPID METABOLISM. A THIRD PROJECT STUDIED THE ROLE OF THE LRP1 PROTEIN IN BONE REMODELING (LU ET AL., JOURNAL OF BONE AND MINERAL RESEARCH 33(10): 1773-1784). THE RESULTS SUGGEST THAT LRP1 IS A CRUCIAL REGULATOR OF BONE MASS AND THAT ITS INHIBITION OF THE RANKL SIGNALING PATHWAY MAY BE USEFUL IN TREATING CONDITIONS OF LOW BONE MASS. XIAOHONG LI'S LABORATORY STUDIED THE ROLE OF TGF-BETA SIGNALING FROM MYELOID CELLS IN METASTATIC BONE LESIONS (GANGULY ET AL., CANCERS 10: 463). THEY SHOWED THAT SUCH SIGNALS PROMOTED OSTEOLYTIC BONE LESIONS AND THAT THE CTHRC1 PROTEIN AND BASIC FIBROBLAST GROWTH FACTOR (BFGF) HAVE DIFFERENT, CELL-SPECIFIC FUNCTIONS THAT CONTRIBUTE TO BONE LESION DEVELOPMENT. IN A SEPARATE STUDY (MENG ET AL., CANCER LETTERS 418: 109-118), THE LI LAB FOUND THAT THE LOSS OF TGF-BETA SIGNALING IN OSTEOBLAST CELLS INCREASED THE AMOUNT OF BFGF AND CORRELATED WITH INCREASED TUMOR CELL PROLIFERATION AND ANGIOGENESIS. BFGF MAY BE A PROMISING TARGET FOR INHIBITING BONE METASTASIS IN PROSTATE AND BREAST CANCER. ACTIVATION OF THE WNT SIGNALING PATHWAY IS A COMMON EVENT IN MANY CANCERS, AND WNT SIGNALING CAN BE HALTED BY INHIBITING AN ENZYME CALLED PORCN. A COLLABORATIVE STUDY BY THE WILLIAMS LAB AND THE VIRSHUP LAB AT DUKE UNIVERSITY FOUND THAT TWO PORCN INHIBITORS CAUSED A LOSS OF BONE VOLUME AND DENSITY (MADAN ET AL., BONE RESEARCH 6: 17). ALENDRONATE, A BISPHOSPHONATE, MITIGATED THE ADVERSE EFFECTS OF ONE OF THE INHIBITORS, SUPPORTING THE USE OF SUCH BONE-PROTECTIVE AGENTS IN THE TREATMENT REGIMEN OF PATIENTS RECEIVING PORCN INHIBITORS. IMPORTANT SCIENTIFIC ADVANCES ALSO WERE MADE BY MEMBERS OF THE STRUCTURAL BIOLOGY PROGRAM. THE LU AND DU LABS USED THE INSTITUTE'S CRYO-ELECTRON MICROSCOPY (CRYO-EM) FACILITY TO STUDY THE STRUCTURE OF THE TRPC3 ION CHANNEL (FAN ET AL., ELIFE 7: E36852), WHICH IS ESSENTIAL FOR NEURON DEVELOPMENT IN THE BRAIN. DYSFUNCTION OF TRPC3 IS LINKED TO NEURODEGENERATIVE DISEASES, AMONG OTHERS. KNOWLEDGE OF ITS ATOMIC-LEVEL STRUCTURE AND MECHANISM OF FUNCTION ARE ESSENTIAL FOR DEVELOPING THERAPIES THAT TARGET TRPC3 DYSFUNCTION. THE TWO LABS ALSO PUBLISHED THE STRUCTURE OF THE ZEBRAFISH TRPM2 ION CHANNEL (WHICH IS SIMILAR TO THE HUMAN MOLECULE BUT IS BETTER SUITED TO STRUCTURAL STUDIES) AND ITS MECHANISM OF ACTIVATION (HUANG ET AL., NATURE 562(7725): 145-149). TRPM2 IS INVOLVED IN BODY TEMPERATURE REGULATION AND THE IMMUNE RESPONSE. NEW INSIGHTS INTO HOW THE CHANNEL WORKS MAY HELP DEVELOP DRUGS TO TREAT TEMPERATURE-RELATED DYSFUNCTION AND NEURODEGENERATIVE DISEASE. THE MELCHER AND XU LABS ALSO PUBLISHED SIGNIFICANT STRUCTURAL STUDIES. AMP-ACTIVATED PROTEIN KINASE (AMPK) REGULATES THE ENERGY LEVEL IN THE CELL, AND ITS DYSREGULATION IS ASSOCIATED WITH DIABETES, CANCER, AND NEURODEGENERATIVE DISEASES. THE MELCHER LAB SOLVED THE STRUCTURES OF AMPK BOUND TO TWO NEW DRUG FORMS, WHICH GAVE INSIGHT INTO HOW THE MOLECULE WORKS AND ITS POTENTIAL USE AS A THERAPEUTIC AGENT (YAN ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY 294: 953-967). THE LAB ALSO STUDIED THE STRUCTURE OF AMPK IN TERMS OF THE PROTEIN'S SUBUNITS AND HOW THEY INTERACT (GU ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY 293: 16994-17007). THEY FOUND THAT THE ADAM SITE, AT THE JOINING OF THE KINASE SUBUNIT AND THE CARBOHYDRATE-BINDING SUBUNIT, MAY FUNCTION AS A HUB FOR INTEGRATING THE VARIETY OF REGULATORY SIGNALS THAT AFFECT THE CELLULAR ENERGY LEVEL. THE XU LAB PUBLISHED THE STRUCTURE OF THE HUMAN RHODOPSIN PROTEIN BOUND TO AN INHIBITORY G PROTEIN, WHICH THEY DETERMINED USING CRYO-EM (KANG ET AL., NATURE 558(7711): 553-558). RHODOPSIN IS FOUND IN THE EYE AND IS ESSENTIAL FOR PERCEIVING LIGHT. THE COMPARISON OF THIS NEW STRUCTURE TO OTHER STRUCTURES OF RHODOPSIN BOUND TO ACTIVATING G PROTEINS OR ARRESTINS PROVIDES A BASIS FOR UNDERSTANDING HOW RHODOPSIN FUNCTIONS IN SIGNALING THE PERCEPTION OF LIGHT. THIS PUBLICATION WAS FEATURED IN THE NIH DIRECTOR'S BLOG. BOTH LABS ALSO CONTRIBUTED TO THE DETERMINATION OF THE STRUCTURE OF THE HUMAN FRIZZLED 4 PROTEIN, WHICH IS INVOLVED IN BLOOD VESSEL DEVELOPMENT IN THE EYE'S RETINA. THE STUDY SUGGESTS THAT FRIZZLED PROTEINS MAY HAVE AN ACTIVATION MECHANISM DIFFERENT FROM THAT OF OTHER G-PROTEIN-COUPLED RECEPTORS LIKE RHODOPSIN (YANG ET AL., NATURE 560(7720: 666-670). HUILIN LI'S LABORATORY PUBLISHED A DIVERSE SET OF PAPERS IN 2018 BASED ON THE USE OF CRYO-EM. ONE WAS A STUDY OF THE YEAST OLIGOSACCHARYLTRANSFERASE ENZYME COMPLEX, WHICH PROVIDED THE FIRST HIGH-RESOLUTION IMAGES OF THE INTERACTIONS OF ITS MULTIPLE SUBUNITS. SEVEN PHOSPHOLIPID MOLECULES MEDIATE MANY OF THE INTER-SUBUNIT INTERACTIONS (BAI ET AL., NATURE 555(7696): 328-333). ANOTHER STUDY FOCUSED ON THE BACTERIAL SURFACE STRUCTURE CALLED A PILUS. USING CRYO-EM, AN INTERMEDIATE STAGE OF THE ASSEMBLY OF THE E. COLI PILUS WAS IMAGED. THE STRUCTURE SUGGESTED A MECHANISM FOR HOW THE GROWING PILUS IS STABILIZED AS IT INCORPORATES THOUSANDS OF SUBUNITS DURING ITS GROWTH, AND HAS IMPLICATIONS FOR THE TREATMENT OF URINARY TRACT INFECTIONS (DU ET AL., NATURE 562(7727): 444-447). THE LI LAB ALSO STUDIED THE STRUCTURE OF THE MTB CLPB COMPLEX, WHICH IS IMPORTANT TO THE SURVIVAL OF MYCOBACTERIUM TUBERCULOSIS. THEY IMAGED THE COMPLEX BOUND TO CASEIN AS A MODEL SUBSTRATE AND IDENTIFIED TWO DIFFERENT CONFORMERS. BASED ON THEIR DIFFERENCES, THEY SUGGEST A MECHANISM FOR HOW THE COMPLEX SUBUNITS ARE ABLE TO MOVE PEPTIDES DURING THE RESCUE OF DAMAGED PROTEINS (YU ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES USA 115(41): E9560-E9569). KNOWLEDGE OF THIS MECHANISM MAY AID IN DEVELOPING FUTURE DRUGS EFFECTIVE AGAINST TUBERCULOSIS. FINALLY, THE LAB REPORTED THE STRUCTURE OF THE MEMBRANE-BOUND HYDROGENASE FROM THE HEAT-ADAPTED MICROBE PYROCOCCUS FURIOSUS. THIS IS AN ANCIENT RESPIRATION SYSTEM THAT OPERATES AT TEMPERATURES NEAR 100 DEGREES C. THE STRUCTURE IS COMPARED WITH THE RELATED QUINONE-REDUCING COMPLEX I AND THE DIFFERENCES IN THEIR ARCHITECTURE ARE DESCRIBED (YU ET AL., CELL 173(7): 1636-1649). FORM 990, PART III, LINE 4B LINE 4B - PROGRAM SERVICE ACTIVITY #2 CENTER FOR EPIGENETICS THE CENTER, ESTABLISHED IN 2014 AND DIRECTED BY PETER A. JONES, PH.D., D.SC. (HON), COMPRISES TEN LABORATORIES STUDYING EPIGENETICS, EPIGENOMICS, AND THE ROLE OF EPIGENETIC DYSFUNCTION IN CANCER, NEURODEGENERATIVE DISEASE, CARDIOVASCULAR DISEASE, AND VIRAL TRANSCRIPTION. DRS. XIAOBING SHI AND HONG WEN JOINED THE CENTER IN 2018. NEW GRANT AWARDS IN THIS FISCAL YEAR FOR CENTER RESEARCHERS AND TRAINEES INCLUDED AN R01, AN R21, AN R37, AND AN F32 FROM THE NATIONAL INSTITUTES OF HEALTH, NEW FUNDING FROM THE MICHIGAN ECONOMIC DEVELOPMENT COMMISSION, A GRANT FROM EVANS MDS, AND TWO NEW FELLOWSHIPS FROM THE CANADIAN INSTITUTES OF HEALTH RESEARCH AND THE AMERICAN SOCIETY OF HEMATOLOGY. TWO NIH GRANT SUBAWARDS WERE ALSO RECEIVED. THE VAN ANDEL RESEARCH INSTITUTE-STAND UP TO CANCER EPIGENETICS DREAM TEAM, LED BY PETER JONES AND STEPHEN BAYLIN, CONTINUED IN 2018 WITH ITS AIMS OF DEVELOPING NEW COMBINATION THERAPIES TO COMBAT CANCER AND MOVING PROMISING THERAPIES INTO CLINICAL TRIALS. THE TEAM FOCUSES ON EPIGENETIC MECHANISMS IN CELLS, WHICH HELP CONTROL WHETHER GENES ARE TURNED ON OR OFF, WITHOUT CHANGING THE DNA SEQUENCE ITSELF. THIS IS DONE PRIMARILY BY THE ADDITION OR REMOVAL OF METHYL GROUPS TO THE DNA OR ADDITION/REMOVAL OF METHYL OR ACETYL GROUPS FROM THE HISTONE PROTEINS AROUND WHICH DNA WRAPS. THE LABORATORY OF PETER JONES PUBLISHED IN 2018 A COMPREHENSIVE MAP OF MORE THAN 500,000 ENDOGENOUS RETROVIRUSES (ERVS) IN THE INTERGENIC REGIONS OF THE HUMAN GENOME. REPRESSIVE EPIGENETIC MARKS FOUND ON THE ERVS DEPENDED ON EVOLUTIONARY AGE, WITH DNA METHYLATION ASSOCIATED WITH YOUNGER AGE AND HISTONE METHYLATION WITH OLDER. THIS FINDING MAY AID IN PREDICTING CANCER RESPONSE TO EPIGENETIC THERAPIES (OHTANI ET AL., GENOME RESEARCH 28(8): 1147-1157). IN ANOTHER STUDY, OF OVARIAN CANCER CELLS, THE INHIBITION OF THE HISTONE METHYLTRANSFERASE ENZYME G9A COMBINED WITH 5-AZA-CDR PRODUCED ANTITUMOR EFFECTS INCLUDING ACTIVATION OF THE VIRAL DEFENSE RESPONSE AND INDUCTION OF CELL DEATH. SUCH A COMBINATION TREATMENT MAY BE A NOVEL STRATEGY FOR TREATING OVARIAN CANCER PATIENTS WHOSE CELLS HAVE HIGH EXPRESSION OF G9A (LIU ET AL., CANCER RESEARCH 78(20): 5754-5766). IN A THIRD 2018 PUBLICATION, THE JONES LAB LINKED THE FREQUENCY OF IMPRINTING OF THE NC886 RNA GENE IN INFANTS TO THE MOTHER'S AGE AT DELIVERY AND TO WHEN CONCEPTION OCCURRED DURING THE YEAR. THEY PROPOSE THAT SUCH IMPRINTING IS "TUNABLE" IN BEING ASSOCIATED WITH THE MATERNAL HAPLOTYPE AND THE PRENATAL ENVIRONMENT, PROVIDING A POSSIBLE WAY OF TRANSMITTING PHENOTYPES FROM MOTHER TO CHILD (PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES USA 115(51): E11970-E11977). THE JONES AND TRICHE LABS CONTRIBUTED TO THE FIRST STUDY OF THE EPIGENETIC DRUG AZACITIDINE IN COMBINATION WITH INTENSIVE CHEMOTHERAPY. THE RESULTS SHOWED THE SAFETY OF THE PAIRING AND OFFERED ENCOURAGING CLINICAL ACTIVITY. DNA METHYLATION OF THE FDFT1 GENE WAS HIGHLY ASSOCIATED WITH PATIENT CLINICAL OUTCOME (BLOOD 131(10): 1145-1148). THE TRICHE LAB ALSO IDENTIFIED A SET OF 14 TRANSPOSABLE ELEMENTS (TES) IN DNA THAT MAY BE A BIOMARKER FOR HIGH- OR LOW-RISK ACUTE MYELOID LEUKEMIA. THIS SET COULD PREDICT PROGNOSIS IN INDEPENDENT COHORTS OF 284 PEDIATRIC PATIENTS AND IN 19 RELAPSED ADULT PATIENTS. STUDIES OF THE UTILITY OF THIS MARKER IN OTHER CANCERS IS WARRANTED (SCIENTIFIC REPORTS 8(1): 16449). IN ANOTHER STUDY OF TES IN HEALTHY INDIVIDUALS, SENESCENT HEMATOPOIETIC STEM AND PROGENITOR CELLS (HSPCS) EXPRESSED MORE TES THAN DID ACTIVE HSPCS, AND SENESCENT CELLS LACKED DNA METHYLATION IN THE REGIONS EXPRESSING MORE TES. THIS IS THE FIRST REPORT CHARACTERIZING THE METHYLATION OF THESE CELLS (EXPERIMENTAL HEMATOLOGY 62: 33-38E6). THE ROTHBART LABORATORY DEVELOPED A HIGH-THROUGHPUT PROTEOMICS PLATFORM THAT MAPS THE SEQUENCE DETERMINANTS OF SUBSTRATE SELECTIVITY OF THE ENZYME LYSINE METHYLTRANSFERASE WITHOUT REQUIRING KNOWLEDGE OF A SUBSTRATE OR TARGET. IN THIS APPROACH, A LYSINE-ORIENTED PEPTIDE LIBRARY CAN BE USED TO IDENTIFY NEW SUBSTRATES AND TO DISCOVER NEW INHIBITORS OF THE ENZYME (CORNETT ET AL., SCIENCE ADVANCES 4(11): EAAV2623). THE LAB ALSO ANALYZED THE ACTIVITIES OF THE E3 UBIQUITIN LIGASES UHRF1 AND UHRF2 AND FOUND CONSERVED MODES OF RECOGNIZING HISTONE PROTEINS BUT DIFFERENT DNA-BINDING PROPERTIES. THE STUDY DESCRIBED THE DIFFERENCES IN THE ACTIVITY AND SUBSTRATES OF THESE TWO ENZYMES AND ASCRIBED THOSE DIFFERENCES TO THEIR CONTRASTING MOLECULAR ARCHITECTURES (VAUGHAN ET AL., NUCLEIC ACIDS RESEARCH 46(9): 4405-4416). FOR A STUDY OF THE SUBSTRATE SELECTIVITY OF UHRF1, THE LAB CONSTRUCTED EXPERIMENTAL SUBSTRATES AND ANALYZED THE ENZYME'S BINDING AND ACTIVITY TOWARD THEM. THE RESULTS SHOWED HOW THE ENZYME CHOOSES BETWEEN DNA AND HISTONE SUBSTRATES AND FOUND A "MOLECULAR SWITCH" THAT REDIRECTS UHRF1 ACTIVITY AWAY FROM HISTONES (VAUGHAN ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES USA 115(35): 8775-8780). THIS STUDY PROVIDES A BASIS FOR FUTURE STUDIES OF UHRF1 FUNCTION AND ITS EFFECT ON THE CHROMATIN ACTIVITY OF THE DNMT1 ENZYME. THE LAIRD AND SHEN LABS REPORTED A NEW CLASS OF ARTIFACTS IN DNA METHYLATION MEASUREMENTS USING COMMON METHYLATION ARRAYS. THEY ALSO REPORTED A SOLUTION THAT ADDRESSES THESE PROBLEMS USING THE R PACKAGE SESAME, A SOLUTION THAT OUTPERFORMED THE EXISTING BEST STANDARDS FOR CROSS-PLATFORM CONSISTENCY (ZHOU ET AL., NUCLEIC ACIDS RESEARCH 46(20): E123). ANOTHER STUDY BY THE TWO LABS WAS BASED ON THE LOSS OF DNA METHYLATION IN CANCER GENOMES, ANALYZING A LARGE AND DIVERSE SET OF DATA SETS BY WHOLE-GENOME BISULFITE SEQUENCING. IN CANCER, LACK OF METHYLATION IN CERTAIN DOMAINS OF THE GENOME LIKELY REFLECTS MITOTIC AGE, WHICH GENERALLY IS CORRELATED WITH CHRONOLOGICAL AGE AND WHICH MIGHT FUNCTION AS A MITOTIC CLOCK (ZHOU ET AL., NATURE GENETICS 50: 591-602). THE LAIRD AND SHEN LABS HAVE ALSO BEEN HEAVILY INVOLVED IN THE CANCER GENOME ATLAS RESEARCH NETWORK. FROM THIS WORK CAME STUDIES TITLED "COMPARATIVE MOLECULAR ANALYSIS OF GASTROINTESTINAL ADENOCARCINOMAS" (LIU ET AL., CANCER CELL 33(4): 721-735.E8) AND "INTEGRATED MOLECULAR CHARACTERIZATION OF TESTICULAR GERM CELL TUMORS" (SHEN ET AL., CELL REPORTS 23(11): 3392-3406). IN ADDITION, A SERIES OF OVER TWO DOZEN "PAN-CANCER" PAPERS WERE PUBLISHED BY THE NETWORK IN THE SPRING OF 2018 IN WHICH DRS. LAIRD AND SHEN (OR BOTH) WERE COAUTHORS. LAIRD WAS THE LAST AUTHOR ON ONE OF THREE FLAGSHIP THEMATIC PAPERS, "CELL-OF-ORIGIN PATTERNS DOMINATE THE MOLECULAR CLASSIFICATION OF 10,000 TUMORS FROM 33 TYPES OF CANCER" (HOADLEY ET AL., CELL 173(2): 291-304.E6), AND SHEN WAS ONE OF SIX EXPERTS INVITED TO AUTHOR A RETROSPECTIVE ON TCGA'S LEGACY. A SAMPLING OF THE PAN-CANCER PAPERS INCLUDES "GENOMIC AND MOLECULAR LANDSCAPE OF DNA DAMAGE REPAIR DEFICIENCY ACROSS THE CANCER GENOME ATLAS" (KNIJNENBURG ET AL., CELL REPORTS 33(4): 721-735.E8); "MACHINE LEARNING IDENTIFIES STEMNESS FEATURES ASSOCIATED WITH ONCOGENIC DEDIFFERENTIATION" (MALTA ET AL., CELL 173(2): 338-354.E15); "THE IMMUNE LANDSCAPE OF CANCER" (THORSSON ET AL., IMMUNITY 48(4): 812-830.E13); AND "ONCOGENIC SIGNALING PATHWAYS IN THE CANCER GENOME ATLAS" (SANCHEZ-VEGA ET AL., CELL 173(2): 321-337.E10). FORM 990, PART III, LINE 4C LINE 4C - PROGRAM SERVICE ACTIVITY #3 CENTER FOR NEURODEGENERATIVE SCIENCE THE CENTER WAS ESTABLISHED IN 2012 UNDER PATRIK BRUNDIN, M.D., PH.D., WHO IS ALSO ASSOCIATE DIRECTOR OF VARI. IT CURRENTLY HAS NINE LABORATORIES STUDYING PARKINSON'S DISEASE, ALZHEIMER'S DISEASE, PRIONS, AND THE RELATIONSHIPS BETWEEN DEPRESSION, SUICIDE, AND BRAIN INFLAMMATION. CENTER RESEARCHERS AND TRAINEES DURING THIS FISCAL YEAR RECEIVED TWO R21 GRANTS FROM THE NATIONAL INSTITUTES OF HEALTH AND FOUR AWARDS FROM THE MICHAEL J. FOX FOUNDATION, AS WELL AS AWARDS FROM THE U.S. DEPARTMENT OF DEFENSE, THE EAST TENNESSEE FOUNDATION, AND MICHIGAN STATE UNIVERSITY. ALSO RECEIVED WAS A FELLOWSHIP FROM THE PARKINSONS'S DISEASE FOUNDATION, AND FOUR GRANT SUBAWARDS. PATRIK BRUNDIN'S LABORATORY BIOCHEMICALLY PROFILED MORE THAN 250 CHEMICALS FOUND IN BRAIN TISSUE AND SERUM FROM A PARKINSON'S DISEASE MOUSE MODEL (GRAHAM ET AL., JOURNAL OF PROTEOME RESEARCH 17(7): 2460-2469). THEY IDENTIFIED THE BEST SIX OF THESE METABOLITES IN TERMS OF IDENTIFYING DISEASED ANIMALS FROM CONTROLS. THE STUDY PROVIDES AN EARLY STEP IN DEVELOPING ROBUST BIOMARKERS FOR PARKINSON'S DISEASE, WHICH ARE LACKING. ANOTHER STUDY PROFILED 18 BILE ACIDS FOUND IN THE SERUM OF MICE HAVING PRODROMAL PARKINSON'S DISEASE (GRAHAM ET AL., METABOLITES 8(4): 71). THE CONCENTRATIONS OF THREE OF THESE COMPOUNDS WERE SIGNIFICANTLY DIFFERENT FROM THOSE OF CONTROL MICE, AND THOSE DATA COULD DISCRIMINATE BETWEEN PRODROMAL AND CONTROL MICE WITH HIGH ACCURACY. THESE COMPOUNDS ARE CANDIDATE BIOMARKERS FOR PREDICTING PARKINSON'S DISEASE AND POSSIBLY ITS PROGRESSION. IN A THIRD STUDY, THE LAB REPORTED THAT 12-18 MONTHS AFTER INJECTION OF ALPHA-SYNUCLEIN FIBRILS INTO THE MOUSE OLFACTORY BULB, THE NUMBER OF BRAIN REGIONS SHOWING PARKINSON'S-LIKE PATHOLOGY INCREASED, BUT AT 23 MONTHS, NO ADDITIONAL REGIONS WERE AFFECTED (REY ET AL., ACTA NEUROPATHOLOGICA 135(1): 65-83). THE REASON FOR THE LACK OF CONTINUED PROGRESSION COULD BE COMPROMISED NEURAL CIRCUITRY DUE TO THE EXTENT OF NEURON DEATH FROM THE PATHOLOGY. VIVIANE LABRIE'S LAB PUBLISHED A PAPER SHOWING THAT, IN TWO INDEPENDENT EPIDEMIOLOGICAL DATA SETS INVOLVING NEARLY 1.7 MILLION INDIVIDUALS FOR UP TO 52 YEARS, REMOVAL OF THE APPENDIX WAS ASSOCIATED WITH A LOWER RISK OF PARKINSON'S DISEASE (KILLINGER ET AL., SCIENCE TRANSLATIONAL MEDICINE 10: EAAR5280). THE STUDY SHOWED THAT THE HEALTHY APPENDIX CONTAINS ALPHA-SYNUCLEIN AGGREGATES LIKE THOSE FOUND IN LEWY BODIES, WHICH ARE A HALLMARK OF PARKINSON'S DISEASE NEURONS. THE AUTHORS CONCLUDED THAT THE APPENDIX CONTAINS FORMS OF ALPHA-SYNUCLEIN THAT AFFECT THE RISK OF DEVELOPING PARKINSON'S DISEASE AND THAT REMOVAL OF THE APPENDIX MAY HAVE BENEFIT IF DONE EARLY IN LIFE, PARTICULARLY FOR PERSONS LIVING IN RURAL AREAS. PRION DISEASES ARE FATAL NEURODEGENERATIVE DISORDERS THAT AFFECT HUMANS AND ANIMALS. THE MA LABORATORY COMPARED ENZYME-DIGESTED AND UNDIGESTED RECOMBINANT PRIONS. A TIME COURSE STUDY SHOWED THAT AN INCREASED CAPABILITY TO SEED THE CONVERSION OF NORMAL PRION PROTEIN TO A PATHOGENIC FORM WAS RELATED TO THE AMOUNT OF ENZYME-RESISTANT RECOMBINANT PRION FRAGMENTS (WANG ET AL., ACTA NEUROPATHOLOGICA COMMUNICATIONS 6: 30). THE MA LAB ALSO COLLABORATED IN A STUDY OF THE ROLE OF 14-3-3 PROTEINS IN THE CELL-TO-CELL TRANSFER OF ALPHA-SYNUCLEIN. SUCH PROTEINS REDUCED ALPHA-SYNUCLEIN TRANSFER AND TOXICITY, BUT INHIBITION OF 14-3-3 PROTEINS ACCELERATED THE TRANSFER. DYSFUNCTION OF 14-3-3 PROTEINS MAY BE A KEY ELEMENT IN ALPHA-SYNUCLEIN PROPAGATION (WANG ET AL., JOURNAL OF NEUROSCIENCE 38(38): 8211-8232). IN ANOTHER PROJECT, THEY STUDIED THE AGGREGATION OF ALPHA-SYNUCLEIN IN BRAIN TISSUE FROM PATIENTS WHO HAD THE NEURODEGENERATIVE DISORDER CALLED MULTIPLE SYSTEM ATROPHY. ADAPTING THE PMCA ASSAY, THEY CONFIRMED THAT THE SEEDING ACTIVITY OF ALPHA-SYNUCLEIN REMAINS ACTIVE EVEN IN FORMALDEHYDE-FIXED TISSUES (BECKER ET AL., MOLECULAR NEUROBIOLOGY 55(11): 8728-8737). THIS STUDY ALSO PROVIDES A BASIS FOR FURTHER ADAPTING THE PMCA ASSAY FOR EVALUATING ALPHA-SYNUCLEIN AGGREGATES AS A BIOMARKER OF DISEASE. DARREN MOORE'S LAB REPORTED A NEW FUNCTIONAL INTERACTION BETWEEN THE PARKIN AND VPS35 PROTEINS, BOTH OF WHICH HAVE BEEN FOUND MUTATED IN INHERITED PARKINSON'S DISEASE (WILLIAMS ET AL., HUMAN MOLECULAR GENETICS 27(18): 3189-3205). PARKIN UBIQUITINATES VPS35 IN HUMAN NEURONS, A PROCESS THAT MAY BE INVOLVED IN REGULATING RETROMER-DEPENDENT SORTING AND WHICH MAY HAVE EFFECTS IN PARKINSON'S DISEASE. IN ANOTHER STUDY, THE LAB FOCUSED ON THE LRRK2 GENE, MUTATIONS IN WHICH CAUSE LATE-ONSET PARKINSON'S DISEASE. SUCH MUTATIONS TYPICALLY CAN GIVE RISE TO THE CHARACTERISTIC LEWY BODIES IN NEURONS BUT CAN ALSO INDUCE TAU-POSITIVE NEUROPATHOLOGY. THE DATA SUGGESTED THAT MUTANT TAU-INDUCED PATHOLOGY IS INDEPENDENT OF LRRK2 EXPRESSION BUT ALSO SHOWED A NOVEL ROLE FOR LRRK2 IN PROMOTING NEURONAL TRANSMISSION OF WILD-TYPE TAU PROTEIN. THIS FINDING MAY AID IN UNDERSTANDING HOW TAU PATHOLOGY DEVELOPS IN THE BRAINS OF PATIENTS WHO HAVE LRRK2-RELATED DISEASE (NGUYEN ET AL., HUMAN MOLECULAR GENETICS 27(1): 120-134). THE COETZEE LABORATORY PUBLISHED A STUDY COMPARING GENOME-WIDE GENE EXPRESSION IN UNDIFFERENTIATED AND DIFFERENTIATED LUHMES CELLS AS MODELS OF THE HUMAN NEURONS AFFECTED BY PARKINSON'S DISEASE. ONLY DIFFERENTIATED CELLS SHOWED AN INCREASE IN GENETIC POLYMORPHISMS THAT CARRY A RISK FOR PARKINSON'S DISEASE (PIERCE ET AL., NEUROBIOLOGY OF DISEASE 118: 53-64). THE LAB ALSO COLLABORATED ON A STUDY OF GENETIC REGULATORY ELEMENTS INVOLVED IN PROSTATE CANCER RISK (GUO ET AL., GENOME BIOLOGY 19: 160). THAT STUDY IDENTIFIED RISK-ASSOCIATED SITES FOR BINDING OF THE CTCF PROTEIN IN LONG-RANGE CHROMATIN LOOPS. THE DELETION OF THOSE SITES VIA THE CRISPR-CAS TECHNIQUE INCREASED GENE EXPRESSION WITHIN THE LOOPS. ANOTHER COLLABORATIVE PROJECT FOCUSED ON COLORECTAL CANCER AND INVOLVED A GENOME-WIDE ASSOCIATION STUDY BASED ON SAMPLES FROM MORE THAN 160,000 INDIVIDUALS (SCHMIT ET AL., JOURNAL OF THE NATIONAL CANCER INSTITUTE, IN PRESS). THE RESULTS PROVIDE INSIGHT INTO THE GENETIC ARCHITECTURE THAT CONTRIBUTES TO COLORECTAL CANCER AND WILL HELP IMPROVE THE SCREENING OF INDIVIDUALS FOR PREDICTING THEIR RISK OF THE DISEASE. FORM 990, PART IX, COLUMN D FUNDRAISING EXPENSES AT VARI WERE INCURRED TO SUPPORT THE MISSION OF THE RESEARCH INSTITUTE THROUGH DONOR SOLICITATION, GRANT SOLICITATION AND EXTRAMURAL PROPOSAL PREPARATION. FORM 990, PART X, LINE 33 VARI NET ASSETS ARE CONSIDERED ON A CONSOLIDATED BASIS WITH VAN ANDEL INSTITUTE (VAI)AND VAN ANDEL EDUCATION INSTITUTE (VAEI). ON A CONSOLIDATED BASIS, NET ASSETS ARE $1,545,485,000 PER AUDITED FINANCIAL STATEMENTS. THE NEGATIVE NET ASSET BALANCE AT VARI IS DUE TO VAI FUNDING EXPENSES ON A CASH BASIS AND THE UNREALIZED LOSS RECORDED IN ASSOCIATION WITH THE INTEREST RATE SWAP. VAI INNOVATIONS LLC 333 BOSTWICK AVENUE NE GRAND RAPIDS MI 495032518 522000823 LICENSING INTELLECTUAL PROPERTY OF VARI MI 0 0 VAN ANDEL RESEARCH INSTITUTE BOSTWICK EVENT MANAGEMENT 333 BOSTWICK AVENUE NE GRAND RAPIDS MI 495032518 522000823 EVENT MANAGEMENT MI 42533 118162 VAN ANDEL RESEARCH INSTITUTE VAN ANDEL INSTITUTE 333 BOSTWICK AVENUE NE GRAND RAPIDS MI 495032518 522000820 SUPPORTING ORGANIZATION FOR VARI AND VAEI MI 501(C)(3) 12C N/A 0 VAN ANDEL EDUCATION INSTITUTE 333 BOSTWICK AVENUE NE GRAND RAPIDS MI 495032518 522000824 OPERATING A SCIENCE EDUCATION PROGRAM MI 501(C)(3) 2 VAN ANDEL INSTITUTE 1 VAN ANDEL INSTITUTE GRADUATE SCHOOL 333 BOSTWICK AVENUE NE GRAND RAPIDS ME 495032518 203340886 OPERATING A GRADUATE SCHOOL MI 501(C)(3) 2 VAN ANDEL EDUCATION INSTITUTE 1 0 0 1 0 1 0 0 0 0 0 0 0 0 1 1 1 1 0 0 VAN ANDEL INSTITUTE C 54765920 ACTUAL AMOUNT PAID VAN ANDEL INSTITUTE E 19640000 TOTAL RECORDED VAN ANDEL INSTITUTE N 313545 ALLOCATION BASED ON SQ. FOOTAGE VAN ANDEL INSTITUTE P 1258660 ACTUAL AMOUNT PAID VAN ANDEL INSTITUTE N 191463 ALLOCATION BASED ON EFFORT VAN ANDEL INSTITUTE O 1283588 ALLOCATION BASED ON EFFORT VAN ANDEL EDUCATION INSTITUTE P 178528 ACTUAL AMOUNT PAID VAN ANDEL EDUCATION INSTITUTE Q 1642569 ACTUAL AMOUNT RECEIVED VAN ANDEL EDUCATION INSTITUTE N 48313 ALLOCATION BASED ON EFFORT VAN ANDEL EDUCATION INSTITUTE O 323896 ALLOCATION BASED ON EFFORT VAN ANDEL INSTITUTE GRADUATE SCHOOL O 79895 APPORTIONED FY18 COMPENSATION VAN ANDEL INSTITUTE GRADUATE SCHOOL N 23262 ALLOCATION BASED ON EFFORT VAN ANDEL INSTITUTE GRADUATE SCHOOL N 176369 ALLOCATION BASED ON SQ. FOOTAGE VAN ANDEL INSTITUTE GRADUATE SCHOOL Q 240227 ACTUAL AMOUNT RECEIVED VAN ANDEL INSTITUTE GRADUATE SCHOOL O 155950 ALLOCATION BASED ON EFFORT VAN ANDEL INSTITUTE Q 6480507 ACTUAL AMOUNT PAID VAN ANDEL INSTITUTE E 5975807 TOTAL RECORDED