2014-10-14T16:05:42-05:00 2013-11-30 861065772 DELOITTE TAX LLP 200 RENAISSANCE CENTER STE 3900 DETROIT MI 48243 990 2012-12-01 522000823 VAN ANDEL RESEARCH INSTITUTE VANA 6162345000 333 BOSTWICK AVENUE NE GRAND RAPIDS MI 49503 TIMOTHY J MYERS 6162345368 2014-10-14 1 LORI BOYCE P00121981 3133963000 2012 2015-11-30 17:44:51Z TIMOTHY J MYERS 333 BOSTWICK AVENUE NE GRAND RAPIDS MI 49503 64017267 0 X WWW.VAI.ORG X 1996 MI MEDICAL RESEARCH ORGANIZATION 5 3 393 0 267491 41120 57997024 54068694 1242591 693011 333140 64454 10471022 7773170 70043777 62599329 341390 302224 0 0 27658068 28311621 0 0 598878 40558351 39419946 68557809 68033791 1485968 -5434462 267685668 224789773 361102589 290456167 -93416921 -65666394 MEDICAL RESEARCH ORGANIZATION 0 0 3254352 58261 THE PROGRAM FOR BIOSPECIMEN SCIENCE HAS FOCUSED ON THE CHANGE IN BIOLOGICAL PARAMETERS AND QUALITY OF BIOSPECIMENS CAUSED BY COLLECTION, PROCESSING, AND STORAGE PROCEDURES. THIS RESEARCH IDENTIFIES EFFECTS ON THE CELL BIOLOGY THAT MAY BE UNRELATED TO THE DISEASE AND MORE SO CAUSED BY THE MANAGEMENT OF THE BIOSPECIMEN. THE RESULTS CAN BE USED TO DEVELOP BEST PRACTICES IN THE MANAGEMENT OF BIOSPECIMENS AND ULTIMATELY IMPROVE THE QUALITY OF RESEARCH FINDINGS. SCHEDULE O PROVIDES FURTHER INFORMATION REGARDING THIS PROGRAM'S ACCOMPLISHMENTS. 1775202 THE LABORATORY OF STRUCTURAL SCIENCES IS FOCUSED ON STUDYING THE STRUCTURES AND FUNCTIONS OF PROTEIN/ LIGAND COMPLEXES THAT PLAY KEY ROLES IN MAJOR HORMONE SIGNALING PATHWAYS. SEE SCHEDULE O FOR FURTHER INFORMATION ABOUT THIS PROGRAM. 1602052 55581 MET IS OVEREXPRESSED IN MANY TYPES OF HUMAN CANCER AND ITS EXPRESSION CORRELATES WITH AN AGGRESSIVE DISEASE AND POOR PROGNOSIS. SINCE DISCOVERING THE C-MET RECEPTOR TYROSINE KINASE AND ITS LIGAND HEPATOCYTE GROWTH FACTOR (HGF/SF) IN THE 1980'S, THE LAB HAS FOCUSED ON INVESTIGATING THE ROLE THESE MOLECULES PLAY IN MALIGNANT PROGRESSION AND METASTASIS. AS PART OF THE EFFORT TO ENHANCE OUR UNDERSTATING OF THIS SIGNALING SYSTEM, OUR LAB FOCUSES ON THE MECHANISMS RESPONSIBLE FOR TUMOR PROGRESSION WITH THE HYPOTHESIS THAT PHENOTYPIC SWITCHING (E-MT/M-ET) AND CHROMOSOME INSTABILITY CAN DRIVE TUMOR PROGRESSION. WE ALSO DEVELOP AND CHARACTERIZE NOVEL ANIMAL RESEARCH MODELS USED IN PRE-CLINICAL EVALUATION OF NEW INHIBITORS THAT TARGET C-MET IN HUMAN CANCERS. SEE SCHEDULE O FOR FURTHER INFORMATION ABOUT THIS PROGRAM. 37107196 302224 579169 37107196 302224 579169 43738802 1 1 0 1 0 0 0 0 0 0 1 0 0 1 1 1 0 1 0 1 1 0 0 0 0 0 0 0 1 1 1 0 0 0 0 0 1 0 0 0 1 0 0 0 0 1 1 1 1 0 0 1 107 0 393 1 1 1 0 0 0 0 0 0 0 0 0 X 5 3 1 1 0 0 0 1 0 1 1 0 0 1 1 1 1 1 1 1 1 0 MI X TIMOTHY J MYERS CFO 6162345368 333 BOSTWICK AVENUE NE GRAND RAPIDS MI 495032518 DAVID VAN ANDEL 36.00 17.00 X X 405693 0 110556 DR GEORGE VANDE WOUDE 50.00 0.00 X 300227 0 26410 DR JAMES FAHNER 1.00 1.00 X 10000 1000 0 DR GARY TARPLEY 1.00 0.00 X 12500 0 0 DR RALPH WEICHSELBAUM 1.00 0.00 X 0 0 0 TIMOTHY MYERS 50.00 3.00 X 231533 0 70637 DAVID WHITESCARVER 50.00 3.00 X 303113 0 92727 DR JANA HALL 50.00 3.00 X 83527 0 21390 DR PATRIK BRUNDIN 45.00 0.00 X 390092 0 64030 DR H ERIC XU 45.00 0.00 X 283371 0 54007 JOHN BENDER DONE 513 45.00 0.00 X 249080 0 50158 DR GISELLE SHOLLER DONE 613 45.00 0.00 X 248918 0 43267 DR SCOTT JEWELL 45.00 0.00 X 331418 0 59268 LOVE COLLINS III 45.00 0.00 X 271344 0 82732 DR JEFFREY TRENT DONE 312 0.00 0.00 X 702479 0 5632 R JACK FRICK DONE 1211 0.00 0.00 X 273377 0 0 4096672 1000 680814 60 1 1 0 BANK OF AMERICA 100 NORTH TYRON ST CHARLOTTE NC 28202 CREDIT ENHANCEMENT FEES 3393605 DK SECURITY INC 5160 FALCONVIEW AVE SE KENTWOOD MI 49512 SECURITY SERVICES 363304 HONIGMAN MILLER SCHWARTZ LLC 130 SOUTH FIRST ST 4TH FL ANN ARBOR MI 482263506 LEGAL/ CONSULTING 361003 WARNER NORCROSS & JUDD 111 LYON ST 900 OLD KENT GRAND RAPIDS MI 495032487 LEGAL/ CONSULTING 210586 CALLAHAN VENTURES LLC 1715 FLOWERS CROSSING GRAND RAPIDS MI 49525 CONSULTING 194206 20 43882066 7595292 2591336 54068694 RESEARCH BILLED REV 541700 693011 439390 253621 693011 208758 208758 358582 358582 1227090 1213702 13388 13388 10230 3158 59932 204236 -144304 -144304 -144304 REL. 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DESCRIPTION OF UNCERTAIN TAX POSITIONS UNDER FIN 48: 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 1,213,702. CHANGE IN BALANCE SHEET PRESENTATION OF TRANSMED SYSTEMS, INC. 633,403. PART XI, LINE 4B - OTHER ADJUSTMENTS: NET ALLOCATED 7,002,239. STATE TAX REFUNDS 10,712. PART XII, LINE 2D - OTHER ADJUSTMENTS: GAIN ON SWAP -32,753,463. RENTAL EXPENSES 1,213,702. PART XII, LINE 4B - OTHER ADJUSTMENTS: NET ALLOCATED 7,002,239. STATE TAX REFUNDS 10,712. PART V - THE VAN ANDEL INSTITUTE (A RELATED ORGANIZATION) HOLDS ENDOWMENT FUNDS FOR BOTH VARI AND THE 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 321384 EUROPE 0 0 UNRELATED TRADE OR BUSINESS 0 1 0 0 0 1 321384 0 321384 0 0 0 0 0 0 1 GRADUATE STUDENT STIPENDS FOR VAN ANDEL GRADUATE SCHOOL AND MICHIGAN STATE UNIVERSITY STUDENTS 7 235232 TUITION PAID FOREIGN NATIONAL STUDENT STIPENDS 10 57346 SCHEDULE I, PART I, LINE 2: STIPENDS ARE PROVIDED TO THE RESEARCH STUDENTS FOR LIVING AND INSURANCE ASSISTANCE. X 0 1 X X X X X 1 0 0 0 0 0 0 1 0 DAVID VAN ANDEL 300014 0 85204 0 20475 0 110054 0 502 0 516249 0 85204 0 DR GEORGE VANDE WOUDE 280755 0 0 0 19472 0 25000 0 1410 0 326637 0 0 0 TIMOTHY MYERS 194070 0 37163 0 300 0 62163 0 8474 0 302170 0 37163 0 DAVID WHITESCARVER 258023 0 25000 0 20090 0 84253 0 8474 0 395840 0 25000 0 DR PATRIK BRUNDIN 374146 0 0 0 15946 0 56263 0 7767 0 454122 0 0 0 DR H ERIC XU 267126 0 15795 0 450 0 45533 0 8474 0 337378 0 15795 0 JOHN BENDER DONE 513 212707 0 17393 0 18980 0 41685 0 8473 0 299238 0 17393 0 DR GISELLE SHOLLER DONE 613 234395 0 14223 0 300 0 41858 0 1409 0 292185 0 14223 0 DR SCOTT JEWELL 265546 0 64557 0 1315 0 50795 0 8473 0 390686 0 31557 0 LOVE COLLINS III 250054 0 20000 0 1290 0 74259 0 8473 0 354076 0 0 0 DR JEFFREY TRENT DONE 312 456207 0 210328 0 35944 0 5280 0 352 0 708111 0 210000 0 R JACK FRICK DONE 1211 18180 0 75732 0 179465 0 0 0 0 0 273377 0 47748 0 PART I, LINE 1A VARI ALLOWS FOR FIRST-CLASS OR CHARTER TRAVEL FOR OFFICERS AND TRUSTEES. PART I, LINE 1B A WRITTEN POLICY IS IN PLACE FOR FIRST CLASS/ CHARTER TRAVEL. PART I, LINE 4A R. JACK FRICK RECEIVED SEVERANCE PAYMENTS OF $169,600 DURING CALENDAR YEAR 2012. PART I, LINE 7 ALL OFFICERS AND OTHER HIGHLY COMPENSATED EMPLOYEES ARE INCLUDED IN A VARIABLE PAY PLAN BASED ON ACHIEVEMENTS OF THE ORGANIZATION AS WELL AS RESPECTIVE INDIVIDUAL PREDETERMINED GOALS AND OBJECTIVES. A MICHIGAN STRATEGIC FUND 521417332 2013-04-01 220000000 REFUND BOND ISSUE 4/10/08 0 0 0 A 220000000 220000000 1 0 1 1 A 0 1 1 1 1 1 0.00910 0.00910 0 0 1 A 0 0 0 1 1 0 0 0 1 A 1 SCHEDULE K PART IV, ARBITRAGE, LINE 2C DATE REBATE COMPUTATION PERFORMED ISSUER NAME: MICHIGAN STRATEGIC FUND DATE THE REBATE COMPUTATION WAS PERFORMED: 11/30/2013 PATRIK BRUNDIN KEY EMPLOYEE CONTRACT X 25000 18355 0 0 1 18355 JVAE FOUNDATION COMMON TRUSTEES 177994 IT CONSULTING/ SERVICES 0 FORM 990, PART VI, SECTION A, LINE 2 VARI AND VAEI SHARE COMMON MANAGEMENT. AS OFFICERS OF VARI, DAVID VAN ANDEL, DR. JANA HALL, TIMOTHY MYERS AND DAVID WHITESCARVER INTERACT AND WORK TOGETHER WITH STEVE TRIEZENBERG, AN OFFICER OF VAEI. FORM 990, PART VI, SECTION A, LINE 3 DURING THE FISCAL YEAR, JERRY CALLAHAN, FORMERLY AN INDEPENDENT CONTRACTOR, BECAME A FULL TIME EMPLOYEE (IN JANUARY 2013) AS THE VICE PRESIDENT OF BUSINESS DEVELOPMENT AND EXTRAMURAL ADMINISTRATION. 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 11 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 FINAL APPROVAL PRIOR TO FILING WITH THE IRS. FORM 990, PART VI, SECTION B, LINE 12C VARI HAS WRITTEN CONFLICT OF INTEREST ("COI") POLICIES AND PROCEDURES (ADMINISTERED BY VAN ANDEL INSTITUTE) WHICH ADMINISTER AND ENFORCE A PROCESS TO IDENTIFY, EVALUATE, AND MANAGE POTENTIAL COIS. THESE POLICIES HAVE BEEN BOARD APPROVED. VAI ADMINISTERS THE COI POLICIES AND PROCEDURES THROUGH TWO COMMITTEES: THE CONFLICTS COMMITTEE ("CC") AND THE INSTITUTIONAL COI COMMITTEE ("ICOIC"). THE COI POLICIES AND PROCEDURES APPLY TO AND SERVE AS A GUIDE FOR EVERYONE IN THE ORGANIZATION. THEY 1) PROVIDE A USEFUL RESOURCE WHEN DEVELOPING ACTIVITIES OR RELATIONSHIPS WITH OUTSIDE ENTITIES OR PERSONS, AND 2) ESTABLISH COMMITTEES TO REVIEW AND MANAGE POTENTIAL COIS AS THEY MAY ARISE. THE CC, CHAIRED BY THE CHIEF LEGAL OFFICER, REQUIRES ANNUAL AND UPDATED DISCLOSURES BY COVERED PERSONS AND REVIEWS AND APPROVES MANAGEMENT PLANS. THE INSTITUTIONAL COI POLICIES AND PROCEDURES SERVE AS A GUIDE FOR MEMBERS OF THE 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 DECIDE HOW TO MANAGE SUCH POTENTIAL COIS 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 VAN ANDEL INSTITUTE'S INDEPENDENT COMPENSATION COMMITTEE 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 THE CONFLICT OF INTEREST POLICY AND FINANCIAL STATEMENTS ARE AVAILABLE TO THE PUBLIC UPON REQUEST. CHANGES IN NET ASSETS OR FUND BALANCES: FORM 990, PART XI, LINE 9: GAIN ON INTEREST RATE SWAP 32,753,463. CHANGE IN BALANCE SHEET PRESENTATION OF TMS 633,403. FORM 990, PART III, LINES 4A-4B LINE 4A - PROGRAM SERVICE ACTIVITY #1 VARI'S PROGRAM FOR BIOSPECIMEN SCIENCE SUPPORTS SCIENTIFIC RESEARCH AND DISCOVERY BY PROVIDING COMPREHENSIVE BIOSPECIMEN SERVICES FOR VARI SCIENTISTS AND EXTERNAL COLLABORATORS. THE PROGRAM FOR BIOSPECIMEN SCIENCE FOCUSES ON THE CHANGE AND QUALITY OF BIOSPECIMENS CAUSED BY COLLECTION, PROCESSING AND STORAGE PROCEDURES. THE PROGRAM'S RESEARCH IDENTIFIES EFFECTS ON THE CELL BIOLOGY OF SAMPLES THAT MAY BE UNRELATED TO THE DISEASE AND MORE SO CAUSED BY THE MANAGEMENT OF THE BIOSPECIMEN. THE RESULTS CAN BE USED TO DEVELOP BEST PRACTICES IN THE MANAGEMENT OF BIOSPECIMENS AND, ULTIMATELY, IMPROVE THE QUALITY OF RESEARCH FINDINGS. THE PROGRAM FOR BIOSPECIMEN SCIENCE ALSO ENCOMPASSES VARI'S NATIONALLY AND INTERNATIONALLY RECOGNIZED BIOREPOSITORY, WHICH PROVIDES SCIENTIFIC EVALUATION ON THE PATTERNS OF DEGRADATION IN BIOSPECIMENS; DATABASE TRACKING AND MANAGEMENT OF BIOSPECIMEN INVENTORY; PROCUREMENT OF SURGICAL TISSUE AND BIOSPECIMENS FROM PATIENT POPULATIONS; QUALITY CONTROL ASSESSMENT OF OPERATIONS FOR THE COLLECTION AND BANKING OF BIOSPECIMENS; AND BIOSPECIMEN PROJECT MANAGEMENT. VARI'S BIOREPOSITORY ALSO SERVES AS THE NATIONAL CANCER INSTITUTE'S COMPREHENSIVE BIOSPECIMEN RESOURCE FOR THE CANCER HUMAN BIOBANK (CAHUB) AND PROVIDES BIOREPOSITORY SERVICES FOR THE MULTIPLE MYELOMA RESEARCH FOUNDATION (MMRF). THE BIOREPOSITORY HAS COLLECTED AND STORED MORE THAN 30,000 BIOSPECIMENS FOR THESE PROGRAMS, WHICH AID SCIENTISTS IN THEIR RESEARCH BY PROVIDING HUMAN TUMOR SAMPLES IN WHICH TO STUDY GENE EXPRESSION (CAHUB) AND TO CONDUCT MOLECULAR PROFILING OF MULTIPLE MYELOMA (MMRF). CURRENTLY, THE BIOREPOSITORY CONTAINS MORE THAN 5,000 CONSENTED, PROSPECTIVELY PROCURED HUMAN BIOSPECIMENS, INCLUDING TISSUES, AND BLOOD BYPRODUCTS AND THEIR DERIVATIVES FROM MORE THAN 400 PATIENTS. ADDITIONALLY, THE BIOREPOSITORY HOUSES AN EXTENSIVE PARAFFIN BLOCK ARCHIVE OF HUMAN DIAGNOSTIC TISSUES, WHICH CURRENTLY EXCEEDS 900,000 BLOCKS GATHERED FROM ABOUT 250,000 CASES. ACQUISITION OF THESE SAMPLES IS CONDUCTED IN PART BY COLLABORATION WITH WEST MICHIGAN HOSPITALS (INCLUDING SPECTRUM HEALTH). THIS BIOREPOSITORY IS A CRUCIAL RESOURCE FOR SCIENTISTS WITH INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL TO STUDY CANCER AND OTHER HUMAN DISEASES USING STORED BIOSPECIMENS FROM THE BIOREPOSITORY. VARI'S BIOREPOSITORY IS ACCREDITED BY THE COLLEGE OF AMERICAN PATHOLOGISTS (CAP) THROUGH ITS BIOREPOSITORY ACCREDITATION PROGRAM (BAP). ITS ACCREDITATION NUMBER IS 8017856 AND COVERS GENERAL BIOREPOSITORY, GENERAL SPECIMEN PROCESSING, NUCLEIC ACID EXTRACTION, SPECIMEN COLLECTION AND PROCUREMENT, SPECIMEN DISTRIBUTION AND AGREEMENTS, SPECIMEN INFORMATICS, AND SPECIMEN STORAGE. VARI'S BIOREPOSITORY ALSO IS A FOUNDING MEMBER OF THE GREAT LAKES BIOREPOSITORY RESEARCH NETWORK (GLBRN). LINE 4B - PROGRAM SERVICE ACTIVITY #2 THE LABORATORY OF STRUCTURAL SCIENCES FOCUSES ON STUDYING THE STRUCTURES AND FUNCTIONS OF PROTEIN/LIGAND COMPLEXES THAT PLAY KEY ROLES IN MAJOR HORMONE SIGNALING PATHWAYS. THE LABORATORY ALSO EXPLORES STRUCTURAL INFORMATION TO DEVELOP THERAPEUTIC AGENTS FOR TREATING HUMAN DISEASES, INCLUDING CANCER AND DIABETES. THE LAB USES A MULTIDISCIPLINARY APPROACH INCLUDING MOLECULAR AND CELLULAR BIOLOGY, BIOCHEMISTRY, ANIMAL PHYSIOLOGY, AND X-RAY CRYSTALLOGRAPHY. THE LAB'S CURRENT WORK FOCUSES ON THREE AREAS: NUCLEAR HORMONE RECEPTORS, THE MET TYROSINE KINASE RECEPTOR, AND G PROTEIN-COUPLED RECEPTORS (GPCRS). IN ADDITION TO THEIR FUNDAMENTAL ROLES IN BIOLOGY, THESE PROTEINS ARE IMPORTANT DRUG TARGETS. IN THE REALM OF NUCLEAR HORMONE RECEPTORS, THE LAB HAS DETERMINED THE CRYSTAL STRUCTURES OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPAR) LIGAND-BINDING DOMAIN (LBD) BOUND TO MANY DIVERSE LIGANDS. THIS AIDS IN OUR UNDERSTANDING OF THE MOLECULAR BASIS OF LIGAND-MEDIATED SIGNALING BY PPARS. WE FOUND THAT THE CRYSTAL STRUCTURES OF THE RECEPTORS ARE BOUND TO COACTIVATORS OR CO-REPRESSORS, WHICH PROVIDES A FRAMEWORK FOR UNDERSTANDING THE MECHANISMS OF PPAR AGONISTS AND ANTAGONISTS, AND THE RECRUITMENT OF COACTIVATORS AND CO-REPRESSORS. THE LAB ALSO FOUND THAT ANDROGEN RECEPTOR (AR) MUTATIONS IN PROSTATE CANCERS OFTEN RESULTS IN ENHANCED BINDING TO A PARTICULAR COACTIVATOR, SRC-3 (WHICH IS ALSO CALLED "AMPLIFIED IN BREAST CANCER1", OR AIB1). LASTLY, WE FOUND THAT RETINOIC ACID IS A LOW-AFFINITY LIGAND FOR COUP-TF, WHICH IS ONE OF THE MOST CONSERVED NUCLEAR RECEPTORS AND HAS ESSENTIAL ROLES IN ANGIOGENESIS, HEART DEVELOPMENT, CENTRAL NERVOUS SYSTEM ACTIVITY, AND METABOLIC HOMEOSTASIS. FOR THE MET TYROSINE KINASE RECEPTOR, THE LAB HAS ENGINEERED AND DETERMINED THE CRYSTAL STRUCTURE OF THE C-MET LIGAND, HEPATOCYTE GROWTH FACTOR, NK1 AND NK2 VARIANTS. IN REGARD TO G PROTEIN-COUPLED RECEPTORS (GPCRS), WE HAVE DETERMINED CRYSTAL STRUCTURES OF THE LIGAND-BINDING DOMAIN OF THE PTH RECEPTOR AND THE CRF RECEPTOR, AND WE ARE DEVELOPING HORMONE ANALOGS FOR TREATING OSTEOPOROSIS, DEPRESSION, AND DIABETES. ADDITIONALLY, WE ARE DEVELOPING A MAMMALIAN OVEREXPRESSION SYSTEM AND PLAN TO USE IT TO EXPRESS FULL-LENGTH GPCRS FOR CRYSTALLIZATION AND STRUCTURAL STUDIES. THE LAB ALSO STUDIES THE PLANT HORMONE ABSCISIC ACID (ABA) AND ITS ASSOCIATED SIGNALING PATHWAYS, WITH THE STRUCTURES OF ABA RECEPTORS BEING HIGHLIGHTED AS ONE OF TOP 10 SCIENTIFIC BREAKTHROUGHS BY SCIENCE IN 2009. THIS WORK HAS SIGNIFICANT IMPLICATIONS FOR ENHANCING DROUGHT RESISTANCE IN PLANTS. FORM 990, PART III, LINES 4C-4D LINE 4C - PROGRAM SERVICE ACTIVITY #3 MET IS OVEREXPRESSED IN MANY TYPES OF HUMAN CANCER AND ITS EXPRESSION CORRELATES WITH AGGRESSIVE DISEASE AND POOR PROGNOSIS (WWW.VAI.ORG/MET). SINCE DISCOVERING THE C-MET RECEPTOR TYROSINE KINASE AND ITS LIGAND HEPATOCYTE GROWTH FACTOR (HGF/SF) IN THE MID-1980S, THE VANDE WOUDE LAB HAS FOCUSED ON INVESTIGATING THE KEY ROLE THESE MOLECULES PLAY IN MALIGNANT PROGRESSION OR THE INVASIVE SPREAD OF THE CANCER FOLLOWED BY METASTATIC COLONIZATION. AS PART OF THE ONGOING EFFORT TO FURTHER ENHANCE OUR UNDERSTATING OF THIS SIGNALING SYSTEM, THE LABORATORY OF MOLECULAR ONCOLOGY FOCUSES ON THE MECHANISMS RESPONSIBLE FOR TUMOR PROGRESSION WITH THE HYPOTHESIS THAT PHENOTYPIC SWITCHING (E-MT/M-ET) AND CHROMOSOME INSTABILITY CAN DRIVE TUMOR PROGRESSION. ADDITIONALLY, WE CONTINUE TO DEVELOP AND CHARACTERIZE NOVEL ANIMAL RESEARCH MODELS THAT ARE USED IN PRECLINICAL EVALUATION OF NEW INHIBITORS THAT TARGET C-MET IN A VARIETY OF HUMAN CANCERS. TUMOR PHENOTYPIC SWITCHING: MECHANISM AND THERAPEUTIC IMPLICATION IN HUMAN CARCINOMAS, CANCER CELLS' ABILITY TO INVADE OTHER TISSUES REQUIRES A BREAKDOWN OF THE JUNCTIONS BETWEEN NEIGHBORING CELLS, A PROCESS CALLED THE EPITHELIAL-TO-MESENCHYMAL TRANSITION (E-MT). EPITHELIAL CELLS LINE BODY CAVITIES, WHILE MESENCHYMAL CELLS ARE CELLS THAT CAN DIFFERENTIATE INTO CELL TYPES SUCH AS BONE, CARTILAGE AND FAT. PARADOXICALLY, METASTATIC CARCINOMAS OFTEN EXHIBIT AN EPITHELIAL PHENOTYPE, LEADING TO THE HYPOTHESIS THAT E-MT IS A TRANSIENT PROCESS INDUCED BY MICROENVIRONMENTAL FACTORS (E.G., THE CONDITIONS THAT SURROUND THE TUMOR). UPON SPREADING TO SECONDARY SITES, MESENCHYMAL CELLS REVERT TO AN EPITHELIAL PHENOTYPE (MESENCHYMAL-TO-EPITHELIAL TRANSITION; M-ET). TYPICALLY, HUMAN CARCINOMA TISSUES AND CELLS EXHIBIT EXTENSIVE DIVERSITY IN BOTH PHENOTYPE (PHYSICAL TRAIT) AND GENOTYPE (GENETIC MAKEUP), SUGGESTING A ROLE FOR GENETIC INSTABILITY IN CELL TYPE DETERMINATION. TO TEST THIS POSSIBILITY, WE HAVE DEVELOPED METHODS TO CONTINUALLY ISOLATE PHENOTYPIC VARIANTS FROM EPITHELIAL OR MESENCHYMAL SUBCLONES OF CARCINOMA CELL LINES. WE HAVE EXPLORED THE SIGNAL PATHWAY UNDERLYING E-MT/M-ET PHENOTYPIC SWITCHING USING SEVERAL APPROACHES, INCLUDING GENE EXPRESSION ANALYSIS, SPECTRAL KARYOTYPING (SKY), AND FLUORESCENT IN SITU HYBRIDIZATION (FISH). WE FOUND THAT CHANGES IN CHROMOSOME CONTENT ARE ASSOCIATED WITH PHENOTYPIC SWITCHING. WE FURTHER SHOWED THAT THESE CHANGES DICTATED THE EXPRESSION OF SPECIFIC GENES, WHICH IN E-MT EVENTS ARE MESENCHYMAL AND IN M-ET EVENTS ARE EPITHELIAL. OUR RESULTS SUGGEST THAT CHROMOSOME INSTABILITY CAN PROVIDE THE DIVERSITY OF GENE EXPRESSION NEEDED FOR TUMOR CELLS TO SWITCH PHENOTYPE. IN VIVO RESEARCH MODELS: MODEL DEVELOPMENT AND PRECLINICAL TREATMENT EVALUATION ANTI-CANCER THERAPY BASED ON BLOCKING THE HGF-MET SIGNALING PATHWAY HAS EMERGED AS AN IMPORTANT GOAL OF PHARMACEUTICAL RESEARCH. ONE OF THE LIMITATIONS OF STUDYING ALTERED MET/HGF/SF SIGNALING IN HUMAN CANCERS IN MOUSE MODELS HAS BEEN THAT THE MOUSE HGF/SF PROTEIN SHOWS LOW AFFINITY FOR HUMAN MET. TO OVERCOME THIS CHALLENGE, OUR LAB DEVELOPED THE TRANSGENIC HUMAN HGF/SCID MOUSE MODEL (HHGFTG-SCID) THAT GENERATES A HUMAN-COMPATIBLE HGF/SF PROTEIN, THUS ALLOWING THE GROWTH OF HUMAN TUMORS (ZHANG ET AL 2005). THIS MODEL HAS BEEN PROVEN AS A VALUABLE PRECLINICAL TOOL FOR IN VIVO STUDY OF MET-DEPENDENT CANCERS AND IS USED TO EVALUATE TREATMENT STRATEGIES THAT AIM TO TARGET THIS PATHWAY (ZHANG ET AL 2010, 2013; XIE ET AL, 2013). FORM 990, PART III, LINE 4D IN 2013, VARI RESEARCHERS FOUND WAYS TO POTENTIALLY DIAGNOSE AND FIGHT SEVERAL DIFFERENT TYPES OF CANCER AND NEURODEGENERATIVE DISEASES. BELOW ARE EXAMPLES OF SIGNIFICANT RESEARCH FINDINGS: - IN 2013 VAI PARTICIPATES IN THE LINKED CLINICAL TRIALS INITIATIVE DESIGNED BY THE CURE PARKINSON'S TRUST TO IDENTIFY NEW TREATMENTS FOR PARKINSON'S DISEASE BY REPURPOSING MEDICATIONS APPROVED TO TREAT OTHER CONDITIONS. - THE VAI'S CENTER FOR NEURODEGENERATIVE SCIENCE DIRECTOR AND COLLEAGUES IN EUROPE SHOWED THAT A MISFOLDED PROTEIN ASSOCIATED WITH PARKINSON'S DISEASE CAN TRAVEL FROM NEURONS IN THE OLFACTORY BULB - ONE OF THE AREAS FIRST IMPACTED BY THE DISEASE - TO OTHER REGIONS. THIS MAY LEAD TO NEW THERAPIES THAT SLOW PROGRESSION OF PARKINSON'S DISEASE. -VAI SCIENTISTS HAVE SHOWN THE INTERACTION BETWEEN MET AND HER2 (ERBB2+) RECEPTORS (TWO IMPORTANT GENES RELATED TO CANCER) IS LINKED TO TUMORS RESISTANT TO TARGETED THERAPIES. - ANXIETY, DEPRESSION AND MIGRAINES VAI SCIENTISTS ALONG WITH COLLEAGUES IN CHINA DISCOVERED THE STRUCTURAL BLUEPRINT THAT WILL AID IN THE DESIGN OF MORE SELECTIVE ACTIVATORS OF SEROTONIN RECEPTORS. SEROTONIN IS A NEUROTRANSMITTER AND ITS RECEPTORS ARE IMPORTANT DRUG TARGETS FOR CONDITIONS SUCH AS ANXIETY, DEPRESSION AND MIGRAINES. - RESEARCH INITIATED IN VAI'S CENTER FOR CANCER AND CELL BIOLOGY AND CONTINUED WITH COLLEAGUES IN THE CENTER FOR SKELETAL DISEASE AND TUMOR METASTASIS HAVE LINKED A DEFICIENCY OF MIG-6, A GENE ASSOCIATED WITH JOINT STABILITY, TO OSTEOARTHRITIS DEVELOPMENT AND THE REGULATION OF CARTILAGE CELLS. THIS WORK COULD LEAD TO DISEASE-MODIFYING TREATMENTS FOR OSTEOARTHRITIS. - VAI SCIENTISTS ARE WORKING TO FURTHER UNDERSTAND A KEY SIGNALING PATHWAY THAT MAY PROVIDE MORE EFFECTIVE TREATMENTS FOR PATIENTS WHOSE PROSTATE CANCER HAS SPREAD TO THEIR BONES. - SCIENTISTS IN VAI'S CENTER FOR SKELETAL DISEASE AND TUMOR METASTASIS HAVE SHOWN THAT A MUTATION OF THE LRP6 GENE CAN LEAD TO SEVERE OSTEOARTHRITIS AND FURTHER CLARIFIES THE ROLES OF THE LRP6 AND LRP5 GENES IN BONE STABILITY. BY USING A GENETIC MODEL, VAI SCIENTISTS WERE ABLE TO ASCERTAIN A CLEAR LINK BETWEEN THE GENES AND THE CELLS RESPONSIBLE FOR THE FORMATION OF BONE. - USING MELANOMA-BASED AVATAR MODELS THAT MIRROR HUMAN TUMOR PROGRESSION, VAI SCIENTISTS IDENTIFIED SEVERAL ACQUIRED DRUG RESISTANCE MECHANISMS TO TARGETED CANCER THERAPIES. THE GROUP ALSO IDENTIFIED A COMBINATION DRUG APPROACH THAT LED TO SUSTAINED REMISSIONS IN A VALIDATED PRE-CLINICAL SYSTEM. - VAI SCIENTISTS HAVE DEVELOPED A NEW METHOD THAT WILL AID IN THE DIAGNOSIS OF PRECANCEROUS CYSTS IN THE PANCREAS, WHICH CAN DEVELOP INTO AN AGGRESSIVE FORM OF CANCER. FORM 990, PART X, LINE 33 VARI NET ASSETS ARE CONSIDERED ON A CONSOLIDATED BASIS WITH VAN ANDEL INSTITUTE (VAI), VAN ANDEL EDUCATION INSTITUTE (VAEI), AND THE TRANSLATIONAL GENOMICS RESEARCH INSTITUTE (2012 ONLY), RELATED PARTIES. ON A CONSOLIDATED BASIS, NET ASSETS ARE $1,173,409,000 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. 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. 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