Attach to Form 990 or Form 990-EZ.
Go to
www.irs.gov/Form990 for instructions and 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 | |||||
|
Total |
||||||
Calendar year (or fiscal year beginning in) ![]() |
(a) 2015 | (b) 2016 | (c) 2017 | (d) 2018 | (e) 2019 | (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) 2015 | (b) 2016 | (c) 2017 | (d) 2018 | (e) 2019 | (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) 2015 | (b) 2016 | (c) 2017 | (d) 2018 | (e) 2019 | (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) 2015 | (b) 2016 | (c) 2017 | (d) 2018 | (e) 2019 | (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) |
||||
| 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) |
||||
| 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): |
|||||
| 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 |
||
| 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 |
||
| 9 Distributable amount for 2019 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-2019 |
(iii) Distributable Amount for 2019 |
|
|---|---|---|---|---|
| 1 Distributable amount for 2019 from Section C, line 6 | ||||
|
2
Underdistributions, if any, for years prior to 2019 (reasonable cause required-- explain in Part VI). See instructions. |
||||
| 3 Excess distributions carryover, if any, to 2019: | ||||
| a From 2014....... | ||||
| b From 2015....... | ||||
| c From 2016....... | ||||
| d From 2017....... | ||||
| e From 2018....... | ||||
| fTotal of lines 3a through e | ||||
| g Applied to underdistributions of prior years | ||||
| h Applied to 2019 distributable amount | ||||
|
i
Carryover from 2014 not applied (see instructions) |
||||
| j Remainder. Subtract lines 3g, 3h, and 3i from 3f. | ||||
| 4Distributions for 2019 from Section D, line 7: | ||||
| $ | ||||
| a Applied to underdistributions of prior years | ||||
| b Applied to 2019 distributable amount | ||||
| c Remainder. Subtract lines 4a and 4b from 4. | ||||
|
5
Remaining underdistributions for years prior to 2019, if any. Subtract lines 3g and 4a from line 2. If the amount is greater than zero, explain in Part VI. See instructions. |
||||
|
6
Remaining underdistributions for 2019. Subtract lines 3h and 4b from line 1. If the amount is greater than zero, explain in Part VI. See instructions. |
||||
|
7 Excess distributions carryover to 2020. Add lines 3j and 4c. |
||||
| 8 Breakdown of line 7: | ||||
| a Excess from 2015..... | ||||
| b Excess from 2016..... | ||||
| c Excess from 2017..... | ||||
| d Excess from 2018..... | ||||
| e Excess from 2019..... | ||||
| Facts And Circumstances Test |
|---|
| Return Reference | Explanation |
|---|
| 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: | GAIN ON INTEREST RATE SWAP 11,609,586. |
| FORM 990, PART III, LINE 2 | VAN ANDEL RESEARCH INSTITUTE (VARI) IS DEDICATED TO DETERMINING THE EPIGENETIC, GENETIC, MOLECULAR, AND CELLULAR ORIGINS OF CANCER, PARKINSON'S DISEASE, AND OTHER ILLNESSES AND TO TRANSLATING THOSE FINDINGS INTO EFFECTIVE THERAPIES. THE INSTITUTE'S SCIENTISTS WORK IN ON-SITE LABORATORIES AND PARTICIPATE IN COLLABORATIONS THAT SPAN THE GLOBE. THE INSTITUTE IS ORGANIZED INTO THE CENTER FOR CANCER AND CELL BIOLOGY, THE CENTER FOR EPIGENETICS, AND THE CENTER FOR NEURODEGENERATIVE SCIENCE. VARI'S LABS ARE SUPPORTED BY AN OUTSTANDING CORE TECHNOLOGIES AND SERVICES GROUP, WHICH PROVIDES A VIVARIUM, A BIOREPOSITORY, AND VALUABLE ON-SITE CAPABILITIES IN IMAGING, PATHOLOGY, BIOINFORMATICS AND BIOSTATISTICS, GENOMICS, FLOW CYTOMETRY, AND CRYO-ELECTRON MICROSCOPY. VARI SCIENTISTS PUBLISHED 116 ARTICLES THIS FISCAL YEAR IN PEER-REVIEWED JOURNALS THAT INCLUDED NATURE, SCIENCE, CELL, NATURE COMMUNICATIONS, NATURE GENETICS, NATURE MEDICINE, SCIENCE TRANSLATIONAL MEDICINE, CELL REPORTS, CELL DISCOVERY, CANCER RESEARCH, CLINICAL CANCER RESEARCH, NUCLEIC ACIDS RESEARCH, GENOME RESEARCH, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES U.S.A., ACTA NEUROPATHOLOGICAL, CANCER CELL, HUMAN MOLECULAR GENETICS, MOLECULAR CELL, MOLECULAR NEURODEGENERATION, ACTA NEUROPATHOLOGICAL COMMUNICATIONS, ELIFE, BONE, JOURNAL OF BIOLOGICAL CHEMISTRY, JOURNAL OF BONE AND MINERAL RESEARCH, CELL AND TISSUE RESEARCH, SCIENTIFIC REPORTS, NJP BREAST CANCER, JOURNAL OF PARKINSON'S DISEASE, HEPATOLOGY, MOVEMENT DISORDERS, BIOCHEMISTRY, NEUROBIOLOGY OF DISEASE, JOURNAL OF NEUROSCIENCE, HUMAN MOLECULAR GENETICS, BLOOD, METABOLITES, JOURNAL OF PROTEOME RESEARCH, MOLECULAR AND CELLULAR PROTEOMICS, AND CURRENT THERAPEUTIC RESEARCH. |
| FORM 990, PART III, LINE 4A | LINE 4A - PROGRAM SERVICE ACTIVITY #1 CENTER FOR CANCER AND CELL BIOLOGY THE CENTER FOR CANCER AND CELL BIOLOGY, DIRECTED BY BART WILLIAMS, PH.D., COMPRISES 16 LABORATORIES ENGAGED IN BASIC RESEARCH IN MOLECULAR AND STRUCTURAL BIOLOGY AND IN TRANSLATIONAL RESEARCH ON CANCERS, SKELETAL DISEASES, AND METABOLISM AND NUTRITION. THE CENTER IS DIVIDED INTO PROGRAMS IN STRUCTURAL BIOLOGY, SKELETAL DISEASE AND CANCER THERAPEUTICS, AND A NEW PROGRAM IN METABOLIC AND NUTRITIONAL PROGRAMMING. NEW FACULTY MEMBERS DRS. RUSSELL JONES, CONNIE KRAWCZYK, ANDREW POSPISILIK, AND ADELHEID LEMPRADL JOINED EXISTING FACULTY DRS. BRIAN HAAB AND NING WU TO ESTABLISH THE PROGRAM. IN THIS FISCAL YEAR, RESEARCHERS AND TRAINEES WITHIN THE CENTER RECEIVED THREE NEW R01 AWARDS AND ONE RENEWAL R01, A U01 AWARD, AND AN F31 FELLOWSHIP FROM THE NATIONAL INSTITUTES OF HEALTH. OTHER NEW AWARDS RECEIVED WERE FROM THE CHILDREN'S TUMOR FOUNDATION, TWO RENEWAL AWARDS WERE RECEIVED FROM THE ARTHRITIS NATIONAL RESEARCH FOUNDATION, AND THE BREAST CANCER RESEARCH FOUNDATION. THE STEENSMA LABORATORY STUDIED THE EFFECT OF THE LOSS OF THE NF1 GENE, WHICH ENCODES THE NEUROFIBROMIN ENZYME, ON BREAST CANCER AND ON ESTROGEN RECEPTOR SIGNALING (DISCHINGER ET AL., NPJ BREAST CANCER 4: 29). THE RESULTS SHOWED A SIGNIFICANT ROLE FOR THE NF1 GENE IN BREAST CANCER AND A POSSIBLE FUNCTIONAL LINK BETWEEN NEUROFIBROMIN AND THE ESTROGEN RECEPTOR, INDICATING THAT THIS GENE MAY BE A MARKER OF PROGNOSIS AND A THERAPEUTIC TARGET FOR ENDOCRINE-RESISTANT BREAST CANCERS. IN ANOTHER STUDY BY THE LAB, SOME MALIGNANT PERIPHERAL NERVE SHEATH TUMORS (MPNSTS), FOR WHICH THERE ARE NO EFFECTIVE THERAPIES, WERE FOUND TO BE SENSITIVE TO THE MET ONCOGENE INHIBITOR CAPMATINIB (PEACOCK ET AL., CANCER RESEARCH 78(13): 3572-3687). A COMBINATION THERAPY OF CAPMATINIB AND THE MEK KINASE INHIBITOR TRAMETINIB RESULTED IN REDUCED RESPONSE VARIABILITY, SUPPRESSION OF RAS/ERK AND PI3K/AKT SIGNALING, AND ENHANCED SUPPRESSION OF TUMOR GROWTH. THE WILLIAMS AND YANG LABS TOGETHER PUBLISHED SEVERAL SKELETAL STUDIES IN 2018. ONE FOCUSED ON OSTEOCHONDROPROGENITOR CELLS, WHICH DEVELOP INTO CELLS THAT CREATE BONE OR CARTILAGE. THE ENZYME SENP6 WAS FOUND TO BE CRUCIAL IN NORMAL OSTEOCHONDROPROGENITORS FOR SKELETAL DEVELOPMENT: LOSS OF THE ENZYME CAUSED PREMATURE AGING OF CELLS AND TISSUES, AND MICE HAVING NO SENP6 HAD SMALLER SKELETONS (LI ET AL., NATURE COMMUNICATIONS 9: 143). ANOTHER STUDY FOUND THAT BONE MARROW STROMAL CELLS PREFERENTIALLY DIFFERENTIATED INTO LIPID-STORING ADIPOCYTES WHEN TREATED WITH GINKGOLIC ACID, WHICH INHIBITS THE SUMOYLATION OF PROTEINS (LIU ET AL., SCIENTIFIC REPORTS 8(1): 2545). THIS PREVIOUSLY UNKNOWN ACTION OF GINKGOLIC ACID MAY HAVE APPLICATION IN TREATING CONDITIONS INVOLVING ABNORMAL LIPID METABOLISM. A THIRD PROJECT STUDIED THE ROLE OF THE LRP1 PROTEIN IN BONE REMODELING (LU ET AL., JOURNAL OF BONE AND MINERAL RESEARCH 33(10): 1773-1784). THE RESULTS SUGGEST THAT LRP1 IS A CRUCIAL REGULATOR OF BONE MASS AND THAT ITS INHIBITION OF THE RANKL SIGNALING PATHWAY MAY BE USEFUL IN TREATING CONDITIONS OF LOW BONE MASS. XIAOHONG LI'S LABORATORY STUDIED THE ROLE OF TGF-BETA SIGNALING FROM MYELOID CELLS IN METASTATIC BONE LESIONS (GANGULY ET AL., CANCERS 10: 463). THEY SHOWED THAT SUCH SIGNALS PROMOTED OSTEOLYTIC BONE LESIONS AND THAT THE CTHRC1 PROTEIN AND BASIC FIBROBLAST GROWTH FACTOR (BFGF) HAVE DIFFERENT, CELL-SPECIFIC FUNCTIONS THAT CONTRIBUTE TO BONE LESION DEVELOPMENT. IN A SEPARATE STUDY (MENG ET AL., CANCER LETTERS 418: 109-118), THE LI LAB FOUND THAT THE LOSS OF TGF-BETA SIGNALING IN OSTEOBLAST CELLS INCREASED THE AMOUNT OF BFGF AND CORRELATED WITH INCREASED TUMOR CELL PROLIFERATION AND ANGIOGENESIS. BFGF MAY BE A PROMISING TARGET FOR INHIBITING BONE METASTASIS IN PROSTATE AND BREAST CANCER. ACTIVATION OF THE WNT SIGNALING PATHWAY IS A COMMON EVENT IN MANY CANCERS, AND WNT SIGNALING CAN BE HALTED BY INHIBITING AN ENZYME CALLED PORCN. A COLLABORATIVE STUDY BY THE WILLIAMS LAB AND THE VIRSHUP LAB AT DUKE UNIVERSITY FOUND THAT TWO PORCN INHIBITORS CAUSED A LOSS OF BONE VOLUME AND DENSITY (MADAN ET AL., BONE RESEARCH 6: 17). ALENDRONATE, A BISPHOSPHONATE, MITIGATED THE ADVERSE EFFECTS OF ONE OF THE INHIBITORS, SUPPORTING THE USE OF SUCH BONE-PROTECTIVE AGENTS IN THE TREATMENT REGIMEN OF PATIENTS RECEIVING PORCN INHIBITORS. IMPORTANT SCIENTIFIC ADVANCES ALSO WERE MADE BY MEMBERS OF THE STRUCTURAL BIOLOGY PROGRAM. THE LU AND DU LABS USED THE INSTITUTE'S CRYO-ELECTRON MICROSCOPY (CRYO-EM) FACILITY TO STUDY THE STRUCTURE OF THE TRPC3 ION CHANNEL (FAN ET AL., ELIFE 7: E36852), WHICH IS ESSENTIAL FOR NEURON DEVELOPMENT IN THE BRAIN. DYSFUNCTION OF TRPC3 IS LINKED TO NEURODEGENERATIVE DISEASES, AMONG OTHERS. KNOWLEDGE OF ITS ATOMIC-LEVEL STRUCTURE AND MECHANISM OF FUNCTION ARE ESSENTIAL FOR DEVELOPING THERAPIES THAT TARGET TRPC3 DYSFUNCTION. THE TWO LABS ALSO PUBLISHED THE STRUCTURE OF THE ZEBRAFISH TRPM2 ION CHANNEL (WHICH IS SIMILAR TO THE HUMAN MOLECULE BUT IS BETTER SUITED TO STRUCTURAL STUDIES) AND ITS MECHANISM OF ACTIVATION (HUANG ET AL., NATURE 562(7725): 145-149). TRPM2 IS INVOLVED IN BODY TEMPERATURE REGULATION AND THE IMMUNE RESPONSE. NEW INSIGHTS INTO HOW THE CHANNEL WORKS MAY HELP DEVELOP DRUGS TO TREAT TEMPERATURE-RELATED DYSFUNCTION AND NEURODEGENERATIVE DISEASE. THE MELCHER AND XU LABS ALSO PUBLISHED SIGNIFICANT STRUCTURAL STUDIES. AMP-ACTIVATED PROTEIN KINASE (AMPK) REGULATES THE ENERGY LEVEL IN THE CELL, AND ITS DYSREGULATION IS ASSOCIATED WITH DIABETES, CANCER, AND NEURODEGENERATIVE DISEASES. THE MELCHER LAB SOLVED THE STRUCTURES OF AMPK BOUND TO TWO NEW DRUG FORMS, WHICH GAVE INSIGHT INTO HOW THE MOLECULE WORKS AND ITS POTENTIAL USE AS A THERAPEUTIC AGENT (YAN ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY 294: 953-967). THE LAB ALSO STUDIED THE STRUCTURE OF AMPK IN TERMS OF THE PROTEIN'S SUBUNITS AND HOW THEY INTERACT (GU ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY 293: 16994-17007). THEY FOUND THAT THE ADAM SITE, AT THE JOINING OF THE KINASE SUBUNIT AND THE CARBOHYDRATE-BINDING SUBUNIT, MAY FUNCTION AS A HUB FOR INTEGRATING THE VARIETY OF REGULATORY SIGNALS THAT AFFECT THE CELLULAR ENERGY LEVEL. THE XU LAB PUBLISHED THE STRUCTURE OF THE HUMAN RHODOPSIN PROTEIN BOUND TO AN INHIBITORY G PROTEIN, WHICH THEY DETERMINED USING CRYO-EM (KANG ET AL., NATURE 558(7711): 553-558). RHODOPSIN IS FOUND IN THE EYE AND IS ESSENTIAL FOR PERCEIVING LIGHT. THE COMPARISON OF THIS NEW STRUCTURE TO OTHER STRUCTURES OF RHODOPSIN BOUND TO ACTIVATING G PROTEINS OR ARRESTINS PROVIDES A BASIS FOR UNDERSTANDING HOW RHODOPSIN FUNCTIONS IN SIGNALING THE PERCEPTION OF LIGHT. THIS PUBLICATION WAS FEATURED IN THE NIH DIRECTOR'S BLOG. BOTH LABS ALSO CONTRIBUTED TO THE DETERMINATION OF THE STRUCTURE OF THE HUMAN FRIZZLED 4 PROTEIN, WHICH IS INVOLVED IN BLOOD VESSEL DEVELOPMENT IN THE EYE'S RETINA. THE STUDY SUGGESTS THAT FRIZZLED PROTEINS MAY HAVE AN ACTIVATION MECHANISM DIFFERENT FROM THAT OF OTHER G-PROTEIN-COUPLED RECEPTORS LIKE RHODOPSIN (YANG ET AL., NATURE 560(7720: 666-670). HUILIN LI'S LABORATORY PUBLISHED A DIVERSE SET OF PAPERS IN 2018 BASED ON THE USE OF CRYO-EM. ONE WAS A STUDY OF THE YEAST OLIGOSACCHARYLTRANSFERASE ENZYME COMPLEX, WHICH PROVIDED THE FIRST HIGH-RESOLUTION IMAGES OF THE INTERACTIONS OF ITS MULTIPLE SUBUNITS. SEVEN PHOSPHOLIPID MOLECULES MEDIATE MANY OF THE INTER-SUBUNIT INTERACTIONS (BAI ET AL., NATURE 555(7696): 328-333). ANOTHER STUDY FOCUSED ON THE BACTERIAL SURFACE STRUCTURE CALLED A PILUS. USING CRYO-EM, AN INTERMEDIATE STAGE OF THE ASSEMBLY OF THE E. COLI PILUS WAS IMAGED. THE STRUCTURE SUGGESTED A MECHANISM FOR HOW THE GROWING PILUS IS STABILIZED AS IT INCORPORATES THOUSANDS OF SUBUNITS DURING ITS GROWTH, AND HAS IMPLICATIONS FOR THE TREATMENT OF URINARY TRACT INFECTIONS (DU ET AL., NATURE 562(7727): 444-447). THE LI LAB ALSO STUDIED THE STRUCTURE OF THE MTB CLPB COMPLEX, WHICH IS IMPORTANT TO THE SURVIVAL OF MYCOBACTERIUM TUBERCULOSIS. THEY IMAGED THE COMPLEX BOUND TO CASEIN AS A MODEL SUBSTRATE AND IDENTIFIED TWO DIFFERENT CONFORMERS. BASED ON THEIR DIFFERENCES, THEY SUGGEST A MECHANISM FOR HOW THE COMPLEX SUBUNITS ARE ABLE TO MOVE PEPTIDES DURING THE RESCUE OF DAMAGED PROTEINS (YU ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES USA 115(41): E9560-E9569). KNOWLEDGE OF THIS MECHANISM MAY AID IN DEVELOPING FUTURE DRUGS EFFECTIVE AGAINST TUBERCULOSIS. FINALLY, THE LAB REPORTED THE STRUCTURE OF THE MEMBRANE-BOUND HYDROGENASE FROM THE HEAT-ADAPTED MICROBE PYROCOCCUS FURIOSUS. THIS IS AN ANCIENT RESPIRATION SYSTEM THAT OPERATES AT TEMPERATURES NEAR 100 DEGREES C. THE STRUCTURE IS COMPARED WITH THE RELATED QUINONE-REDUCING COMPLEX I AND THE DIFFERENCES IN THEIR ARCHITECTURE ARE DESCRIBED (YU ET AL., CELL 173(7): 1636-1649). |
| FORM 990, PART III, LINE 4B | LINE 4B - PROGRAM SERVICE ACTIVITY #2 CENTER FOR EPIGENETICS THE CENTER, ESTABLISHED IN 2014 AND DIRECTED BY PETER A. JONES, PH.D., D.SC. (HON), COMPRISES TEN LABORATORIES STUDYING EPIGENETICS, EPIGENOMICS, AND THE ROLE OF EPIGENETIC DYSFUNCTION IN CANCER, NEURODEGENERATIVE DISEASE, CARDIOVASCULAR DISEASE, AND VIRAL TRANSCRIPTION. DRS. XIAOBING SHI AND HONG WEN JOINED THE CENTER IN 2018. NEW GRANT AWARDS IN THIS FISCAL YEAR FOR CENTER RESEARCHERS AND TRAINEES INCLUDED AN R01, AN R21, AN R37, AND AN F32 FROM THE NATIONAL INSTITUTES OF HEALTH, NEW FUNDING FROM THE MICHIGAN ECONOMIC DEVELOPMENT COMMISSION, A GRANT FROM EVANS MDS, AND TWO NEW FELLOWSHIPS FROM THE CANADIAN INSTITUTES OF HEALTH RESEARCH AND THE AMERICAN SOCIETY OF HEMATOLOGY. TWO NIH GRANT SUBAWARDS WERE ALSO RECEIVED. THE VAN ANDEL RESEARCH INSTITUTE-STAND UP TO CANCER EPIGENETICS DREAM TEAM, LED BY PETER JONES AND STEPHEN BAYLIN, CONTINUED IN 2018 WITH ITS AIMS OF DEVELOPING NEW COMBINATION THERAPIES TO COMBAT CANCER AND MOVING PROMISING THERAPIES INTO CLINICAL TRIALS. THE TEAM FOCUSES ON EPIGENETIC MECHANISMS IN CELLS, WHICH HELP CONTROL WHETHER GENES ARE TURNED ON OR OFF, WITHOUT CHANGING THE DNA SEQUENCE ITSELF. THIS IS DONE PRIMARILY BY THE ADDITION OR REMOVAL OF METHYL GROUPS TO THE DNA OR ADDITION/REMOVAL OF METHYL OR ACETYL GROUPS FROM THE HISTONE PROTEINS AROUND WHICH DNA WRAPS. THE LABORATORY OF PETER JONES PUBLISHED IN 2018 A COMPREHENSIVE MAP OF MORE THAN 500,000 ENDOGENOUS RETROVIRUSES (ERVS) IN THE INTERGENIC REGIONS OF THE HUMAN GENOME. REPRESSIVE EPIGENETIC MARKS FOUND ON THE ERVS DEPENDED ON EVOLUTIONARY AGE, WITH DNA METHYLATION ASSOCIATED WITH YOUNGER AGE AND HISTONE METHYLATION WITH OLDER. THIS FINDING MAY AID IN PREDICTING CANCER RESPONSE TO EPIGENETIC THERAPIES (OHTANI ET AL., GENOME RESEARCH 28(8): 1147-1157). IN ANOTHER STUDY, OF OVARIAN CANCER CELLS, THE INHIBITION OF THE HISTONE METHYLTRANSFERASE ENZYME G9A COMBINED WITH 5-AZA-CDR PRODUCED ANTITUMOR EFFECTS INCLUDING ACTIVATION OF THE VIRAL DEFENSE RESPONSE AND INDUCTION OF CELL DEATH. SUCH A COMBINATION TREATMENT MAY BE A NOVEL STRATEGY FOR TREATING OVARIAN CANCER PATIENTS WHOSE CELLS HAVE HIGH EXPRESSION OF G9A (LIU ET AL., CANCER RESEARCH 78(20): 5754-5766). IN A THIRD 2018 PUBLICATION, THE JONES LAB LINKED THE FREQUENCY OF IMPRINTING OF THE NC886 RNA GENE IN INFANTS TO THE MOTHER'S AGE AT DELIVERY AND TO WHEN CONCEPTION OCCURRED DURING THE YEAR. THEY PROPOSE THAT SUCH IMPRINTING IS "TUNABLE" IN BEING ASSOCIATED WITH THE MATERNAL HAPLOTYPE AND THE PRENATAL ENVIRONMENT, PROVIDING A POSSIBLE WAY OF TRANSMITTING PHENOTYPES FROM MOTHER TO CHILD (PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES USA 115(51): E11970-E11977). THE JONES AND TRICHE LABS CONTRIBUTED TO THE FIRST STUDY OF THE EPIGENETIC DRUG AZACITIDINE IN COMBINATION WITH INTENSIVE CHEMOTHERAPY. THE RESULTS SHOWED THE SAFETY OF THE PAIRING AND OFFERED ENCOURAGING CLINICAL ACTIVITY. DNA METHYLATION OF THE FDFT1 GENE WAS HIGHLY ASSOCIATED WITH PATIENT CLINICAL OUTCOME (BLOOD 131(10): 1145-1148). THE TRICHE LAB ALSO IDENTIFIED A SET OF 14 TRANSPOSABLE ELEMENTS (TES) IN DNA THAT MAY BE A BIOMARKER FOR HIGH- OR LOW-RISK ACUTE MYELOID LEUKEMIA. THIS SET COULD PREDICT PROGNOSIS IN INDEPENDENT COHORTS OF 284 PEDIATRIC PATIENTS AND IN 19 RELAPSED ADULT PATIENTS. STUDIES OF THE UTILITY OF THIS MARKER IN OTHER CANCERS IS WARRANTED (SCIENTIFIC REPORTS 8(1): 16449). IN ANOTHER STUDY OF TES IN HEALTHY INDIVIDUALS, SENESCENT HEMATOPOIETIC STEM AND PROGENITOR CELLS (HSPCS) EXPRESSED MORE TES THAN DID ACTIVE HSPCS, AND SENESCENT CELLS LACKED DNA METHYLATION IN THE REGIONS EXPRESSING MORE TES. THIS IS THE FIRST REPORT CHARACTERIZING THE METHYLATION OF THESE CELLS (EXPERIMENTAL HEMATOLOGY 62: 33-38E6). THE ROTHBART LABORATORY DEVELOPED A HIGH-THROUGHPUT PROTEOMICS PLATFORM THAT MAPS THE SEQUENCE DETERMINANTS OF SUBSTRATE SELECTIVITY OF THE ENZYME LYSINE METHYLTRANSFERASE WITHOUT REQUIRING KNOWLEDGE OF A SUBSTRATE OR TARGET. IN THIS APPROACH, A LYSINE-ORIENTED PEPTIDE LIBRARY CAN BE USED TO IDENTIFY NEW SUBSTRATES AND TO DISCOVER NEW INHIBITORS OF THE ENZYME (CORNETT ET AL., SCIENCE ADVANCES 4(11): EAAV2623). THE LAB ALSO ANALYZED THE ACTIVITIES OF THE E3 UBIQUITIN LIGASES UHRF1 AND UHRF2 AND FOUND CONSERVED MODES OF RECOGNIZING HISTONE PROTEINS BUT DIFFERENT DNA-BINDING PROPERTIES. THE STUDY DESCRIBED THE DIFFERENCES IN THE ACTIVITY AND SUBSTRATES OF THESE TWO ENZYMES AND ASCRIBED THOSE DIFFERENCES TO THEIR CONTRASTING MOLECULAR ARCHITECTURES (VAUGHAN ET AL., NUCLEIC ACIDS RESEARCH 46(9): 4405-4416). FOR A STUDY OF THE SUBSTRATE SELECTIVITY OF UHRF1, THE LAB CONSTRUCTED EXPERIMENTAL SUBSTRATES AND ANALYZED THE ENZYME'S BINDING AND ACTIVITY TOWARD THEM. THE RESULTS SHOWED HOW THE ENZYME CHOOSES BETWEEN DNA AND HISTONE SUBSTRATES AND FOUND A "MOLECULAR SWITCH" THAT REDIRECTS UHRF1 ACTIVITY AWAY FROM HISTONES (VAUGHAN ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES USA 115(35): 8775-8780). THIS STUDY PROVIDES A BASIS FOR FUTURE STUDIES OF UHRF1 FUNCTION AND ITS EFFECT ON THE CHROMATIN ACTIVITY OF THE DNMT1 ENZYME. THE LAIRD AND SHEN LABS REPORTED A NEW CLASS OF ARTIFACTS IN DNA METHYLATION MEASUREMENTS USING COMMON METHYLATION ARRAYS. THEY ALSO REPORTED A SOLUTION THAT ADDRESSES THESE PROBLEMS USING THE R PACKAGE SESAME, A SOLUTION THAT OUTPERFORMED THE EXISTING BEST STANDARDS FOR CROSS-PLATFORM CONSISTENCY (ZHOU ET AL., NUCLEIC ACIDS RESEARCH 46(20): E123). ANOTHER STUDY BY THE TWO LABS WAS BASED ON THE LOSS OF DNA METHYLATION IN CANCER GENOMES, ANALYZING A LARGE AND DIVERSE SET OF DATA SETS BY WHOLE-GENOME BISULFITE SEQUENCING. IN CANCER, LACK OF METHYLATION IN CERTAIN DOMAINS OF THE GENOME LIKELY REFLECTS MITOTIC AGE, WHICH GENERALLY IS CORRELATED WITH CHRONOLOGICAL AGE AND WHICH MIGHT FUNCTION AS A MITOTIC CLOCK (ZHOU ET AL., NATURE GENETICS 50: 591-602). THE LAIRD AND SHEN LABS HAVE ALSO BEEN HEAVILY INVOLVED IN THE CANCER GENOME ATLAS RESEARCH NETWORK. FROM THIS WORK CAME STUDIES TITLED "COMPARATIVE MOLECULAR ANALYSIS OF GASTROINTESTINAL ADENOCARCINOMAS" (LIU ET AL., CANCER CELL 33(4): 721-735.E8) AND "INTEGRATED MOLECULAR CHARACTERIZATION OF TESTICULAR GERM CELL TUMORS" (SHEN ET AL., CELL REPORTS 23(11): 3392-3406). IN ADDITION, A SERIES OF OVER TWO DOZEN "PAN-CANCER" PAPERS WERE PUBLISHED BY THE NETWORK IN THE SPRING OF 2018 IN WHICH DRS. LAIRD AND SHEN (OR BOTH) WERE COAUTHORS. LAIRD WAS THE LAST AUTHOR ON ONE OF THREE FLAGSHIP THEMATIC PAPERS, "CELL-OF-ORIGIN PATTERNS DOMINATE THE MOLECULAR CLASSIFICATION OF 10,000 TUMORS FROM 33 TYPES OF CANCER" (HOADLEY ET AL., CELL 173(2): 291-304.E6), AND SHEN WAS ONE OF SIX EXPERTS INVITED TO AUTHOR A RETROSPECTIVE ON TCGA'S LEGACY. A SAMPLING OF THE PAN-CANCER PAPERS INCLUDES "GENOMIC AND MOLECULAR LANDSCAPE OF DNA DAMAGE REPAIR DEFICIENCY ACROSS THE CANCER GENOME ATLAS" (KNIJNENBURG ET AL., CELL REPORTS 33(4): 721-735.E8); "MACHINE LEARNING IDENTIFIES STEMNESS FEATURES ASSOCIATED WITH ONCOGENIC DEDIFFERENTIATION" (MALTA ET AL., CELL 173(2): 338-354.E15); "THE IMMUNE LANDSCAPE OF CANCER" (THORSSON ET AL., IMMUNITY 48(4): 812-830.E13); AND "ONCOGENIC SIGNALING PATHWAYS IN THE CANCER GENOME ATLAS" (SANCHEZ-VEGA ET AL., CELL 173(2): 321-337.E10). |
| FORM 990, PART III, LINE 4C | LINE 4C - PROGRAM SERVICE ACTIVITY #3 CENTER FOR NEURODEGENERATIVE SCIENCE THE CENTER WAS ESTABLISHED IN 2012 UNDER PATRIK BRUNDIN, M.D., PH.D., WHO IS ALSO ASSOCIATE DIRECTOR OF VARI. IT CURRENTLY HAS NINE LABORATORIES STUDYING PARKINSON'S DISEASE, ALZHEIMER'S DISEASE, PRIONS, AND THE RELATIONSHIPS BETWEEN DEPRESSION, SUICIDE, AND BRAIN INFLAMMATION. CENTER RESEARCHERS AND TRAINEES DURING THIS FISCAL YEAR RECEIVED TWO R21 GRANTS FROM THE NATIONAL INSTITUTES OF HEALTH AND FOUR AWARDS FROM THE MICHAEL J. FOX FOUNDATION, AS WELL AS AWARDS FROM THE U.S. DEPARTMENT OF DEFENSE, THE EAST TENNESSEE FOUNDATION, AND MICHIGAN STATE UNIVERSITY. ALSO RECEIVED WAS A FELLOWSHIP FROM THE PARKINSONS'S DISEASE FOUNDATION, AND FOUR GRANT SUBAWARDS. PATRIK BRUNDIN'S LABORATORY BIOCHEMICALLY PROFILED MORE THAN 250 CHEMICALS FOUND IN BRAIN TISSUE AND SERUM FROM A PARKINSON'S DISEASE MOUSE MODEL (GRAHAM ET AL., JOURNAL OF PROTEOME RESEARCH 17(7): 2460-2469). THEY IDENTIFIED THE BEST SIX OF THESE METABOLITES IN TERMS OF IDENTIFYING DISEASED ANIMALS FROM CONTROLS. THE STUDY PROVIDES AN EARLY STEP IN DEVELOPING ROBUST BIOMARKERS FOR PARKINSON'S DISEASE, WHICH ARE LACKING. ANOTHER STUDY PROFILED 18 BILE ACIDS FOUND IN THE SERUM OF MICE HAVING PRODROMAL PARKINSON'S DISEASE (GRAHAM ET AL., METABOLITES 8(4): 71). THE CONCENTRATIONS OF THREE OF THESE COMPOUNDS WERE SIGNIFICANTLY DIFFERENT FROM THOSE OF CONTROL MICE, AND THOSE DATA COULD DISCRIMINATE BETWEEN PRODROMAL AND CONTROL MICE WITH HIGH ACCURACY. THESE COMPOUNDS ARE CANDIDATE BIOMARKERS FOR PREDICTING PARKINSON'S DISEASE AND POSSIBLY ITS PROGRESSION. IN A THIRD STUDY, THE LAB REPORTED THAT 12-18 MONTHS AFTER INJECTION OF ALPHA-SYNUCLEIN FIBRILS INTO THE MOUSE OLFACTORY BULB, THE NUMBER OF BRAIN REGIONS SHOWING PARKINSON'S-LIKE PATHOLOGY INCREASED, BUT AT 23 MONTHS, NO ADDITIONAL REGIONS WERE AFFECTED (REY ET AL., ACTA NEUROPATHOLOGICA 135(1): 65-83). THE REASON FOR THE LACK OF CONTINUED PROGRESSION COULD BE COMPROMISED NEURAL CIRCUITRY DUE TO THE EXTENT OF NEURON DEATH FROM THE PATHOLOGY. VIVIANE LABRIE'S LAB PUBLISHED A PAPER SHOWING THAT, IN TWO INDEPENDENT EPIDEMIOLOGICAL DATA SETS INVOLVING NEARLY 1.7 MILLION INDIVIDUALS FOR UP TO 52 YEARS, REMOVAL OF THE APPENDIX WAS ASSOCIATED WITH A LOWER RISK OF PARKINSON'S DISEASE (KILLINGER ET AL., SCIENCE TRANSLATIONAL MEDICINE 10: EAAR5280). THE STUDY SHOWED THAT THE HEALTHY APPENDIX CONTAINS ALPHA-SYNUCLEIN AGGREGATES LIKE THOSE FOUND IN LEWY BODIES, WHICH ARE A HALLMARK OF PARKINSON'S DISEASE NEURONS. THE AUTHORS CONCLUDED THAT THE APPENDIX CONTAINS FORMS OF ALPHA-SYNUCLEIN THAT AFFECT THE RISK OF DEVELOPING PARKINSON'S DISEASE AND THAT REMOVAL OF THE APPENDIX MAY HAVE BENEFIT IF DONE EARLY IN LIFE, PARTICULARLY FOR PERSONS LIVING IN RURAL AREAS. PRION DISEASES ARE FATAL NEURODEGENERATIVE DISORDERS THAT AFFECT HUMANS AND ANIMALS. THE MA LABORATORY COMPARED ENZYME-DIGESTED AND UNDIGESTED RECOMBINANT PRIONS. A TIME COURSE STUDY SHOWED THAT AN INCREASED CAPABILITY TO SEED THE CONVERSION OF NORMAL PRION PROTEIN TO A PATHOGENIC FORM WAS RELATED TO THE AMOUNT OF ENZYME-RESISTANT RECOMBINANT PRION FRAGMENTS (WANG ET AL., ACTA NEUROPATHOLOGICA COMMUNICATIONS 6: 30). THE MA LAB ALSO COLLABORATED IN A STUDY OF THE ROLE OF 14-3-3 PROTEINS IN THE CELL-TO-CELL TRANSFER OF ALPHA-SYNUCLEIN. SUCH PROTEINS REDUCED ALPHA-SYNUCLEIN TRANSFER AND TOXICITY, BUT INHIBITION OF 14-3-3 PROTEINS ACCELERATED THE TRANSFER. DYSFUNCTION OF 14-3-3 PROTEINS MAY BE A KEY ELEMENT IN ALPHA-SYNUCLEIN PROPAGATION (WANG ET AL., JOURNAL OF NEUROSCIENCE 38(38): 8211-8232). IN ANOTHER PROJECT, THEY STUDIED THE AGGREGATION OF ALPHA-SYNUCLEIN IN BRAIN TISSUE FROM PATIENTS WHO HAD THE NEURODEGENERATIVE DISORDER CALLED MULTIPLE SYSTEM ATROPHY. ADAPTING THE PMCA ASSAY, THEY CONFIRMED THAT THE SEEDING ACTIVITY OF ALPHA-SYNUCLEIN REMAINS ACTIVE EVEN IN FORMALDEHYDE-FIXED TISSUES (BECKER ET AL., MOLECULAR NEUROBIOLOGY 55(11): 8728-8737). THIS STUDY ALSO PROVIDES A BASIS FOR FURTHER ADAPTING THE PMCA ASSAY FOR EVALUATING ALPHA-SYNUCLEIN AGGREGATES AS A BIOMARKER OF DISEASE. DARREN MOORE'S LAB REPORTED A NEW FUNCTIONAL INTERACTION BETWEEN THE PARKIN AND VPS35 PROTEINS, BOTH OF WHICH HAVE BEEN FOUND MUTATED IN INHERITED PARKINSON'S DISEASE (WILLIAMS ET AL., HUMAN MOLECULAR GENETICS 27(18): 3189-3205). PARKIN UBIQUITINATES VPS35 IN HUMAN NEURONS, A PROCESS THAT MAY BE INVOLVED IN REGULATING RETROMER-DEPENDENT SORTING AND WHICH MAY HAVE EFFECTS IN PARKINSON'S DISEASE. IN ANOTHER STUDY, THE LAB FOCUSED ON THE LRRK2 GENE, MUTATIONS IN WHICH CAUSE LATE-ONSET PARKINSON'S DISEASE. SUCH MUTATIONS TYPICALLY CAN GIVE RISE TO THE CHARACTERISTIC LEWY BODIES IN NEURONS BUT CAN ALSO INDUCE TAU-POSITIVE NEUROPATHOLOGY. THE DATA SUGGESTED THAT MUTANT TAU-INDUCED PATHOLOGY IS INDEPENDENT OF LRRK2 EXPRESSION BUT ALSO SHOWED A NOVEL ROLE FOR LRRK2 IN PROMOTING NEURONAL TRANSMISSION OF WILD-TYPE TAU PROTEIN. THIS FINDING MAY AID IN UNDERSTANDING HOW TAU PATHOLOGY DEVELOPS IN THE BRAINS OF PATIENTS WHO HAVE LRRK2-RELATED DISEASE (NGUYEN ET AL., HUMAN MOLECULAR GENETICS 27(1): 120-134). THE COETZEE LABORATORY PUBLISHED A STUDY COMPARING GENOME-WIDE GENE EXPRESSION IN UNDIFFERENTIATED AND DIFFERENTIATED LUHMES CELLS AS MODELS OF THE HUMAN NEURONS AFFECTED BY PARKINSON'S DISEASE. ONLY DIFFERENTIATED CELLS SHOWED AN INCREASE IN GENETIC POLYMORPHISMS THAT CARRY A RISK FOR PARKINSON'S DISEASE (PIERCE ET AL., NEUROBIOLOGY OF DISEASE 118: 53-64). THE LAB ALSO COLLABORATED ON A STUDY OF GENETIC REGULATORY ELEMENTS INVOLVED IN PROSTATE CANCER RISK (GUO ET AL., GENOME BIOLOGY 19: 160). THAT STUDY IDENTIFIED RISK-ASSOCIATED SITES FOR BINDING OF THE CTCF PROTEIN IN LONG-RANGE CHROMATIN LOOPS. THE DELETION OF THOSE SITES VIA THE CRISPR-CAS TECHNIQUE INCREASED GENE EXPRESSION WITHIN THE LOOPS. ANOTHER COLLABORATIVE PROJECT FOCUSED ON COLORECTAL CANCER AND INVOLVED A GENOME-WIDE ASSOCIATION STUDY BASED ON SAMPLES FROM MORE THAN 160,000 INDIVIDUALS (SCHMIT ET AL., JOURNAL OF THE NATIONAL CANCER INSTITUTE, IN PRESS). THE RESULTS PROVIDE INSIGHT INTO THE GENETIC ARCHITECTURE THAT CONTRIBUTES TO COLORECTAL CANCER AND WILL HELP IMPROVE THE SCREENING OF INDIVIDUALS FOR PREDICTING THEIR RISK OF THE DISEASE. |
| FORM 990, PART IX, COLUMN D | FUNDRAISING EXPENSES AT VARI WERE INCURRED TO SUPPORT THE MISSION OF THE RESEARCH INSTITUTE THROUGH DONOR SOLICITATION, GRANT SOLICITATION AND EXTRAMURAL PROPOSAL PREPARATION. |
| FORM 990, PART X, LINE 33 | VARI NET ASSETS ARE CONSIDERED ON A CONSOLIDATED BASIS WITH VAN ANDEL INSTITUTE (VAI)AND VAN ANDEL EDUCATION INSTITUTE (VAEI). ON A CONSOLIDATED BASIS, NET ASSETS ARE $1,545,485,000 PER AUDITED FINANCIAL STATEMENTS. THE NEGATIVE NET ASSET BALANCE AT VARI IS DUE TO VAI FUNDING EXPENSES ON A CASH BASIS AND THE UNREALIZED LOSS RECORDED IN ASSOCIATION WITH THE INTEREST RATE SWAP. |
| Software ID: | |
| Software Version: |