Attach to Form 990 or Form 990-EZ.
Go to
www.irs.gov/Form990 for the latest information.
| (i) Name of supported organization | (ii) EIN | (iii) Type of organization (described on lines 1- 10 above (see instructions)) | (iv) Is the organization listed in your governing document? | (v) Amount of monetary support (see instructions) | (vi) Amount of other support (see instructions) | |
|---|---|---|---|---|---|---|
| Yes | No | |||||
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Total |
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Calendar year (or fiscal year beginning in) ![]() |
(a) 2014 | (b) 2015 | (c) 2016 | (d) 2017 | (e) 2018 | (f) Total | |
|---|---|---|---|---|---|---|---|
| 1 | Gifts, grants, contributions, and membership fees received. (Do not include any "unusual grant.") .. | ||||||
| 2 | Tax revenues levied for the organization's benefit and either paid to or expended on its behalf.... | ||||||
| 3 | The value of services or facilities furnished by a governmental unit to the organization without charge.. | ||||||
| 4 | Total. Add lines 1 through 3 | ||||||
| 5 | The portion of total contributions by each person (other than a governmental unit or publicly supported organization) included on line 1 that exceeds 2% of the amount shown on line 11, column (f).. | ||||||
| 6 | Public support. Subtract line 5 from line 4. | ||||||
Calendar year
(or fiscal year beginning in) ![]() |
(a) 2014 | (b) 2015 | (c) 2016 | (d) 2017 | (e) 2018 | (f) Total | |
|---|---|---|---|---|---|---|---|
| 7 | Amounts from line 4.. | ||||||
| 8 | Gross income from interest, dividends, payments received on securities loans, rents, royalties and income from similar sources... | ||||||
| 9 | Net income from unrelated business activities, whether or not the business is regularly carried on.. | ||||||
| 10 | Other income. Do not include gain or loss from the sale of capital assets (Explain in Part VI.).. | ||||||
| 11 | Total support. Add lines 7 through 10 | ||||||
Calendar year (or fiscal year beginning in) ![]() |
(a) 2014 | (b) 2015 | (c) 2016 | (d) 2017 | (e) 2018 | (f) Total | |
|---|---|---|---|---|---|---|---|
| 1 | Gifts, grants, contributions, and membership fees received. (Do not include any "unusual grants.") . | ||||||
| 2 | Gross receipts from admissions, merchandise sold or services performed, or facilities furnished in any activity that is related to the organization's tax-exempt purpose | ||||||
| 3 | Gross receipts from activities that are not an unrelated trade or business under section 513 ..... | ||||||
| 4 | Tax revenues levied for the organization's benefit and either paid to or expended on its behalf... | ||||||
| 5 | The value of services or facilities furnished by a governmental unit to the organization without charge | ||||||
| 6 | Total. Add lines 1 through 5 | ||||||
| 7a | Amounts included on lines 1, 2, and 3 received from disqualified persons | ||||||
| b | Amounts included on lines 2 and 3 received from other than disqualified persons that exceed the greater of $5,000 or 1% of the amount on line 13 for the year. | ||||||
| c | Add lines 7a and 7b.. | ||||||
| 8 | Public support. (Subtract line 7c from line 6.) | ||||||
Calendar year (or fiscal year beginning in) ![]() |
(a) 2014 | (b) 2015 | (c) 2016 | (d) 2017 | (e) 2018 | (f) Total | |
|---|---|---|---|---|---|---|---|
| 9 | Amounts from line 6... | ||||||
| 10a | Gross income from interest, dividends, payments received on securities loans, rents, royalties and income from similar sources.. | ||||||
| b | Unrelated business taxable income (less section 511 taxes) from businesses acquired after June 30, 1975. | ||||||
| c | Add lines 10a and 10b. | ||||||
| 11 | Net income from unrelated business activities not included in line 10b, whether or not the business is regularly carried on. | ||||||
| 12 | Other income. Do not include gain or loss from the sale of capital assets (Explain in Part VI.) .. | ||||||
| 13 | Total support. (Add lines 9, 10c, 11, and 12.).. | ||||||
| Section A - Adjusted Net Income | (A) Prior Year |
(B) Current Year (optional) |
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| 1 | Net short-term capital gain | 1 | ||||
| 2 | Recoveries of prior-year distributions | 2 | ||||
| 3 | Other gross income (see instructions) | 3 | ||||
| 4 | Add lines 1 through 3 | 4 | ||||
| 5 | Depreciation and depletion | 5 | ||||
| 6 | Portion of operating expenses paid or incurred for production or collection of gross income or for management, conservation, or maintenance of property held for production of income (see instructions) | 6 | ||||
| 7 | Other expenses (see instructions) | 7 | ||||
| 8 | Adjusted Net Income (subtract lines 5, 6 and 7 from line 4) | 8 | ||||
| Section B - Minimum Asset Amount | (A) Prior Year |
(B) Current Year (optional) |
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| 1 | Aggregate fair market value of all non-exempt-use assets (see instructions for short tax year or assets held for part of year): | 1 | ||||
| a | Average monthly value of securities | 1a | ||||
| b | Average monthly cash balances | 1b | ||||
| c | Fair market value of other non-exempt-use assets | 1c | ||||
| d | Total (add lines 1a, 1b, and 1c) | 1d | ||||
| e |
Discount claimed for blockage or other factors (explain in detail in Part VI): |
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| 2 | Acquisition indebtedness applicable to non-exempt use assets | 2 | ||||
| 3 | Subtract line 2 from line 1d | 3 | ||||
| 4 | Cash deemed held for exempt use. Enter 1-1/2% of line 3 (for greater amount, see instructions). | 4 | ||||
| 5 | Net value of non-exempt-use assets (subtract line 4 from line 3) | 5 | ||||
| 6 | Multiply line 5 by .035 | 6 | ||||
| 7 | Recoveries of prior-year distributions | 7 | ||||
| 8 | Minimum Asset Amount (add line 7 to line 6) | 8 | ||||
| Section C - Distributable Amount | Current Year | |||||
| 1 | Adjusted net income for prior year (from Section A, line 8, Column A) | 1 | ||||
| 2 | Enter 85% of line 1 | 2 | ||||
| 3 | Minimum asset amount for prior year (from Section B, line 8, Column A) | 3 | ||||
| 4 | Enter greater of line 2 or line 3 | 4 | ||||
| 5 | Income tax imposed in prior year | 5 | ||||
| 6 | Distributable Amount. Subtract line 5 from line 4, unless subject to emergency temporary reduction (see instructions) | 6 | ||||
| Section D - Distributions | Current Year | |
|---|---|---|
| 1 Amounts paid to supported organizations to accomplish exempt purposes | ||
|
2
Amounts paid to perform activity that directly furthers exempt purposes of supported organizations, in excess of income from activity |
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| 3 Administrative expenses paid to accomplish exempt purposes of supported organizations | ||
| 4 Amounts paid to acquire exempt-use assets | ||
| 5 Qualified set-aside amounts (prior IRS approval required) | ||
| 6 Other distributions (describe in Part VI). See instructions | ||
| 7Total annual distributions. Add lines 1 through 6. | ||
|
8
Distributions to attentive supported organizations to which the organization is responsive (provide details in Part VI). See instructions |
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| 9 Distributable amount for 2018 from Section C, line 6 | ||
| 10 Line 8 amount divided by Line 9 amount | ||
| Section E - Distribution Allocations (see instructions) |
(i) Excess Distributions |
(ii) Underdistributions Pre-2018 |
(iii) Distributable Amount for 2018 |
|
|---|---|---|---|---|
|
1
Distributable amount for 2018 from Section C, line 6 |
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2
Underdistributions, if any, for years prior to 2018 (reasonable cause required-- explain in Part VI). See instructions. |
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| 3 Excess distributions carryover, if any, to 2018: | ||||
| a From 2013....... | ||||
| b From 2014....... | ||||
| c From 2015....... | ||||
| d From 2016....... | ||||
| e From 2017....... | ||||
| fTotal of lines 3a through e | ||||
| g Applied to underdistributions of prior years | ||||
| h Applied to 2018 distributable amount | ||||
|
i
Carryover from 2013 not applied (see instructions) |
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| j Remainder. Subtract lines 3g, 3h, and 3i from 3f. | ||||
| 4Distributions for 2018 from Section D, line 7: | ||||
| $ | ||||
| a Applied to underdistributions of prior years | ||||
| b Applied to 2018 distributable amount | ||||
| c Remainder. Subtract lines 4a and 4b from 4. | ||||
|
5
Remaining underdistributions for years prior to 2018, if any. Subtract lines 3g and 4a from line 2. If the amount is greater than zero, explain in Part VI. See instructions. |
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|
6
Remaining underdistributions for 2018. Subtract lines 3h and 4b from line 1. If the amount is greater than zero, explain in Part VI. See instructions. |
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7 Excess distributions carryover to 2019. Add lines 3j and 4c. |
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| 8 Breakdown of line 7: | ||||
| a Excess from 2014...... | ||||
| b Excess from 2015..... | ||||
| c Excess from 2016..... | ||||
| d Excess from 2017..... | ||||
| e Excess from 2018..... | ||||
| Facts And Circumstances Test |
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| Return Reference | Explanation |
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| Software ID: | |
| Software Version: |
Attach to Form 990 or 990-EZ.
Go to www.irs.gov/Form990 for the latest information.
| Return Reference | Explanation |
|---|---|
| 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: | LOSS ON INTEREST RATE SWAP -48,117,024. |
| 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, THE INSTITUTE IS ORGANIZED INTO THE CENTER FOR CANCER AND CELL BIOLOGY, THE CENTER FOR EPIGENETICS, AND THE CENTER FOR NEURODEGENERATIVE SCIENCE. THE INSTITUTE'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, METABOLOMICS AND BIOENERGETICS AND CRYO-ELECTRON MICROSCOPY. VARI SCIENTISTS PUBLISHED 111 ARTICLES IN THIS FISCAL YEAR IN PEER-REVIEWED JOURNALS THAT INCLUDED NATURE, SCIENCE, CELL REPORTS, NATURE COMMUNICATIONS, NATURE STRUCTURAL AND MOLECULAR BIOLOGY, SCIENCE ADVANCES, CELL REPORTS, NATURE IMMUNOLOGY, CANCER RESEARCH, IMMUNITY, CLINICAL CANCER RESEARCH, MOLECULAR NEURODEGENERATION, LANCET NEUROLOGY, NUCLEIC ACIDS RESEARCH, TRENDS IN NEUROSCIENCES, GENOME BIOLOGY, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES U.S.A., CANCER CELL, THERANOSTICS, ELIFE, MOLECULAR CELL, JOURNAL OF THE NATIONAL CANCER INSTITUTE, ACTA NEUROPATHOLOGICA COMMUNICATIONS, EUROPEAN HEART JOURNAL, CIRCULATION RESEARCH, GASTROENTEROLOGY, JOURNAL OF BIOLOGICAL CHEMISTRY, NJP PARKINSON'S DISEASE, PROTEIN SCIENCE, MOLECULAR CELL, BIOCHEMISTRY, BIOINFORMATICS, CLINICAL EPIGENETICS, ISCIENCE, NEUROBIOLOGY OF DISEASE, MOLECULAR AND CELLULAR PROTEOMICS, MOLECULAR CANCER THERAPEUTICS, AND JOURNAL OF CHEMICAL THEORY AND COMPUTATION. |
| 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 14 LABORATORIES ENGAGED IN BASIC RESEARCH IN MOLECULAR AND STRUCTURAL BIOLOGY AND IN TRANSLATIONAL RESEARCH ON CANCER, SKELETAL DISEASES, AND METABOLISM AND NUTRITION. THE CENTER IS DIVIDED INTO PROGRAMS IN STRUCTURAL BIOLOGY; SKELETAL DISEASE AND CANCER THERAPEUTICS; AND METABOLIC AND NUTRITIONAL PROGRAMMING. IN THIS FISCAL YEAR, RESEARCHERS AND TRAINEES WITHIN THE CENTER RECEIVED THREE NEW R01'S, A U01, AN R35, AND AN F31 FELLOWSHIP FROM THE NATIONAL INSTITUTES OF HEALTH. OTHER NEW AWARDS WERE FROM THE NATIONAL SCIENCE FOUNDATION, DEPARTMENT OF DEFENSE, DEPARTMENT OF ENERGY, AND THE BREAST CANCER RESEARCH FOUNDATION. TWO NEW RESEARCH CONTRACTS WERE SIGNED IN 2019, AND FOUR GRANT SUBAWARDS AND TWO NON-NIH POSTDOCTORAL FELLOWSHIPS WERE RECEIVED. IN THE STRUCTURAL BIOLOGY PROGRAM, HUILIN LI'S LAB PRODUCED SEVERAL PAPERS. THEY STUDIED THE DRS2P-CDC50P COMPLEX THAT MAINTAINS CELL MEMBRANE ASYMMETRY, SOLVING THE CRYO-EM STRUCTURES OF INTACT DRS2P-CDC50P ISOLATED FROM S. CEREVISIAE IN THE INACTIVE APO FORM AND IN THE PI4P-ACTIVATED FORM AT 2.8 ANGSTROM AND 3.3 ANGSTROM RESOLUTION, RESPECTIVELY. THIS STUDY UNCOVERED THE MECHANISM BY WHICH THE ENZYME IS ACTIVATED (BAI ET AL., NATURE COMMUNICATIONS 10: 4142). ANOTHER STUDY REPORTED THE CRYO-EM STRUCTURES OF THE S. CEREVISIAE PMT1-PMT2 COMPLEX. EACH SUBUNIT CONTAINS 11 TRANSMEMBRANE HELICES AS WELL AS A LUMENAL BETA-TREFOIL FOLD TERMED THE MIR DOMAIN. FROM THESE STRUCTURES, THE LAB WAS ABLE TO SHOW HOW THE ENZYMES RECOGNIZE THEIR SUBSTRATE MOLECULES. (BAI ET AL., NATURE STRUCTURAL AND MOLECULAR BIOLOGY 26: 704-711). A THIRD PAPER REPORTED THE STRUCTURES OF THE RV3679-RV3680 COMPLEX IN THE TUBERCULOSIS-CAUSING MYCOBACTERIUM TUBERCULOSIS. THESE PROTEINS HAVE NEVER BEEN THOROUGHLY STUDIED BEFORE, AND THIS WORK FOUND THAT THEY ARE SIMILAR TO THE UKARYOTIC GET3 AND ARSA PROTEINS. THIS PAPER THUS HAS IDENTIFIED A NEW CLASS OF BACTERIAL PROTEINS THAT HAVE FUNCTIONS WE DO NOT YET UNDERSTAND (HU ET AL., JOURNAL OF BACTERIOLOGY 201(14): E00159-19). FINALLY, THE H. LI LAB PARTICIPATED IN DEVELOPING COMPOUNDS THAT ARE POTENT INHIBITORS OF THE M. TUBERCULOSIS PROTEASOME, WHICH IS A CELLULAR COMPONENT THAT BREAKS DOWN UNNEEDED OR DAMAGED PROTEINS. THE STRUCTURE OF THE PROTEOSOME PLUS INHIBITOR SUGGESTS WHY THE INHIBITORS WORK ONLY AGAINST THE BACTERIAL PROTEOSOME BUT NOT THE HUMAN CELL PROTEOSOME. THIS KNOWLEDGE COULD AID THE DEVELOPMENT OF NEW DRUGS AGAINST TUBERCULOSIS (ZHAN ET AL., JOURNAL OF MEDICINAL CHEMISTRY 62(20): 9246-9253). STRUCTURAL RESEARCH IN THE MELCHER AND XU LABS ALSO PRODUCED SEVERAL PAPERS. ONE STUDY DEVELOPED NEW DRUG CANDIDATES AGAINST ASTHMA BASED ON STRUCTURAL ANALYSES OF THE GLUCOCORTICOID RECEPTOR (GR). ONE OF THOSE COMPOUNDS, VSG158, REPRESSED LUNG INFLAMMATION AND WAS 10 TIMES MORE POTENT IN A MOUSE MODEL THAN THE BEST GLUCOCORTICOID NOW IN CLINICAL USE, FLUTICASONE FUROATE. BOTH VSG158 AND VSG159 DELIVERED EFFECTIVE TREATMENT AND REDUCED OFF-TARGET AND SIDE EFFECTS. THEY HAVE PHARMACOKINETIC PROPERTIES THAT ARE SUITABLE FOR INHALATION TREATMENT OF ASTHMA (HE ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES U.S.A. 116(14): 6932-6937). THE LABS ALSO COMPLETED A STUDY ON THE HUMAN PARATHYROID HORMONE RECEPTOR-1 (PTH1R), WHICH IS A THERAPEUTIC TARGET IN OSTEOPOROSIS AND HYPOPARATHYROIDISM. THE STRUCTURE OF PTH1R BOUND TO A LONG-ACTING PTH ANALOG AND A STIMULATORY G PROTEIN WAS SOLVED. THIS RESEARCH PROVIDES INSIGHT INTO THE DYNAMICS OF PTH BINDING TO THE RECEPTOR AND RECEPTOR ACTIVATION (ZHAO ET AL., SCIENCE 364(6436): 148-153). THEY ALSO PUBLISHED A PAPER ON THE ARTHROBACTER GLOBIFORMIS URICASE ENZYME, WHICH HAS POTENTIAL AS A DRUG AGAINST HYPERURICEMIA-RELATED DISEASES. DISULFIDE BOND CROSS-LINKING PROTECTED THE ENZYME FROM DEGRADATION. SUCH INTRODUCTION OF DISULFIDE BONDS MAY BE A GENERAL AVENUE FOR IMPROVING THE STABILITY OF MANY MULTIMERIC PROTEINS, WHICH COULD IMPROVE THEIR VALUE IN MEDICAL USE (SHI ET AL., ACTA PHARMACOLOGICA SINICA 40: 1364-1372). THE LU AND DU LABS TOGETHER PUBLISHED A STUDY ON THE HUMAN TRPM2 PROTEIN, WHICH IS INVOLVED IN BODY TEMPERATURE SENSING AND IN IMMUNE RESPONSES. THEY SHOWED THE STRUCTURAL REARRANGEMENTS AND CHANNEL ACTIVATION OF TRPM2 THAT WAS INDUCED BY THE BINDING OF ADPR IN TWO SPECIFIC LOCATIONS ON THE PROTEIN, AND THAT THE ACTIVATION PROCESS DIFFERS BETWEEN THE TRPM2 PROTEINS FROM VERTEBRATES AND INVERTEBRATES. THE STUDY PROVIDES INSIGHT INTO TRPM2 ACTIVATION AND ITS PHARMACOLOGICAL PROPERTIES (HUANG ET AL., ELIFE 8: E50175). THE HAAB LAB MADE PROGRESS IN ITS WORK ON DIAGNOSTICS AND BIOMARKERS OF PANCREATIC CANCER. THEY VALIDATED THAT A GLYCAN CALLED STRA WAS A BETTER BIOMARKER OF PANCREATIC DUCTAL ADENOCARCINOMA THAN THE TRADITIONAL BIOMARKER, CA19-9. IN TWO PANELS, ONE FOR SPECIFICITY AND ONE FOR SENSITIVITY, STRA WAS STATISTICALLY BETTER THAN CA19-9 IN BOTH. THIS WORK MAY IMPROVE DIFFERENTIAL DIAGNOSIS AMONG PATIENTS WITH SUSPECTED PANCREATIC CANCER (STAAL ET AL., CLINICAL CANCER RESEARCH 25(9): 2745-2754). THE LAB ALSO DEVELOPED A NEW WAY TO ANALYZE N-GLYCOPROTEINS IN SERUM. THE ANALYSIS USES MATRIX-ASSISTED LASER DESORPTION/IONIZATION MASS SPECTROMETRY IMAGING (MALDI MSI) AND ANTIBODY SLIDE ARRAYS. THIS NOVEL APPROACH CAN BE USED TO ANALYZE ANY GLYCOPROTEIN HAVING A VALIDATED ANTIBODY, AND IT CAN BE ADAPTED TO ANY BIOLOGICAL FLUID OR TISSUE SAMPLE THAT CAN BE ANALYZED BY ANTIBODY ARRAYS (BLACK ET AL., ANALYTICAL CHEMISTRY 91(13): 8429-8435). THIRD, THE LAB HAS DEVELOPED SOFTWARE CALLED SIGNALFINDER THAT USES A NEW ALGORITHM AND PERFORMS ROBUSTLY FOR THE AUTOMATED IDENTIFICATION OF MULTIPLE MARKERS IN A SINGLE SAMPLE. TWO UTILITIES PROVIDE 1) QUANTIFICATION AND MAPPING OF RELATIONSHIPS BETWEEN AN UNLIMITED NUMBER OF MARKERS AND 2) COMPOSITE PICTURES OF THE SIGNALS OR COLOCALIZATION ANALYSIS ON BRIGHTFIELD STAINED IMAGES. SIGNALFINDER ALLOWS HIGH-THROUGHPUT, RIGOROUS ANALYSES OF WHOLE-SLIDE, MULTIMARKER DATA (BARNETT ET AL., AMERICAN JOURNAL OF PATHOLOGY 189(7): 1402-1412). THE STEENSMA LAB COAUTHORED A STUDY SHOWING THAT THE KRAS G13D MUTATION OF THE RAS GTPASE ENZYME APPEARS IN 25% OF KRAS-DRIVEN COLORECTAL CANCERS, BUT THAT MUTATION IS FOUND ONLY RARELY IN HRAS OR NRAS FORMS. THE KRAS G13D DESTABILIZES THE ENZYME'S NUCLEOTIDE-BINDING POCKET. THESE RESULTS IN PART EXPLAIN THE HIGHER FREQUENCY OF THE G13D MUTANT IN KRAS OVER THE OTHER ISOFORMS OF RAS (JOHNSON ET AL., CELL REPORTS 28(6): 1538-1550.E7). THE KRAWCZYK LAB PUBLISHED A REVIEW OF THE CURRENT UNDERSTANDING OF EPIGENETIC REGULATION OF DENDRITIC CELL FUNCTION. DENDRITIC CELLS ARE A KEY PART OF THE INNATE IMMUNE SYSTEM, AND EPIGENETIC MECHANISMS CONTRIBUTE TO THE HEALTH OF DENDRITIC CELLS AND ARE IMPORTANT FOR THEIR PRECISE RESPONSE TO STIMULI. ENVIRONMENTAL FACTORS SUCH AS CHEMICALS, NUTRIENTS, AND AGING HAVE EFFECTS ON THE EPIGENOME OF DENDRITIC CELLS AND SO AFFECT THE REGULATION OF HOST IMMUNITY (BOUKHALED ET AL., FRONTIERS IN IMMUNOLOGY 10: 1119). RUSSELL JONES' LAB COAUTHORED A PAPER REPORTING ON A CONNECTION BETWEEN THE METABOLIC ACTIVITY OF IMMUNE CELLS AND DISEASE. THEY MEASURED GLYCOLYSIS AND OXYGEN CONSUMPTION RATE IN B CELLS FROM PATIENTS WHO HAD A PRIMARY ANTIBODY DEFICIENCY. THE HIGHEST OXYGEN CONSUMPTION WAS FOUND IN THREE PATIENTS WHO HAD PERSISTENT POLYCLONAL B CELL LYMPHOCYTOSIS. THE STUDY FOUND THAT MUTATIONS IN THE SDHA GENE ACTIVATED A PATHWAY THAT ENDED WITH PRODUCTION OF INFLAMMATORY CYTOKINES AND THAT BLOCKING IL-6 COULD PREVENT SYSTEMIC INFLAMMATION AND LESSEN CLINICAL DISEASE (BURGENER ET AL., NATURE IMMUNOLOGY 20(10): 1311-1321). |
| FORM 990, PART III, LINE 4B | LINE 4B - PROGRAM SERVICE ACTIVITY #2 CENTER FOR EPIGENETICS THE CENTER, ESTABLISHED IN 2014 AND DIRECTED BY ANDREW POSPISILIK, PH.D., COMPRISES 11 LABORATORIES STUDYING EPIGENETICS, EPIGENOMICS, AND THE ROLE OF EPIGENETIC DYSFUNCTION IN CANCER, NEURODEGENERATIVE DISEASE, CARDIOVASCULAR DISEASE, AND VIRAL TRANSCRIPTION. NEW GRANT AWARDS IN THIS FISCAL YEAR FOR CENTER RESEARCHERS AND TRAINEES INCLUDED TWO R01S AND AN R50 FROM THE NATIONAL INSTITUTES OF HEALTH, AS WELL AS A POSTDOCTORAL F32 AND A PRE-DOCTORAL FELLOWSHIP. TWO NIH GRANT SUB-AWARDS WERE ALSO RECEIVED. THE VAN ANDEL INSTITUTE-STAND UP TO CANCER EPIGENETICS DREAM TEAM, LED BY PETER JONES AND STEPHEN BAYLIN, CONTINUED IN 2019 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 THE DNA WRAPS. THE ROTHBART LAB REPORTED THAT THE UHRF1 PROTEIN FUNCTIONS AS A CHROMATIN READER TO MAINTAIN CANCER-SPECIFIC DNA METHYLATION IN HUMAN COLORECTAL CANCER CELLS. DISRUPTING THAT ACTIVITY REVERSES DNA HYPERMETHYLATION, REACTIVATES EPIGENETICALLY SILENCED TUMOR SUPPRESSOR GENES, AND REDUCES CANCER CELL ONCOGENIC PROPERTIES. THIS RESULT SUGGESTS THE TARGETING OF THIS PROTEIN MAY BE RELEVANT IN DEVELOPING THERAPEUTIC AGENTS THAT DEMETHYLATE DNA (KONG ET AL., CANCER CELL 35(4): 633-648). THE LAB ALSO DEVELOPED A HIGH-THROUGHPUT PROTEOMICS PLATFORM THAT MAPS THE SELECTIVITY OF THE LYSINE METHYLTRANSFERASE ENZYME WITHOUT NEEDING PRIOR KNOWLEDGE OF A SUBSTRATE OR TARGET PROTEOME. THE STUDY DEMONSTRATED THE PREDICTIVE POWER OF THIS PLATFORM AND ITS USEFULNESS FOR GUIDING THE STUDY OF LYSINE METHYLATION SIGNALING (CORNETT ET AL., SCIENCE ADVANCES 4(11): EAAV2623). IN ANOTHER PAPER, THE SRA FINGER LOOP WAS IDENTIFIED AS A REGULATOR OF UHRF1 UBIQUITIN TARGETING AND OF THE MAINTENANCE OF DNA METHYLATION. THESE RESULTS PROVIDE INSIGHT INTO THE REGULATION OF UHRF1 E3 LIGASE ACTIVITY, SUGGESTING THAT ITS SRA FINGER LOOP REGULATES ITS CONFORMATION AND FUNCTION (VAUGHAN ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY 294(43): 15724-15732). PETER JONES' LAB PUBLISHED A STUDY ON CORRECTING THE VITAMIN C DEFICIENCY OF MYELOID CANCER PATIENTS. ORAL SUPPLEMENTATION LED TO AN INCREASE IN THE 5HMC/5MC RATIO RELATIVE TO PLACEBO-TREATED PATIENTS AND MAY ENHANCE THE EFFECTS OF INHIBITORS (DNMTI'S) OF METHYLTRANSFERASE ENZYMES. THE CLINICAL VALUE OF ORAL VITAMIN C SUPPLEMENTATION TO DNMTI THERAPY SHOULD BE STUDIED IN A LARGE, RANDOMIZED, PLACEBO-CONTROLLED TRIAL (GILLBERG ET AL., CLINICAL EPIGENETICS 11: 143). ANOTHER STUDY LINKED THE FREQUENCY OF IMPRINTING OF THE NC886 DIFFERENTIALLY METHYLATED REGION (DMR) IN INFANTS TO THE MOTHER'S AGE AT DELIVERY AND TO THE SEASON OF CONCEPTION. BASED ON THE RESULTS, THEY PROPOSE THAT THE IMPRINTING OF THIS DMR IS "TUNABLE" IN BEING ASSOCIATED WITH MATERNAL HAPLOTYPE AND PRENATAL ENVIRONMENT, PROVIDING A POSSIBLE MECHANISM FOR TRANSMITTING INFORMATION FROM MOTHER TO CHILD (CARPENTER ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES U.S.A. 115(51): E11970-E11977). THE LAB ALSO PUBLISHED A REVIEW OF EPIGENETIC THERAPY IN IMMUNO-ONCOLOGY. INHIBITORS OF DNA METHYLATION HAVE BECOME A MAINSTAY TREATMENT FOR BLOOD CANCERS. SUCH INHIBITORS CAUSE CELLS TO MOUNT AN INNATE IMMUNE RESPONSE, AND OTHER EPIGENETIC INHIBITORS CAN PRODUCE SIMILAR EFFECTS. THESE DEVELOPMENTS OPEN NEW AVENUES FOR THE TREATMENT OF CANCERS (JONES ET AL., NATURE REVIEWS CANCER 19: 151-161). THE PFEIFER LAB QUANTIFIED DNA CYTOSINE MODIFICATIONS IN DIFFERENTIATING NEURONS ISOLATED FROM MOUSE BRAIN AT THE PEAK OF EMBRYONIC NEUROGENESIS. LOCAL DNA REGIONS HAVING LITTLE METHYLATION (HYPOMETHYLATION) WERE MUCH MORE COMMON THAN HYPERMETHYLATION. THE HYPOMETHYLATED REGIONS STRONGLY OVERLAPPED WITH THE BINDING SITES OF THE KEY NEURONAL TRANSCRIPTION FACTOR NEUROD2. THESE DATA SUGGEST A CRUCIAL ROLE FOR NEUROD2 DURING NEURON DEVELOPMENT, AND THE STUDY IS A STEP TOWARD AN EFFECTIVE APPROACH TO CONVERTING OTHER CELL TYPES INTO NEURONS FOR USE IN REGENERATIVE MEDICINE (HAHN ET AL., SCIENCE ADVANCES 5(10): EAAX0080). THE PFEIFER AND SZABO LABS PUBLISHED A STUDY IN WHICH THE CATALYTIC DOMAIN OF EITHER THE EHMT2 OR THE SETDB1 METHYLTRANSFERASE ENZYME WAS DELETED IN GROWING OOCYTES. THE DELETIONS SIGNIFICANTLY REDUCED H3K9ME2 OR H3K9ME3, RESPECTIVELY, IN THE MATERNAL PRONUCLEUS. THE ASYMMETRY OF GLOBAL 5MC OXIDATION WAS SIGNIFICANTLY LESS IN THE ZYGOTES HAVING MATERNAL MUTATION IN EHMT2 OR SETD1. THESE ENZYMES SEEM TO HAVE ROLES IN THE STRUCTURAL ASPECTS OF ZYGOTE DEVELOPMENT (ZENG ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES U.S.A. 116(22): 10834-10841). A STUDY FROM THE JOVINGE LAB ON GENE EXPRESSION ANALYSIS REVEALED THAT THE MOLECULAR BEACON (MB)-POSITIVE CARDIOMYOCYTE SUBPOPULATION HAD PATTERNS CONSISTENT WITH NUCLEAR DIVISION, CHROMOSOME SEGREGATION, AND M-G1 TRANSITION. DUAL MBS TARGETING THE CDC20 AND SPG20 MRNAS ALLOWED THE IDENTIFICATION OF CYTOKINETIC EVENTS SUCH AS CDC20(HIGH)SPG20(HIGH). THIS WORK PROVIDES AN ALTERNATIVE APPROACH FOR SORTING CARDIOMYOCYTES THAT HAVE TRUE MITOTIC POTENTIAL (MILLIRON ET AL., CIRCULATION RESEARCH 125(12): 1070-1086). THE LAB ALSO EVALUATED THE SAFETY OF CROSS-SPECIES SENDAI VIRAL REPROGRAMMING OF INDUCED PLURIPOTENT STEM CELLS, AND THEY STUDIED THE DYNAMICS OF DNA TRANSCRIPTION DURING REPROGRAMMING AND DIFFERENTIATION. THIS STUDY DEMONSTRATED THE SUCCESSFUL USE OF A CLINICALLY RELEVANT METHOD TO REPROGRAM DIFFERENTIATED MOUSE CELLS AND THEIR POTENTIAL FOR GENERATING SPECIALIZED TYPES OF CARDIAC CELLS (TARNAWSKI ET AL., CELLULAR REPROGRAMMING 21(2): 78-88). A THIRD PROJECT ANALYZED CARDIAC CELLS FROM EARLY-STAGE DEVELOPING HEARTS BY USING SINGLE-CELL RNA SEQUENCING. THE DATA SHOWED HOW VARIATIONS IN CELL CYCLE ACTIVITY SELECTIVELY PROMOTE CARDIAC CHAMBER GROWTH DURING DEVELOPMENT; REVEALED CHAMBER-SPECIFIC, CELL CYCLE-LINKED TRANSCRIPTIONAL SHIFTS; AND OPEN THE WAY TO A DEEPER UNDERSTANDING OF THE ORIGINS OF CONGENITAL HEART DISEASE (LI ET AL, DEVELOPMENT 146(12): DEV173476). THE SHEN AND LAIRD LABS JOINTLY PRODUCED A SYSTEMATIC ANALYSIS OF THE EFFECTS OF SYNCHRONIZING A LARGE-SCALE, DEEPLY CHARACTERIZED, MULTI-OMIC DATA SET TO THE CURRENT HUMAN REFERENCE GENOME. THE HG19 AND HG38 CANCER GENOME ATLAS DATA SETS ARE VERY HIGHLY CONCORDANT AND PROVIDE A RUBRIC THAT ENCOURAGES SIMILAR COMPARISONS AS NEW DATA EMERGE AND AS THE REFERENCE DATA EVOLVE (GAO ET AL., CELL SYSTEMS 9(1): 24-34.E10). THEY ALSO PUBLISHED A STUDY USING DNA METHYLATION PROFILING TO DIFFERENTIATE MALIGNANT LUNG TUMORS FROM BENIGN SOLITARY PULMONARY NODULES, WHICH REQUIRES BETTER NON-INVASIVE DIAGNOSTIC TOOLS. THE RESEARCH RESULTED IN A SENSITIVE, BLOOD-BASED, NON?INVASIVE DIAGNOSTIC ASSAY FOR DETECTING EARLY-STAGE LUNG CANCER AND FOR DIFFERENTIATING LUNG CANCERS FROM BENIGN PULMONARY NODULES (LIANG ET AL., THERANOSTICS 9(7): 2056-2070). THE LAIRD LAB PRODUCED A VIDEO SHOWING HOW BOTH TIGHT REPRESSION AND ROBUST UP-REGULATION ARE POSSIBLE THROUGH REVERSIBLE, TUNABLE REMOTE-CONTROL SYSTEM THEY DEVELOPED, WHICH CAN BE APPLIED AND WITHDRAWN REPEATEDLY IN ORGANISMS. THE SYSTEM USES ENHANCED LAC REPRESSION AND TET ACTIVATION SYSTEMS TO MANIPULATE A TARGET GENE WITHIN A BIOLOGICAL SYSTEM (VANDER SCHAAF ET AL., JOURNAL OF VISUALIZED EXPERIMENTS 145). THE SHEN LAB COLLABORATED IN A STUDY OF ARID1A, A PROTEIN INVOLVED IN CHROMATIN REMODELING AND A FACTOR IN ENDOMETRIAL CANCER. THE AUTHORS PROPOSE THAT ARID1A NORMALLY MAINTAINS ENDOMETRIAL EPITHELIAL CELL IDENTITY AND THAT COEXISTENT ARID1A AND PI3K MUTATIONS PROMOTE EPITHELIAL TRANSDIFFERENTIATION AND COLLECTIVE INVASION. THESE FINDINGS SUPPORT A ROLE FOR COLLECTIVE EPITHELIAL INVASION IN THE SPREAD OF ABNORMAL ENDOMETRIAL TISSUE (WILSON ET AL., NATURE COMMUNICATIONS 10: 3554). |
| FORM 990, PART III, LINE 4B (CONT.) |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|
| 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. IN 2019, IT HAD NINE LABORATORIES STUDYING PARKINSON'S DISEASE, ALZHEIMER'S DISEASE, PRIONS, AND THE RELATIONSHIPS BETWEEN DEPRESSION, SUICIDE, AND BRAIN INFLAMMATION. THE NEWEST LABORATORY, THAT OF HONG-YUAN CHU, PH.D., FOCUSES ON NEURAL CIRCUITS AND NEURODEGENERATION. CENTER RESEARCHERS AND TRAINEES DURING THIS FISCAL YEAR RECEIVED TWO R01S, TWO R21S, AND A U01 GRANT FROM THE NATIONAL INSTITUTES OF HEALTH, AND AWARDS FROM THE FARMER FAMILY FOUNDATION, THE MICHAEL J. FOX FOUNDATION, AND THE CREUTZFELDT-JAKOB DISEASE FOUNDATION. A POSTDOCTORAL FELLOWSHIP WAS RECEIVED FROM THE AMERICAN PARKINSON DISEASE ASSOCIATION, AND TWO NEW RESEARCH CONTRACTS WERE SIGNED. THE COETZEE LAB PUBLISHED A STUDY OF 19 (OF 142) BREAST CANCER GENE RISK LOCI THAT ARE LIKELY TO FUNCTION IN THE MCF-7 BREAST CANCER CELL LINE AND ARE SUITED FOR TARGETED MANIPULATION. HOWEVER, THE RISK LOCI CANNOT BE MAPPED TO SPECIFIC CTCF BINDING SITES, AND THE GENES LINKED TO RISK SITES DID NOT SHOW FUNCTIONAL ENRICHMENT. THE IDENTITY OF THESE RISK ENHANCERS AND THEIR ASSOCIATED GENES SUGGESTS THAT SOME RISK MAY FUNCTION DURING LATER STAGES OF CANCER PROGRESSION (BOOMS ET AL., CANCER EPIDEMIOLOGY, BIOMARKERS AND PREVENTION 28(10): 1735-1745). THE LAB ALSO PUBLISHED A FUNCTIONAL ANALYSIS AND FINE MAPPING OF THE 9P22.2 CHROMOSOME AND ITS RELATIONSHIP TO AN OVARIAN CANCER SUSCEPTIBILITY LOCUS. THE BNC2 GENE WAS ESTABLISHED AS THE MOST LIKELY TARGET GENE. THE STUDY UNCOVERED A COMPREHENSIVE REGULATORY LANDSCAPE AT 9P22.2 AND SUGGESTS A LIKELY MECHANISM FOR AN INDIVIDUAL'S SUSCEPTIBILITY TO OVARIAN CANCER (BUCKLEY ET AL., CANCER RESEARCH 79(3): 467-481). THE PATRIK BRUNDIN AND THE MA LABS STUDIED THE "ENGRAILED1" GENE AND ITS EFFECT ON ALPHA-SYNUCLEIN AGGREGATION IN NEURONS. EN1(+/-) MICE INJECTED WITH SYNUCLEIN FIBRILS HAD A NEARLY THREEFOLD INCREASE IN SYNUCLEIN-POSITIVE NEURONS IN THE SUBSTANTIA NIGRA. THEY ALSO SHOWED SIGNIFICANT INCREASES IN THE AMYGDALA AND VENTRAL TEGMENTAL AREA AND MORE AGGREGATION IN SEVERAL CORTICAL REGIONS. THIS STUDY IS ANOTHER STEP IN DEFINING THE GENES THAT CAUSE PARKINSON'S DISEASE. (CHATTERJEE ET AL., JOURNAL OF PARKINSON'S DISEASE 9(2): 315-326). A STUDY BY THE PATRIK BRUNDIN LAB FOUND THAT THE ABSENCE OR THE HYPERSTIMULATION OF MICROGLIAL CELLS AFFECTED ALPHA-SYNUCLEIN TRANSFER IN THE MOUSE BRAIN. THE RESULTS SUGGEST THAT UNDER RESTING, NONINFLAMMATORY CONDITIONS, MICROGLIA MODULATE THE TRANSFER OF ALPHA-SYN AND THAT DRUGS WHICH REGULATE NEUROINFLAMMATION COULD BE A WAY TO LIMIT THE SPREAD OF PARKINSON'S DISEASE PATHOLOGY (GEORGE ET AL., MOLECULAR NEURODEGENERATION 14: 34). THE LABRIE LAB STUDIED 1.2 MILLION CPG AND CPH SITES IN ENHANCERS WITHIN PREFRONTAL CORTEX NEURONS AND IDENTIFIED 1224 DIFFERENTIALLY METHYLATED ENHANCER REGIONS. CPH METHYLATION LOSS, WHICH IS NORMAL IN AGING NEURONS, IS ACCELERATED IN ALZHEIMER'S DISEASE. THEY ALSO FOUND THAT NEURONS IN ALZHEIMER'S DISEASE HAVE A LARGE CLUSTER OF SIGNIFICANTLY HYPOMETHYLATED ENHANCERS IN THE DSCAML1 GENE (LI ET AL., NATURE COMMUNICATIONS 10: 2246). IN ANOTHER PROJECT, THE LAB STUDIED THE DISRUPTION OF CIRCADIAN RHYTHMS, WHICH MAY INCREASE RISK FOR MALIGNANT, PSYCHIATRIC, METABOLIC, AND OTHER DISEASES. THIS STUDY SHOWED THAT OSCILLATING CYTOSINE MODIFICATIONS (OSC-MODCS) ARE FOUND IN HUMAN NEUTROPHILS, THAT THEY MAY PLAY A ROLE IN GENE REGULATION, AND THAT THEY ARE LINKED TO COMPLEX DISEASES SUCH AS CANCER. OSC-MODCS CAN ALSO EXPLAIN PARTS OF EPIGENETIC VARIATION ARE SIGNATURES OF AGING (OH ET AL., GENOME BIOLOGY 20(1): 2). THE LABRIE AND SZAB LABS COLLABORATED ON A STUDY OF NEURONS ISOLATED FROM THE PREFRONTAL CORTEX OF PATIENTS HAVING SCHIZOPHRENIA OR BIPOLAR DISORDER. PROMINENT HYPOMETHYLATION OF AN ENHANCER OF THE IGF2 GENE WAS FOUND IN NEURONS. THAT ENHANCER TARGETS THE NEARBY TYROSINE HYDROXYLASE GENE, WHICH RESPONSIBLE FOR DOPAMINE SYNTHESIS. THE DATA SUGGEST THAT HYPOMETHYLATION ACTIVATES THE ENHANCER AT IGF2, WHICH MAY INCREASE THE DOPAMINE SYNTHESIS THAT IS ASSOCIATED WITH MAJOR PSYCHOSIS (PAI ET AL., NATURE COMMUNICATIONS 10: 2046). THE MOORE AND MA LABS PUBLISHED RESEARCH SHOWING THAT, UNLIKE PHYSIOLOGICAL ALPHA-SYNUCLEIN, DISEASE-CAUSING FORMS OF SYNUCLEIN AGGREGATES PREFERENTIALLY BIND TO MITOCHONDRIA AND AFFECT CELLULAR RESPIRATION. THIS INDICATES THAT MITOCHONDRIAL DYSFUNCTION HAS A ROLE IN ALPHA-SYNUCLEIN-RELATED DISEASES, AND IT ALSO SUGGESTS AN EXPLANATION OF THE FORMATION AND THE PECULIAR MORPHOLOGY OF LEWY BODIES (WANG ET AL., ACTA NEUROPATHOLOGICA COMMUNICATIONS 7: 41). THE MOORE, LABRIE, AND MA LABS USED A KNOCK-IN MOUSE MODEL TO SHOW THE AGE-RELATED PATHOGENIC EFFECTS OF A MUTATION IN THE VPS35 GENE IN PARKINSON'S DISEASE. THAT MODEL REPRODUCED KEY NEUROPATHOLOGICAL HALLMARKS OF PD, INCLUDING PROGRESSIVE DEGENERATION OF NIGROSTRIATAL DOPAMINERGIC NEURONS AND WIDESPREAD AXON PATHOLOGY. UNEXPECTEDLY, ENDOGENOUS D620N VPS35 EXPRESSION ALSO PRODUCED STRONG, TAU-POSITIVE, SOMATODENDRITIC PATHOLOGY THROUGHOUT THE BRAIN, WHICH RAISES THE POSSIBILITY OF INTERPLAY BETWEEN MUTANT VPS35 AND TAU IN PARKINSON'S DISEASE NEURODEGENERATION (CHEN ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES U.S.A. 116(12): 5765-5774). THE MOORE LABORATORY ALSO CONTRIBUTED TO A STUDY OF RAT MODELS OF PARKINSON'S DISEASE IN ORDER TO OPTIMIZE ALPHA-SYNUCLEIN ACCUMULATION AND NIGROSTRIATAL DEGENERATION AND TO UNDERSTAND THE TIME COURSE OF BOTH PROCESSES. THE FINDINGS CAN HELP DEVELOP A REPRODUCIBLE SYNUCLEINOPATHY MODEL IN RATS THAT WOULD BE VALUABLE FOR STUDYING PATHOGENIC MECHANISMS OF PARKINSON'S DISEASE AND DISEASE-MODIFYING THERAPIES (PATTERSON ET AL., NEUROBIOLOGY OF DISEASE 130: 104525). THE LENA BRUNDIN LAB ASSAYED TRYPTOPHAN AND METABOLITE LEVELS AND THE EXPRESSION OF KYNURENINE PATHWAY ENZYMES IN PLACENTAL TISSUE FROM WOMEN WITH AND WITHOUT PRE-ECLAMPSIA. TRYPTOPHAN AND THE INFLAMMATORY MEDIATOR SAA WERE BOTH REDUCED IN PLACENTAS FROM WOMEN WITH PRE-ECLAMPSIA. THERE WAS ALSO AN INCREASED KYNURENINE/TRYPTOPHAN RATIO, BUT NO SIGNIFICANT CHANGE IN DOWNSTREAM METABOLITES (KEATON ET AL., INTERNATIONAL JOURNAL OF TRYPTOPHAN RESEARCH 12). ANOTHER STUDY MEASURED 45 IMMUNOBIOLOGICAL FACTORS IN PERIPHERAL BLOOD AND SHOWED THAT THE PROFILE OF PATIENTS AT INCREASED RISK OF SUICIDE DIFFERED FROM THE PROFILE ASSOCIATED WITH DEPRESSION. INCREASED INTERLEUKIN-6 AND HIGHER NUMBERS OF LYMPHOCYTES, MONOCYTES, WHITE BLOOD CELLS, AND POLYMORPHONUCLEAR LEUKOCYTES SIGNIFICANTLY AFFECTED SUICIDE RISK; THE LAST TWO HAD THE STRONGEST INFLUENCE. INTERLEUKIN-8 WAS INDEPENDENTLY AND NEGATIVELY ASSOCIATED WITH INCREASED SUICIDE RISK. THE SUICIDE RISK PROFILE INDICATED THAT GRANULOCYTE-MEDIATED BIOLOGICAL MECHANISMS COULD BE ACTIVATED IN THOSE PATIENTS (KEATON ET AL., JOURNAL OF AFFECTIVE DISORDERS 247: 57-65). THE LAB ALSO COLLABORATED ON A THIRD PAPER STUDYING BLOOD LEVELS OF INTERLEUKIN-6 (IL-6), 2-ARACHIDONOYLGLYCEROL (2-AG), AND PICOLINIC ACID (PIC) IN PERSONS HAVING A HISTORY OF MOOD, ANXIETY, OR PERSONALITY DISORDERS AND IN CONTROL SUBJECTS. THE STUDY SHOWED SIGNIFICANT ASSOCIATIONS BETWEEN IL-6 LEVEL AND PLASMA 2-AG AND PIC ACROSS ALL SUBJECTS. THE DATA PROVIDE EVIDENCE OF INTERPLAY BETWEEN THESE MOLECULES AND SUGGEST THAT THESE FACTORS INFLUENCE PERSONALITY TRAITS (HEILMAN ET AL., PSYCHONEUROENDOCRINOLOGY 110: 104434). THE GUERREIRO AND BRAS LABS PUBLISHED A STUDY OF A SEVERE, ADULT-ONSET, FAMILIAL DEGENERATIVE BRAIN DISEASE KNOWN AS HDLS-S. THEIR RECENT ASSESSMENT OF SEVERAL FAMILY MEMBERS AND DNA SEQUENCING ANALYSES SHOWED THAT THE P.CYS152PHE VARIANT IN THE AARS (ALANYL TRNA SYNTHETASE) GENE IS THE PROBABLE CAUSE OF THIS DISEASE. THE STUDY IDENTIFIES AARS AS A TARGET FOR RESEARCH INTO DEVELOPING A THERAPY FOR THIS DISEASE (SUNDAL ET AL., ACTA NEUROPATHOLOGICA COMMUNICATIONS 7: 188). |
| 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 $1,576,560,000 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. |
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