2018-10-22T08:38:17-05:00 2017-11-30 861065772 DELOITTE TAX LLP 200 RENAISSANCE CENTER STE 3900 DETROIT MI 48243 990 2016-12-01 522000823 VAN ANDEL RESEARCH INSTITUTE VANA 6162345000 333 BOSTWICK AVENUE NE GRAND RAPIDS MI 49503 TIMOTHY J MYERS VICE PRESIDENT & CFO 6162345368 2018-10-22 1 ANNE FULTON P00941863 3133963000 155.130.133.20 2018-10-22 09:37:10 ED P 1EE6A5E81395B9FE30C17C399D7BCA7C06F9E4C4 1EE6A5E81395B9FE30C17C399D7BCA7C06F9E4C4 2016 2018-06-14 16:35:46Z TIMOTHY J MYERS 333 BOSTWICK AVENUE NE GRAND RAPIDS MI 49503 84632935 0 X WWW.VAI.ORG X 1996 MI MEDICAL RESEARCH ORGANIZATION 6 5 449 17 97094 12590 50933876 71484792 1303818 1122867 588028 993632 6683167 9465550 59508889 83066841 1008183 1012021 0 0 35314051 36040459 0 0 850682 36321022 38499186 72643256 75551666 -13134367 7515175 247782645 247321206 344529031 329139789 -96746386 -81818583 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 9117655 326109 162826 CENTER FOR CANCER AND CELL BIOLOGY SCHEDULE O PROVIDES FURTHER INFORMATION REGARDING THIS PROGRAM'S ACCOMPLISHMENTS. 9673133 631077 25843 CENTER FOR EPIGENETICSSCHEDULE O PROVIDES FURTHER INFORMATION REGARDING THIS PROGRAM'S ACCOMPLISHMENTS. 6249490 45835 286150 CENTER FOR NEURODEGENERATIVE SCIENCESEE SCHEDULE O FOR FURTHER INFORMATION ABOUT THIS PROGRAM'S ACCOMPLISHMENTS. 28176737 9000 648048 28176737 9000 648048 53217015 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 1 125 0 449 1 1 1 0 0 0 0 1 1 0 0 0 0 X 6 5 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 442120 0 129404 DR GEORGE VANDE WOUDE TRUSTEE/INVESTIGATOR (ENDED 9/30/17) 45.00 0.00 X 302486 0 28328 DR JAMES FAHNER TRUSTEE 1.00 1.00 X 10000 2000 0 DR RALPH WEICHSELBAUM TRUSTEE 1.00 0.00 X 9000 0 0 DR MAX WICHA TRUSTEE 1.00 0.00 X 4500 0 0 DR MICHELLE LEBEAU TRUSTEE 1.00 0.00 X 6500 0 0 DR TOM DEMEESTER TRUSTEE 1.00 0.00 X 6500 0 0 DR JANA HALL CHIEF OPERATIONS OFFICER 52.00 3.00 X 394557 0 118663 TIMOTHY MYERS V.P. & CHIEF FINANCIAL OFFICER 50.00 3.00 X 298609 0 85683 DR PETER JONES CHIEF SCIENTIFIC OFFICER & RES. DIR. 53.00 0.00 X 703892 0 187623 KATHY VOGELSANG CHIEF INVESTMENT OFFICER 45.00 0.00 X 431378 0 285963 DR PATRIK BRUNDIN ASSOCIATE RESEARCH DIRECTOR 45.00 0.00 X 476236 0 101475 DR GERALD CALLAHAN V.P., INNOVATIONS & COLLABORATIONS 45.00 0.00 X 349955 0 103683 DR PETER LAIRD INVESTIGATOR 45.00 0.00 X 393922 0 60411 DR GERD PFEIFER INVESTIGATOR 45.00 0.00 X 347966 0 47795 DAVID WHITESCARVER FORMER SECRETARY/V.P.(ENDED 8/31/16) 0.00 0.00 X 367546 0 61794 4545167 2000 1210822 67 1 1 0 PRESIDIO NETWORK SOLUTIONS GROUP LLC PO BOX 677638 DALLAS TX 752677638 CONSULTING SERVICES 394030 DK SECURITY INC 5160 FALCONVIEW AVE SE KENTWOOD MI 49512 SECURITY SERVICES 310903 BECKMAN COULTER DEPT CH10164 PALATINE IL 600550164 SERVICE CONTRACT 262610 HONIGMAN MILLER SCHWARTZ LLC 660 WOODWARD AVE DETROIT MI 48226 LEGAL / CONSULTING 259150 TRANE PO BOX 98167 CHICAGO IL 60693 SERVICE CONTRACT 147718 14 63224 45881651 14303760 11236157 7335360 71484792 RESEARCH BILLED REV 541700 1122867 1048997 73870 1122867 853253 853253 1306364 1306364 1511149 1525162 -14013 -14013 -14013 162311 21932 140379 140379 140379 8385 63224 19000 -10615 -10615 ALLOCATED ADMIN. 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PART XI, LINE 2D - OTHER ADJUSTMENTS: RENTAL EXPENSES 1,525,162. FUNDRAISING EVENT EXPENSE 19,000. PART XI, LINE 4B - OTHER ADJUSTMENTS: NET ALLOCATED 7,001,053. PART XII, LINE 2D - OTHER ADJUSTMENTS: RENTAL EXPENSES 1,525,162. FUNDRAISING EVENT EXPENSE 19,000. GAIN ON INTEREST RATE SWAP -7,335,352. PART XII, LINE 4B - OTHER ADJUSTMENTS: NET ALLOCATED 7,001,053. 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 174172 EUROPE 0 0 PROGRAM SERVICES RESEARCH COLLABORATION - RESEARCH SERVICES 565830 0 1 0 0 0 1 740002 0 740002 EUROPE RESEARCH COLLABORATION 144536 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 40270 31885 8385 5848 GRIFFINS 31339 31339 13152 71609 63224 8385 19000 19000 -10615 1 JOHNS HOPKINS UNIVERSITY 3400 N CHARLES STREET BALTIMORE MD 21218 520595110 501C3 146253 RESEARCH COLLABORATION UNIVERSITY OF SOUTHERN CALIFORNIA 1450 BIGGY STREET LOS ANGELES CA 90089 951642394 501C3 48684 RESEARCH COLLABORATION MEMORIAL SLOAN-KETTERING CANCER CENTER 1275 YORK AVENUE NEW YORK NY 10065 131924236 501C3 150000 RESEARCH COLLABORATION INSTITUTE FOR CANCER RESEARCH 333 COTTMAN AVE INSTITUTIONAL ADVANCEMENT PHILADELPHIA PA 19111 232003072 501C3 97467 RESEARCH COLLABORATION MICHIGAN STATE UNIVERSITY 220 TROWBRIDGE RD EAST LANSING MI 48824 386005984 501C3 155875 RESEARCH COLLABORATION FRIENDS OF CRESCENT PARK 301 BOSTWICK NE GRAND RAPIDS MI 49503 264562012 501C3 9000 SUPPORT CRESCENT PARK MAINTENANCE 6 0 GRADUATE STUDENT STIPENDS FOR MICHIGAN STATE UNIVERSITY STUDENTS 3 116586 GRADUATE STUDENT STIPENDS VAN ANDEL INSTITUTE GRADUATE SCHOOL 2 50668 FOREIGN NATIONAL STIPENDS 6 63366 GUEST STUDENT STIPENDS 2 27851 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 X 1 0 0 1 0 0 0 0 0 DAVID VAN ANDEL CHAIRMAN / CEO 334231 0 88200 0 19689 0 128500 0 904 0 571524 0 88200 0 DR GEORGE VANDE WOUDE TRUSTEE/INVESTIGATOR (ENDED 9/30/17) 282706 0 0 0 19780 0 26500 0 1828 0 330814 0 0 0 DR JANA HALL CHIEF OPERATIONS OFFICER 334482 0 56511 0 3564 0 108000 0 10663 0 513220 0 56511 0 TIMOTHY MYERS V.P. & CHIEF FINANCIAL OFFICER 250302 0 47502 0 805 0 75020 0 10663 0 384292 0 47502 0 DR PETER JONES CHIEF SCIENTIFIC OFFICER & RES. DIR. 548834 0 130200 0 24858 0 176960 0 10663 0 891515 0 130200 0 KATHY VOGELSANG CHIEF INVESTMENT OFFICER 276056 0 135000 0 20322 0 275300 0 10663 0 717341 0 135000 0 DR PATRIK BRUNDIN ASSOCIATE RESEARCH DIRECTOR 424339 0 49575 0 2322 0 90812 0 10663 0 577711 0 49575 0 DR GERALD CALLAHAN V.P., INNOVATIONS & COLLABORATIONS 260026 0 76719 0 13210 0 93020 0 10663 0 453638 0 76719 0 DR PETER LAIRD INVESTIGATOR 368114 0 23486 0 2322 0 49748 0 10663 0 454333 0 0 0 DR GERD PFEIFER INVESTIGATOR 339168 0 5234 0 3564 0 37132 0 10663 0 395761 0 0 0 DAVID WHITESCARVER FORMER SECRETARY/V.P.(ENDED 8/31/16) 242497 0 65033 0 60016 0 54685 0 7109 0 429340 0 61531 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 $46,698 FROM VAN ANDEL INSTITUTE FOR CALENDER YEAR 2016. PART I, LINE 5 BONUS IS PAID BASED ON GRANT REVENUE EARNED FOR ELIGIBLE PROGRAM PARTICIPANTS. A MICHIGAN STRATEGIC FUND 521417332 000000000 2013-04-01 220000000 REFUND BOND ISSUE 4/10/08 0 0 0 A 220000000 220000000 1 0 1 1 A 0 0 1 1 1 1 0.00450 0.00450 0 0 1 A 0 0 0 1 1 0 0 0 1 A 1 DATE REBATE COMPUTATION PERFORMED ISSUER NAME: MICHIGAN STRATEGIC FUND DATE THE REBATE COMPUTATION WAS PERFORMED: 11/30/2014 X 1 7335360 FMV 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 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 7,335,352. 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. WITH EPIGENETICS AS ITS COMMON THREAD, VARI IS ORGANIZED INTO THE CENTER FOR CANCER AND CELL BIOLOGY, THE CENTER FOR EPIGENETICS, AND THE CENTER FOR NEURODEGENERATIVE SCIENCE. THE CORE TECHNOLOGIES AND SERVICES GROUP PROVIDES A VIVARIUM, A BIOREPOSITORY, AND VALUABLE ON-SITE CAPABILITIES IN IMAGING, PATHOLOGY, BIOINFORMATICS, GENOMICS, FLOW CYTOMETRY, AND CRYO-ELECTRON MICROSCOPY. RESEARCH BY VARI SCIENTISTS WAS PUBLISHED IN 136 ARTICLES IN MAJOR PEER-REVIEWED JOURNALS THAT INCLUDED NATURE, NATURE COMMUNICATIONS, NATURE GENETICS, CELL, PHYSIOLOGICAL REVIEWS, CELL RESEARCH, CELL REPORTS, GENES AND DEVELOPMENT, CLINICAL CANCER RESEARCH, NUCLEIC ACIDS RESEARCH, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES U.S.A., ONCOGENE, CANCER CELL, BONE, NEURON, HUMAN MOLECULAR GENETICS, NATURE REVIEWS NEUROLOGY, LANCET NEUROLOGY, MOLECULAR CARCINOGENESIS, EPIGENETICS AND CHROMATIN, JOURNAL OF VIROLOGY, JOURNAL OF BIOLOGICAL CHEMISTRY, JOURNAL OF CELL SCIENCE, ANALYTICAL CHEMISTRY, SCIENTIFIC REPORTS, JOURNAL OF BACTERIOLOGY, JOURNAL OF PARKINSON'S DISEASE, JOURNAL OF NEUROSCIENCE, NEUROPHARMACOLOGY, MOVEMENT DISORDERS, BIOCHEMISTRY, CANCER LETTERS, NEUROBIOLOGY OF DISEASE, JOURNAL OF MOLECULAR NEUROSCIENCE, GENOME BIOLOGY, PROTEIN SCIENCE, PLOS ONE, ONCOTARGET, AND PLOS PATHOGENS. 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 12 LABORATORIES ENGAGED IN BASIC RESEARCH IN MOLECULAR AND STRUCTURAL BIOLOGY AND IN TRANSLATIONAL RESEARCH ON CANCERS, THE TUMOR MICROENVIRONMENT, AND SKELETAL DISEASES. DR. WEI LU AND JUAN DU JOINED THE CENTER DURING THE YEAR. IN THIS FISCAL YEAR, RESEARCHERS WITHIN THE CENTER RECEIVED A NEW R01 AWARD FROM THE NATIONAL INSTITUTES OF HEALTH, NEW AWARDS FROM THE ARTHRITIS NATIONAL RESEARCH FOUNDATION, ST. BALDRICK'S FOUNDATION, AND ALEX'S LEMONADE STAND, AND A RENEWAL AWARD FROM THE BREAST CANCER RESEARCH FOUNDATION. A NEW RESEARCH CONTRACT WAS SIGNED IN 2017, AND FIVE GRANT SUBAWARDS WERE ALSO RECEIVED. THE NEW VARI SUITE OF CRYOGENIC-ELECTRON MICROSCOPY (CRYO-EM) INSTRUMENTS BEGAN OPERATION IN SPRING 2017. THE LU LABORATORY MADE EXCELLENT USE OF THIS NEW CAPABILITY TO DETERMINE THE STRUCTURE OF THE CA(2+)-ACTIVATED, NON-SELECTIVE HUMAN TRPM4 ION CHANNEL BOUND TO THE CA(2+) ION AND A MODULATOR. THIS MOLECULE IS COMMON IN HUMAN CELLS AND DIRECTLY AFFECTS CRUCIAL PROCESSES SUCH AS CARDIAC RHYTHM, CELL DEPOLARIZATION, AND THE IMMUNE RESPONSE (WINKLER ET AL., NATURE 552(7684): 200-204). OTHER MOLECULAR STRUCTURE STUDIES ALSO MADE IMPORTANT SCIENTIFIC ADVANCES. JASMONATE IS A PLANT HORMONE VITAL IN NORMAL DEVELOPMENT AND IN RESPONDING TO STRESSES LIKE DROUGHT. THE STRUCTURE OF A KEY CELL SIGNALING NODE CALLED THE MYC3-CMID COMPLEX WAS DETERMINED BY THE MELCHER LAB. THIS STRUCTURE SHOWED THE MOLECULAR MECHANISM THAT IS USED BY PLANT CELLS TO APPROPRIATELY CONTROL HORMONAL SIGNALING (ZHANG ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES U.S.A. 117(7): 1720-1725). THE MELCHER AND XU LABS ALSO STUDIED THE GLUCAGON RECEPTOR, WHICH HAS A CENTRAL ROLE IN GLUCOSE METABOLISM AND HOMEOSTASIS AND THUS IS A KEY THERAPEUTIC TARGET IN DIABETES AND OBESITY. THE LABS DISCOVERED TWO WAYS TO ACTIVATE THE RECEPTOR, WHICH IS IMPORTANT PHARMACOLOGICALLY, AND ONE OF THOSE PROVIDES A MODEL FOR HOW OTHER CLASS B G-PROTEIN-COUPLED RECEPTORS FUNCTION (YIN ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY 292(24): 9865-9881). WNT SIGNALING AFFECTS PROCESSES SUCH AS EMBRYOGENESIS AND THE DEVELOPMENT OF CANCER, BUT HOW WNT SIGNALING IS ACTIVATED IS POORLY UNDERSTOOD. A STUDY OF THE STRUCTURE OF WNT5A BOUND TO THE FRIZZLED RECEPTOR BY THE MELCHER AND XU LABS FOUND THAT WNT BINDING CAUSED TWO DOMAINS OF THE RECEPTOR TO BIND TOGETHER. THIS KNOWLEDGE IMPROVES OUR UNDERSTANDING OF HOW WNT SIGNALING FUNCTIONS WITHIN THE CELL AND AT THE CELL MEMBRANE (DEBRUINE ET AL., GENES AND DEVELOPMENT 31(9): 916-926). THE GROHAR LAB CONDUCTED A PHASE I/II TRIAL TO DETERMINE THE DOSE-LIMITING TOXICITY, MAXIMUM TOLERATED DOSE, AND PHARMACOKINETICS OF MITHRAMYCIN AGAINST REFRACTORY SOLID TUMORS AND REFRACTORY EWING SARCOMA. LIVER TOXICITY PRECLUDED THE ADMINISTRATION OF MITHRAMYCIN AT A DOSE REQUIRED TO INHIBIT THE EWS-FLI1 TRANSCRIPTION FACTOR, A KEY DRIVER OF EWING SARCOMA TUMORS (GROHAR ET AL., CANCER CHEMOTHERAPY AND PHARMACOLOGY 80(3): 645-652). IN A STUDY OF 201 PATIENTS WITH PRIMARY GASTRIC CARCINOMA, THE VANDE WOUDE LAB AND COLLABORATORS FOUND THAT THE EXPRESSION OF THE MET4 RECEPTOR PREDICTED POOR PROGNOSIS OF GASTRIC CANCERS WITH H. PYLORI INFECTION. H. PYLORI STIMULATED MET-POSITIVE GASTRIC CANCERS AND ACTIVATED MET DOWNSTREAM SIGNALING, PROMOTING CANCER PROLIFERATION AND ANTI-APOPTOTIC ACTIVITY (SAKAMOTO ET AL., CANCER SCIENCE 108(3): 322-330). THE VANDE WOUDE LAB ALSO PUBLISHED A STUDY OUTLINING A PARADIGM OF TUMOR METASTASIS. PRIMARY EPITHELIAL CARCINOMA CELLS THAT LOSE CHROMOSOMES CARRYING GENES FOR INTERCELLULAR JUNCTIONS DEVELOP AN INVASIVE PHENOTYPE, AND SUBSEQUENT CHROMOSOME CHANGES (SUCH AS LOSS OF 10P) GENERATE CELLS THAT CAN GENERATE EPITHELIAL TUMORS AT THE METASTATIC SITE (GAO, ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES U.S.A. 113(51): 14793-14798). THE WILLIAMS LAB PUBLISHED A STUDY ON HOW THE LOSS OF THE TUMOR SUPPRESSORS SMAD4 AND APC IN LUMINAL PROSTATE CELLS PRODUCED INVASIVE, CASTRATION-RESISTANT PROSTATE CANCER IN MICE. THOSE CELLS ALSO COMMONLY LOST THE ANDROGEN RECEPTOR. UPON ANDROGEN CYCLING, TUMORS WERE FOUND TO DISAPPEAR IN THESE MICE (VALKENBURG ET AL., ONCOTARGET 8(46): 80265-80277). THE LAB ALSO FOUND THAT WHILE DELETION OF THE CDC73 GENE IN MESENCHYMAL PROGENITOR CELLS CAUSED EMBRYONIC DEATH, A SIMILAR DELETION IN OSTEOBLASTS AND OSTEOCYTES INCREASED CORTICAL AND TRABECULAR BONE MASS. THESE RESULTS REFLECT THE ROLE OF PARAFIBROMIN IN TRANSCRIPTIONAL REGULATION, TERMINAL DIFFERENTIATION, AND BONE HOMEOSTASIS (DROSCHA ET AL., BONE 98: 68-78). THE YANG LABORATORY DEVELOPED A MOUSE MODEL HAVING A MUTATED SCLT1 GENE, WHICH CAUSED A LOSS OF CILIA IN KIDNEY CELLS AND RESULTED IN CYSTIC KIDNEY, AMONG OTHER SYMPTOMS. THE DATA SUGGEST THAT INHIBITION OF STAT3 MAY BE A PROMISING TARGET FOR TREATING SCLT1-RELATED CYSTIC KIDNEY DISEASE (LI ET AL., HUMAN MOLECULAR GENETICS 26(15): 2949-2960). THE WU LAB FOUND THAT THIOREDOXIN INTERACTING PROTEIN (TXNIP) IS RESPONSIBLE FOR MEDIATING AKT-DEPENDENT ACUTE GLUCOSE INFLUX AFTER GROWTH FACTOR STIMULATION. TXNIP FUNCTIONS AS AN ADAPTOR FOR THE BASAL ENDOCYTOSIS OF GLUT4 IN VIVO; ITS ABSENCE ALLOWS EXCESS GLUCOSE UPTAKE IN MUSCLE AND ADIPOSE TISSUES, CAUSING HYPOGLYCEMIA DURING FASTING. THUS, TXNIP SERVES AS A KEY NODE OF SIGNAL REGULATION FOR MODULATING GLUCOSE INFLUX THROUGH GLUCOSE TRANSPORTERS GLUT1 AND GLUT4 (WALDHART ET AL., CELL REPORTS 19(10): 2005-2013). THE MACKEIGAN LAB PUBLISHED A CATALOG OF THE GENOMIC LANDSCAPE OF TUBEROUS SCLEROSIS COMPLEX (TSC) HAMARTOMAS. THEY DETERMINED THAT TSC LESIONS CONTAIN A LOW MUTATIONAL BURDEN RELATIVE TO CARCINOMAS, BUT A SUBSET OF THE TUMORS HAVE LARGE-SCALE CHROMOSOMAL ABERRATIONS, AND HIGHLY CONSERVED MOLECULAR SIGNATURES FOR EACH TYPE EXIST. THE PAPER PROVIDES A FRAMEWORK THAT UNIFIES THE GENOMIC AND TRANSCRIPTOMIC DIMENSIONS OF COMPLEX TUMORS (MARTIN, ET AL., NATURE COMMUNICATIONS 8: 15816). THE HAAB LAB CONTINUED ITS WORK ON CHARACTERIZING THE PROTEINS FOUND IN PANCREATIC CANCER. THEY DEVELOPED AN ASSAY FOR OBTAINING INFORMATION ABOUT PROTEIN GLYCOSYLATION USING A MINIMAL AMOUNT (11 NANOGRAMS) OF PROTEIN, AS WELL AS AN ALGORITHM TO INTERPRET THE DATA AND PROVIDE PREDICTIONS ABOUT THE GLYCAN MOTIFS PRESENT IN THE SAMPLE. THE METHOD WAS ALSO EFFECTIVE FOR ANALYZING THE GLYCOSYLATION OF A CANCER BIOMARKER IN HUMAN PLASMA, MUC5AC, USING ONLY 20 MICROLITERS OF PLASMA (REATINI ET AL., ANALYTICAL CHEMISTRY 88(23): 11584-11592). THEY ALSO DEVELOPED A LANGUAGE AND AN ALGORITHM FOR THE ANALYSIS AND DESCRIPTION OF HIGHLY COMPLEX GLYCAN MOTIFS. THE ALGORITHM EVALUATES CHANGES IN LECTIN BINDING UPON TREATMENT WITH EXOGLYCOSIDASES. THE COMPLEX FEATURES IDENTIFIED WERE NOT ACCESSIBLE TO ANALYSIS USING PREVIOUS METHODS. THIS WORK WILL FACILITATE THE PRECISE DETERMINATION AND DESCRIPTION OF LECTIN AND GLYCOSIDASE SPECIFICITIES (KLAMER ET AL., ANALYTICAL CHEMISTRY 89(22): 12342-12350). IN A THIRD PAPER, THE HAAB LAB IDENTIFIED A CARBOHYDRATE ANTIGEN, STRA THAT IS AS ACCURATE A SERUM BIOMARKER OF PANCREATIC CANCER AS THE CANCER ANTIGEN CA19-9. THE STRA AND CA19-9 GLYCANS DEFINE SEPARATE SUBPOPULATIONS OF CANCER CELLS AND COULD TOGETHER HAVE VALUE FOR CLASSIFYING SUBTYPES OF PANCREATIC ADENOCARCINOMA (BARNETT ET AL., SCIENTIFIC REPORTS 7: 4020). FORM 990, PART III, LINE 4B LINE 4B - PROGRAM SERVICE ACTIVITY #2 CENTER FOR EPIGENETICS THE CENTER, ESTABLISHED IN 2014 AND DIRECTED BY PETER JONES, PH.D., D.SC., COMPRISES TEN LABORATORIES STUDYING EPIGENETICS AND EPIGENOMICS AND THE ROLE OF EPIGENETIC DYSFUNCTION IN CANCER AND NEURODEGENERATIVE DISEASE, CARDIOVASCULAR DISEASE, AND VIRAL TRANSCRIPTION. DR. TIMOTHY TRICHE JR. JOINED THE CENTER IN LATE 2017. NEW FUNDING IN THIS FISCAL YEAR FOR CENTER RESEARCHERS INCLUDED TWO R35 AWARDS, TWO R01 AWARDS, AND AN F31 GRANT FROM THE NATIONAL INSTITUTES OF HEALTH, A NEW GRANT FROM THE MICHIGAN ECONOMIC DEVELOPMENT CORPORATION, AND AN AMERICAN CANCER SOCIETY FELLOWSHIP. THE VARI-SU2C EPIGENETICS DREAM TEAM, LED BY PETER JONES AND STEPHEN BAYLIN, CONTINUED IN 2017 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 ACETYL GROUPS FROM THE HISTONE PROTEINS THE DNA IS WRAPPED AROUND. THE TEAM WAS AWARDED TWO OF THE TEN NEW SU2C CATALYST GRANTS FOR STUDIES OF EPIGENETIC THERAPIES AGAINST LUNG AND BLADDER CANCER. BOTH THE LAIRD AND SHEN LABORATORIES CONTRIBUTED TO A SERIES OF STUDIES UNDER THE CANCER GENOME ATLAS RESEARCH NETWORK THAT PRODUCED GENOMIC AND MOLECULAR CHARACTERIZATIONS OF VARIOUS CANCERS, INCLUDING ESOPHAGEAL CARCINOMA AND PANCREATIC DUCTAL ADENOCARCINOMA. THESE STUDIES PROVIDE A FRAMEWORK FOR MORE RATIONAL CATEGORIZING OF TUMORS AND A FOUNDATION FOR NEW THERAPIES (CANCER GENOME ATLAS RESEARCH NETWORK, CANCER CELL 32(2): 185-203.E13; CELL 171(4): 950-965; NATURE 541(7636): 169-175; CHERNIACK ET AL., CANCER CELL 31(3): 411-423). THE TWO LABS ALSO WERE COAUTHORS ON A STUDY OF 1000 BREAST CANCER SAMPLES THAT ACCURATELY CLASSIFIED MUTATIONS OF THE BRCA1 OR BRCA2 GENES KNOWN TO IMPAIR HOMOLOGOUS DNA RECOMBINATION. EPIGENETIC SILENCING OF THE RAD51C AND BRCA1 GENES BY PROMOTER METHYLATION WAS FREQUENTLY FOUND IN BASAL-LIKE BREAST CANCERS OF YOUNG INDIVIDUALS OF AFRICAN DESCENT (POLAK, NATURE GENETICS 49(10): 1476-1486). THE JONES LAB PUBLISHED A STUDY OF THE CHROMATIN REMODELING MOLECULE ARID1A, WHICH IS OFTEN MUTATED IN OVARIAN CLEAR CELL CARCINOMA (OCCC) AND ENDOMETRIOSIS PRECURSOR LESIONS. KNOCKING DOWN ARID1A IN AN IMMORTALIZED ENDOMETRIOSIS CELL LINE WAS SUFFICIENT TO PRODUCE CHANGES INDICATIVE OF NEOPLASTIC TRANSFORMATION, AS EVIDENCED BY HIGHER EFFICIENCY OF ANCHORAGE-INDEPENDENT GROWTH, INCREASED PROPENSITY TO ADHERE TO COLLAGEN, AND GREATER CAPACITY TO INVADE BASEMENT MEMBRANE EXTRACT IN VITRO (LAKSHMINARASIMHAN ET AL., CANCER LETTERS 401: 11-19). IN ANOTHER STUDY, THE LAB CATEGORIZED THE AGGRESSIVENESS OF INDIVIDUAL PROSTATE CANCER FOCI BASED ON DNA METHYLATION PATTERNS IN PRIMARY FOCI AND MATCHED LYMPH NODE METASTASES. THIS STUDY PROVIDES A CLASSIFICATION OF PROSTATE CANCER AGGRESSIVENESS THAT HAS THE POTENTIAL TO IMPROVE CLINICAL DECISION-MAKING, SUCH AS TARGETED BIOPSY APPROACHES FOR EARLY DIAGNOSIS AND ACTIVE SURVEILLANCE (MUNDBJERG ET AL., GENOME BIOLOGY 18(1): 3). IN A STAND UP TO CANCER COLLABORATIVE STUDY, THE LAB PARTICIPATED IN THE FIRST TRIAL OF CRC PATIENTS WITH COMBINATION EPIGENETIC THERAPY. THE TRIAL SHOWED TOLERABLE THERAPY WITHOUT SIGNIFICANT CLINICAL ACTIVITY, AS DETERMINED BY RECIST RESPONSES. A REVERSAL OF HYPERMETHYLATION WAS SEEN IN A SUBSET OF PATIENTS, AND THAT REVERSAL CORRELATED WITH IMPROVED PROGRESSION-FREE SURVIVAL (AZAD ET AL., ONCOTARGET 8(21): 35326-35338). HUILIN LI'S LAB PUBLISHED SEVERAL STRUCTURAL STUDIES. THEIR PAPER ON THE MCM2-7 HELICASE CORE EMPLOYED THE NEW CRYO-EM INSTRUMENTS INSTALLED AT VARI IN 2017. THE ARCHITECTURE OF THE CORE DOUBLE HEXAMER SUGGESTS THAT DNA LAGGING-STRAND EXTRUSION BEGINS IN THE MIDDLE AREA THAT IS COMPOSED OF THE ZINC FINGER DOMAINS OF BOTH HEXAMERS. THE N-TIER RING MOVEMENTS MAY BE THE CAUSE OF DNA STRAND SEPARATION AND LAGGING-STRAND EXTRUSION (NOGUCHI ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES U.S.A. 114(45): E9529-E9538). ALSO PUBLISHED WAS THE CRYSTAL STRUCTURE OF NEARLY FULL-LENGTH HEXAMERIC ATPASE FROM MYCOBACTERIUM TUBERCULOSIS, THE BACTERIUM THAT CAUSES TUBERCULOSIS. THE STRUCTURE SHOWED AN UBIQUITIN-LIKE BETA-GRASP DOMAIN THAT PRECEDES THE PROTEASOME-ACTIVATING CARBOXYL TERMINUS. THIS STRUCTURE EXPLAINS WHY MPA IS UNABLE TO STIMULATE ROBUST PROTEIN DEGRADATION IN VITRO IN THE ABSENCE OF OTHER, YET-TO-BE-IDENTIFIED CO-FACTORS (WU ET AL., MOLECULAR MICROBIOLOGY 105(2): 227-241). ANOTHER PROJECT ANALYZED M. TUBERCULOSIS HOMOLOGUES OF THE EUKARYOTIC PROTEASOME CHAPERONE PROTEIN PAC2. THE LAB SOLVED THE STRUCTURE OF A PREDICTED PROTEASOME ASSEMBLY FACTOR, RV2125, AND ISOLATED A GENETIC MUTANT OF RV2125 IN M. TUBERCULOSIS. THE STUDY INDICATED THAT PROTEINS RV2125 AND RV2714 DO NOT FUNCTION AS PROTEASOME ASSEMBLY CHAPERONES AND ARE UNLIKELY TO HAVE ROLES IN PROTEASOME BIOLOGY IN MYCOBACTERIA (BAI ET AL., JOURNAL OF BACTERIOLOGY 19(9): E00846-16). THE ROTHBART LABORATORY DEVELOPED AN INTEGRATED PIPELINE FOR THE DESIGN, FABRICATION, AND USE OF PEPTIDE MICROARRAYS FOR PROFILING THE SPECIFICITY OF HISTONE ANTIBODIES. THIS PIPELINE HAS BEEN USED TO SCREEN MANY COMMERCIAL, WIDELY USED HISTONE ANTIBODIES, AND DATA FROM THESE EXPERIMENTS ARE FREELY AVAILABLE THROUGH THE ONLINE HISTONE ANTIBODY SPECIFICITY DATABASE. THIS METHODOLOGY CAN BE BROADLY APPLIED TO THE ANALYSIS OF ANTIBODIES SPECIFIC TO PROTEINS HAVING POST-TRANSLATIONAL MODIFICATIONS (CORNETT ET AL., JOURNAL OF VISUALIZED EXPERIMENTS 126: E55912). IN THE TRIEZENBERG LAB, THE HUMAN-DERIVED HD10.6 CELL LINE WAS DEVELOPED, WHICH HAS THE PROPERTIES OF A SENSORY NEURON. HERPES SIMPLEX VIRUS INFECTION IN THESE CELLS RESEMBLES A LATENT INFECTION, INCLUDING REACTIVATION TO PRODUCE NEWLY INFECTIOUS VIRUS; REACTIVATION CAN BE INDUCED BY DEPLETION OF NERVE GROWTH FACTOR. THUS, WE NOW HAVE A CELL CULTURE MODEL FOR LATENCY THAT IS DERIVED FROM THE NORMAL HOST FOR THIS VIRUS (THELLMAN ET AL., JOURNAL OF VIROLOGY 91(12): 00080-17). THE PFEIFER LAB COAUTHORED AN ARTICLE REPORTING THAT SCIATIC NERVE LESIONS IN ADULT MICE LED TO INCREASED AMOUNTS OF TET3 AND 5-HYDROXYMETHYLCYTOSINE IN DORSAL ROOT GANGLION (DRG) NEURONS. TET3 IS REQUIRED FOR ROBUST AXON REGENERATION OF DRG NEURONS AND BEHAVIORAL RECOVERY. THE STUDY'S RESULTS SUGGEST THAT THERE IS AN EPIGENETIC BARRIER THAT CAN BE REMOVED BY ACTIVE DNA DEMETHYLATION TO PERMIT AXON REGENERATION IN THE ADULT MAMMALIAN NERVOUS SYSTEM (NEURON 94(2): 337-346). FORM 990, PART III, LINE 4C LINE 4C - PROGRAM SERVICE ACTIVITY #3 CENTER FOR NEURODEGENERATIVE SCIENCE THE CENTER WAS ESTABLISHED IN 2011 UNDER PATRIK BRUNDIN, M.D., PH.D., WHO IS ALSO ASSOCIATE DIRECTOR OF VARI. THE CENTER CURRENTLY HAS SEVEN LABORATORIES STUDYING PARKINSON'S DISEASE, AGING, PRIONS, AND THE RELATIONSHIPS BETWEEN DEPRESSION, SUICIDE, AND BRAIN INFLAMMATION. CENTER RESEARCHERS DURING THIS FISCAL YEAR RECEIVED FOUR NEW NATIONAL INSTITUTES OF HEALTH AWARDS, THREE R01'S AND AN R21, AS WELL AS AWARDS FROM THE U.S. DEPARTMENT OF DEFENSE, THE CURE PARKINSON'S TRUST, THE PARKINSON'S DISEASE FOUNDATION, AND THE AMERICAN PARKINSON'S DISEASE FOUNDATION. A NEW RESEARCH CONTRACT WAS SIGNED AND A GRANT SUBAWARD WAS ALSO RECEIVED. THE COETZEE LABORATORY FOCUSES ON THE APPLICATION OF GENOME-WIDE ASSOCIATION STUDIES (GWAS) TO PARKINSON'S DISEASE. IN ONE STUDY, THEY ANALYZED 7607 SINGLE-NUCLEOTIDE CHANGES (SNPS) IN GENES RELATED TO PARKINSON'S DISEASE RISK, AS WELL AS 23,759 LD-ASSOCIATED VARIANTS. A SINGLE LARGE LD BLOCK ON CHROMOSOME 6 (6P21) CONTAINED MULTIPLE HLA-MHC-II GENES. THESE GENES CODE FOR PROTEINS THAT FORM PART OF THE BODY'S IMMUNE SYSTEM, SUGGESTING A DIRECT EFFECT ON THE ORIGIN OF PARKINSON'S DISEASE (PIERCE AND COETZEE, PLOS ONE 12(4): E0175882). THE LAB ALSO CONTRIBUTED TO THE WORK OF THE ONCOARRAY CONSORTIUM. THE CONSORTIUM GENOTYPED 447,705 SAMPLES. A TOTAL OF 494,763 SNPS PASSED QUALITY CONTROL STEPS WITH A SAMPLE SUCCESS RATE OF 97%. ONGOING ANALYSES WILL SHED LIGHT ON THE ETIOLOGY OF, AND RISK ASSESSMENT FOR, MANY TYPES OF CANCER (AMOS ET AL., CANCER, EPIDEMIOLOGY, BIOMARKERS & PREVENTION 26(1): 126-135). THE MA LABORATORY PUBLISHED THE RESULTS OF SEVERAL STUDIES ON PRION PROTEIN AND PRION DISEASE. ONE PROJECT INVESTIGATED THE ROLE OF FOUR CONSECUTIVE THREONINE AMINO ACIDS IN THE PRION PROTEIN SEQUENCE. THREONINES TEND TO FORM BETA-SHEET STRUCTURES, WHICH IS A PRIMARY STRUCTURE OF PATHOGENIC PRIONS. THE STUDY PROVIDED NEW INSIGHTS INTO THE COMPLEX RELATIONSHIPS AMONG PRION PROTEIN STABILITY, THE CONFORMATIONAL CHANGE FROM NORMAL TO PATHOGENIC PROTEIN, AND THE STRUCTURE OF PRIONS (ABSKHARON ET AL., SCIENTIFIC REPORTS 6: 38877). IN ANOTHER PROJECT, DIFFERENT PROTEASE-RESISTANT, RECOMBINANT PRION PROTEIN CONFORMERS (RPRP-RES) HAD SIMILARITIES IN RECOGNITION BY CONFORMATIONAL ANTIBODIES AGAINST PRIONS AND IN THEIR GUANIDINE HYDROCHLORIDE DENATURATION PROFILES, SUGGESTING A SIMILAR OVERALL ARCHITECTURE. THE STUDY SUGGESTS THAT RELATIVELY SMALL STRUCTURAL FEATURES DETERMINE RPRP-RES PATHOGENICITY AND THAT IN VIVO SEEDING ABILITY DOES NOT NECESSARILY RESULT IN PATHOGENICITY (WANG ET AL., PLOS PATHOGENS 13(7): E1006491). THE LAB ALSO COLLABORATED ON A PAPER SHOWING THE INHIBITION OF FAST AXONAL TRANSPORT AS A TOXIC EFFECT OF CELLULAR PRION PROTEIN. THIS EFFECT INVOLVES ACTIVATION OF CASEIN KINASE 2 (CK2), WHICH PHOSPHORYLATES AND INHIBITS LIGHT CHAIN SUBUNITS OF THE PROTEIN KINESIN. CK2 MAY BE A THERAPEUTIC TARGET FOR PREVENTING THE LOSS OF NEURONAL CONNECTIVITY IN PRION DISEASES (ZAMPONI ET AL., PLOS ONE 12(12): E0188340). THE LABORATORY OF PATRIK BRUNDIN STUDIES THE ORIGIN OF PARKINSON'S DISEASE AND WORKS TO DEVELOP NEW WAYS TO SLOW OR HALT ITS PROGRESSION. THE LAB HAS GENERATED A C. ELEGANS MODEL THAT MIRRORS THE PROPAGATION OF ALPHA-SYNUCLEIN AGGREGATES IN THE BRAIN; THESE AGGREGATES ARE THE HALLMARK OF PARKINSON'S DISEASE. USING THIS MODEL, THE NEURON-TO-NEURON TRANSMISSION OF ALPHA-SYNUCLEIN CAN BE MONITORED IN A LIVE ANIMAL OVER ITS LIFE SPAN. CHANGES IN AUTOPHAGY OR EXO/ENDOCYTOSIS WERE FOUND TO AFFECT THE TRANSFER OF ALPHA-SYNUCLEIN (TYSON ET AL., SCIENTIFIC REPORTS 7: 7506). ANOTHER PUBLICATION WAS A REVIEW OF FINDINGS THAT SUPPORT THE IDEA THAT ALPHA-SYNUCLEIN CAN ACT AS A PRION, FOCUSING ON TRIGGERS OF ALPHA-SYNUCLEIN MISFOLDING, WHY SYNUCLEIN AGGREGATES ESCAPE CELLULAR DEGRADATION UNDER DISEASE CONDITIONS, AND WHETHER DIFFERENT STRAINS OF ALPHA-SYNUCLEIN FIBRILS CAN UNDERLIE DIFFERENCES IN THE DISTRIBUTION OF AGGREGATES IN DIFFERENT SYNUCLEIN-RELATED DISEASES (BRUNDIN AND MELKI, JOURNAL OF NEUROSCIENCE 37(41): 9808-9818). DR. BRUNDIN ALSO COAUTHORED A COMPREHENSIVE OVERVIEW OF PARKINSON'S DISEASE (NATURE REVIEWS DISEASE PRIMERS 3: 17013). DR. LENA BRUNDIN'S LAB STUDIES DEPRESSION, SUICIDALITY, AND BRAIN INFLAMMATION. ONE PROJECT STUDIED THE INFLAMMATION BIOMARKERS SERUM AMYLOID A (SAA), C-REACTIVE PROTEIN, INTERLEUKIN-6, AND TUMOR NECROSIS FACTOR ALPHA. SAA WAS MOST ROBUSTLY ASSOCIATED WITH DEPRESSIVE SYMPTOMS AND MIGHT CONSTITUTE A CROSS-MARKER OF DEPRESSED MOOD AND FATIGUE (ACTA PSYCHIATRICA SCANDINAVICA 135(5): 409-418). IN COLLABORATION WITH THE PATRIK BRUNDIN LABORATORY, THE LAB LOOKED AT EXENDIN-4, A DRUG THAT IS IN CLINICAL TRIALS AGAINST PARKINSON'S DISEASE, TO SEE WHETHER IT DIRECTLY REDUCES BRAIN INFLAMMATION. EXENDIN-4 TREATMENT SIGNIFICANTLY PREVENTED DEPRESSIVE-LIKE BEHAVIOR AT 24 H AFTER INJECTION OF LIPOPOLYSACCHARIDE, INDICATING THAT THE DRUG ENGAGED A TARGET IN THE BRAIN, POSSIBLY AFFECTING DOPAMINE METABOLISM (VENTORP ET AL., JOURNAL OF PARKINSON'S DISEASE 7(2): 263-273). THE MOORE LAB PUBLISHED A STUDY OF THE PARKINSON'S DISEASE-RELATED PROTEIN CALLED PARKIN, WHICH IS ASSOCIATED WITH CERTAIN EARLY-ONSET CASES AND WHICH CONTROLS TRANSCRIPTION OF THE PGC-1A PROTEIN THAT REGULATES MITOCHONDRIA. IN CORTICAL NEURONS, COEXPRESSION OF PGC-1A AND PARKIN INCREASED THE NUMBER OF MITOCHONDRIA AND ENHANCED MAXIMAL RESPIRATION, AMONG OTHER EFFECTS. MITOCHONDRIA ARE IMPORTANT FOR THE SURVIVAL OF NEURONS IN PARKINSON'S DISEASE, AND THESE RESULTS HIGHLIGHT THE IMPORTANCE OF PARKIN AND PGC-1A IN SYNERGISTICALLY CONTROLLING MITOCHONDRIAL QUALITY AND FUNCTION (ZHENG ET AL., HUMAN MOLECULAR GENETICS 26(3): 582-598). THE LAB ALSO PUBLISHED CRITICAL REVIEWS ON MECHANISMS OF LRRK2-DEPENDENT NEURODEGENERATION (ISLAM AND MOORE, BIOCHEMICAL SOCIETY TRANSACTIONS 45(1): 163-172) AND ON THE ROLE OF VPS35 IN PARKINSON'S DISEASE AND THE MECHANISMS UNDERLYING NEURODEGENERATION CAUSED BY MUTATIONS IN THE VPS35 GENE (WILLIAMS ET AL., JOURNAL OF PARKINSON'S DISEASE 7(2): 219-233). BECAUSE DIFFERENCES IN DNA TRANSCRIPTION IN HISTOLOGICALLY AND GENETICALLY IDENTICAL CELLS IS WIDESPREAD, BUT POORLY UNDERSTOOD, THE LABRIE LAB ANALYZED EPIGENETIC PROFILES OF THE MOUSE LACTASE GENE (LCT) IN CELLS OF THE SMALL INTESTINE. AGE- AND PHENOTYPE-SPECIFIC FACTORS (E.G., LACTOSE EXPOSURE AFTER WEANING) PRODUCED CHANGES IN THE EPIGENETIC MODIFICATIONS AND CTCF BINDING AT SOME REGULATORY ELEMENTS, WHICH CORRESPONDED TO THE CHANGES IN TRANSCRIPTION. SUCH CHANGES MAY CONTRIBUTE TO THE FUNCTIONAL SPECIALIZATION OF THE CELLS IN INTESTINAL SUBREGIONS (OH ET AL., SCIENTIFIC REPORTS 7: 41843). THE HYPOTHESIS THAT ABNORMAL ALPHA-SYNUCLEIN ORIGINATES IN THE GUT HAS RECENTLY BEEN PUT FORWARD. THE LABRIE LAB PUBLISHED A REVIEW OF THE POSSIBILITY THAT ALPHA-SYNUCLEIN AGGREGATION COULD BE SEEDED BY INGESTION, HIGHLIGHTING CURRENT EVIDENCE FOR THE GUT-TO-BRAIN HYPOTHESIS OF PARKINSON'S DISEASE AND PUTTING THIS IN CONTEXT OF AVAILABLE ROUTES THE GI TRACT. ALSO REVIEWED WAS EPIDEMIOLOGICAL EVIDENCE THAT DIETARY FACTORS MAY BE INVOLVED IN PD (KILLINGER AND LABRIE, NPJ PARKINSON'S DISEASE 3: 33). 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 $1,557,030,000 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 33591 119044 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 45881651 ACTUAL AMOUNT PAID VAN ANDEL INSTITUTE E 37840000 TOTAL RECORDED VAN ANDEL INSTITUTE N 294412 ALLOCATION BASED ON SQ. FOOTAGE VAN ANDEL INSTITUTE P 1274449 ACTUAL AMOUNT PAID VAN ANDEL INSTITUTE N 158388 ALLOCATION BASED ON EFFORT VAN ANDEL INSTITUTE O 1198029 ALLOCATION BASED ON EFFORT VAN ANDEL EDUCATION INSTITUTE P 171373 ACTUAL AMOUNT PAID VAN ANDEL EDUCATION INSTITUTE Q 1110235 ACTUAL AMOUNT RECEIVED VAN ANDEL EDUCATION INSTITUTE N 39967 ALLOCATION BASED ON EFFORT VAN ANDEL EDUCATION INSTITUTE O 302306 ALLOCATION BASED ON EFFORT VAN ANDEL INSTITUTE GRADUATE SCHOOL O 79093 APPORTIONED FY17 COMPENSATION VAN ANDEL INSTITUTE GRADUATE SCHOOL N 19243 ALLOCATION BASED ON EFFORT VAN ANDEL INSTITUTE GRADUATE SCHOOL N 165607 ALLOCATION BASED ON SQ. FOOTAGE VAN ANDEL INSTITUTE GRADUATE SCHOOL Q 223711 ACTUAL AMOUNT RECEIVED VAN ANDEL INSTITUTE GRADUATE SCHOOL O 145555 ALLOCATION BASED ON EFFORT VAN ANDEL INSTITUTE Q 5604544 ACTUAL AMOUNT PAID VAN ANDEL INSTITUTE E 7814516 TOTAL RECORDED