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. THOMAS CURRAN JR. IS ALSO AN OFFICER OF VAIGS. GERALD CALLAHAN AND THOMAS CURRAN JR. ARE KEY EMPLOYEES OF VAI AND VAEI. |
| FORM 990, PART VI, SECTION A, LINE 2 | BUSINESS RELATIONSHIP: DAVID VAN ANDEL, GERALD CALLAHAN |
| 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 -27,091,392. |
| 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, METABOLIC DISORDERS, 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 BIOINFORMATICS AND BIOSTATISTICS, CRYO-ELECTRON MICROSCOPY, FLOW CYTOMETRY, IMAGING, GENOMICS, METABOLOMICS AND BIOENERGETICS, PATHOLOGY, AND TRANSGENICS. VARI SCIENTISTS PUBLISHED 136 ARTICLES IN THIS FISCAL YEAR IN PEER-REVIEWED JOURNALS THAT INCLUDED NATURE, CELL, CELL REPORTS, ELIFE, NATURE COMMUNICATIONS, NATURE STRUCTURAL AND MOLECULAR BIOLOGY, CELL METABOLISM, NEUROLOGY, CELL STEM CELL, CANCER CELL, CANCER RESEARCH, MOVEMENT DISORDERS, CHEMICAL SCIENCE, MOLECULAR CELL, CIRCULATION RESEARCH, NATURE NEUROSCIENCE, LANCET NEUROLOGY, ISCIENCE, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES U.S.A., ONCOGENE, CLINICAL CANCER RESEARCH, NEURO-ONCOLOGY, NATURE MATERIALS, BLOOD, EUROPEAN JOURNAL OF NEUROLOGY, CYTOMETRY A, TRENDS IN NEUROSCIENCES, GENOME BIOLOGY, PLOS COMPUTATIONAL BIOLOGY, PLOS GENETICS, JOURNAL OF BIOLOGICAL CHEMISTRY, JOURNAL OF VETERINARY INTERNAL MEDICINE, MOLECULAR CANCER THERAPEUTICS, GENES, NEUROBIOLOGY OF DISEASE, CELL REPORTS MEDICINE, CRISPR JOURNAL, EMBO REPORTS, SCIENTIFIC REPORTS, STRUCTURE, FASEB JOURNAL, CALCIFIED TISSUE INTERNATIONAL, EPIGENETICS AND CHROMATIN, JOURNAL OF MOLECULAR BIOLOGY, JOURNAL OF PARKINSON'S DISEASE, BIOCHEMICAL JOURNAL, JOURNAL OF CLINICAL MEDICINE, BIOANALYSIS, AND JOURNAL OF CHEMICAL PHYSICS. |
| 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 TWO R01 AWARDS, TWO R35 AWARDS, AN R21 AWARD, AND AN F99 FELLOWSHIP FROM THE NATIONAL INSTITUTES OF HEALTH. OTHER NEW GRANTS WERE FROM THE PEW CHARITABLE TRUSTS, THE SLOAN FOUNDATION, AND THE BREAST CANCER RESEARCH FOUNDATION. TWO NON-NIH POSTDOCTORAL FELLOWSHIPS WERE ALSO RECEIVED, FROM THE AMERICAN HEART ASSOCIATION AND THE AMERICAN CANCER SOCIETY. THE WILLIAMS LAB PRODUCED SEVERAL STUDIES ON BONE-RELATED ISSUES. A PROJECT ON GALECTIN-3 UNCOVERED THE MECHANISM FOR SEX-DEPENDENT EFFECTS OF LOSS OF THIS MOLECULE ON AGING BONE. GALECTIN-3 MAY BE A THERAPEUTIC TARGET AGAINST THE LOSS OF SEX HORMONE PRODUCTION SUCH AS OCCURS FOLLOWING MENOPAUSE IN WOMEN OR IN ANDROGEN DEPLETION THERAPY FOR PROSTATE CANCER PATIENTS (MAUPIN ET AL., CALCIFIED TISSUE INTERNATIONAL 106(3): 283-293). ANOTHER STUDY RELATED TO INDIVIDUALS WHO HAVE LOST THE FUNCTION OF THE LRP5 PROTEIN; THEY DEVELOP OSTEOPOROSIS AND DEFECTIVE RETINAL VASCULATURE. THE LAB USED CRISPR-CAS9 TECHNOLOGY TO KNOCK OUT THE LRP5 GENE IN RATS, WHICH PROVIDES A NEW MODEL FOR STUDYING THE ROLE OF WNT SIGNALING IN THE DEVELOPMENT OF BONE AND THE RETINA, AS WELL AS FOR RESEARCH INTO HOW TO TREAT PATIENTS WHO HAVE MUTANT FORMS OF LRP5 (UBELS ET AL., CRISPR JOURNAL 3(4): 284-298). THE LAB ALSO COLLABORATED WITH A JOHNS HOPKINS LABORATORY TO STUDY THE FRIZZLED-4 (FZD4) RECEPTOR PROTEIN. THE DATA SHOWED THAT FZD4 MAY HAVE OVERLAPPING FUNCTIONS WITH FZD8, BUT THAT FZD4 IS REQUIRED FOR NORMAL BONE DEVELOPMENT AND MINERALIZATION (KUSHWAHA ET AL., JOURNAL OF CELL PHYSIOLOGY 235(10): 6673-6683). IN THE STRUCTURAL BIOLOGY PROGRAM, THE LI LAB PUBLISHED THE FIRST CRYOELECTRON MICROSCOPY STRUCTURE OF THE EUKARYOTIC ENDOPLASMIC RETICULUM MEMBRANE COMPLEX, WHICH INSERTS PROTEINS THROUGH A MEMBRANE. PART OF THE STRUCTURE RESEMBLES A PROKARYOTIC INSERTASE ENZYME, SHOWING CONSERVATION OF STRUCTURE THROUGHOUT EVOLUTION AND SUGGESTING THAT THEIR ENZYME MECHANISMS MAY BE SIMILAR (BAI ET AL., NATURE 584(7821): 475-478). ANOTHER PAPER REPORTED A HIGH-RESOLUTION STRUCTURE FOR THE EUKARYOTIC CMG HELICASE. DETAILS OF THE STRUCTURE ALLOWED THE AUTHORS TO DESCRIBE HOW THE HELICASE PULLS THE DNA THROUGH A MOLECULAR TUNNEL, ALLOWING IT TO SEPARATE THE TWO DNA STRANDS FOR REPLICATION (YUAN ET AL., NATURE COMMUNICATIONS 11: 688). A THIRD PROJECT PRODUCED AN ATOMIC STRUCTURE FOR THE POLYMERASE EPSILON ENZYME, WHICH IS A DIMER OF TWO DIFFERENT POL "MODULES". THE SOLVED STRUCTURE SUGGESTS THAT A FOLD IN THE DBP2 SUBUNIT DIRECTS THE DNA LEADING STRAND FROM THE CMG COMPLEX TO THE POL EPISILON ACTIVE SITE (YUAN ET AL., NATURE COMMUNICATIONS 11: 356). THESE LAST TWO PAPERS TOGETHER SHED NEW LIGHT ON THE ATOMIC-LEVEL MECHANISM OF HOW DNA IS REPLICATED IN THE CELL. THE DU AND LU LABS PUBLISHED THREE PAPERS IN THE PRESTIGIOUS JOURNAL NATURE ON THE STRUCTURES OF ION CHANNELS, WHICH ARE PROTEINS THAT ALLOW IONS INTO AND OUT OF CELLS. THEY PUBLISHED STRUCTURES FOR THE HUMAN CALHM2 ION CHANNEL IN AN ACTIVE AND AN INHIBITED STATE. THEY ALSO PROPOSED A GATING MECHANISM FOR CALHM2 IN WHICH THE S1 HELIX COARSELY ADJUSTS, AND THE N-TERMINAL HELIX FINE-TUNES, THE PORE SIZE (CHOI ET AL., NATURE 576(7785): 163-167). PANNEXIN IS A PROTEIN INVOLVED IN BLOOD PRESSURE REGULATION AND OTHER IMPORTANT PROCESSES. THE LABS SOLVED THE STRUCTURES OF HUMAN PANNEXIN 1 (PANX1) IN THREE STATES, AT DOWN TO 2.8-ANGSTROM RESOLUTION. THEY WERE ABLE TO DESCRIBE ITS GATING MECHANISM FOR TWO DIFFERENT ION PATHWAYS, AS WELL AS THE ROLE OF CARBENOXOLONE AS A BLOCKER OF THE PANNEXIN CHANNEL (RUAN ET AL., NATURE 584(7822): 646-651). FINALLY, THEY ALSO STUDIED THE PROTON-ACTIVATED CHLORIDE CHANNEL (PAC), WHICH IS INVOLVED IN TISSUE INJURY. THEIR PAPER DESCRIBED THE CHANGES OF PROTEIN CONFORMATION WITH A CHANGE IN PH IN THE CELLULAR ENVIRONMENT, AND ALSO THE MOLECULAR ASSEMBLY OF THE THREE PAC SUBUNITS. THESE RESULTS PROVIDE A BASIS FOR UNDERSTANDING THE ATOMIC-LEVEL MECHANISMS OF PAC (RUAN ET AL., NATURE 588(7837): 350-354). THE STRUCTURAL LAB OF KARSTEN MELCHER PUBLISHED SEVERAL PAPERS IN COLLABORATION WITH LABS AT VARI AND ELSEWHERE. METHYLTRANSFERASES ARE ENZYMES THAT PLACE METHYL GROUPS ONTO DNA, AN IMPORTANT EPIGENETIC MODIFICATION. THE LABS OF MELCHER AND PETER JONES SOLVED THE STRUCTURES OF TWO SUCH ENZYMES, DNMT3A AND DNMT3B, BOUND TO NUCLEOSOMES. THE STRUCTURES SUGGEST THAT IN ORDER TO ADD THE METHYL GROUP, THE DNA MUST BE MOVED RELATIVE TO THE NUCLEOSOME CORE (XU ET AL., NATURE 586(7827): 151-155). ANOTHER STUDY USED MOLECULAR DYNAMICS SIMULATIONS TO DETERMINE HOW THE DRUG FENTANYL BINDS TO THE MU-OPIOID RECEPTOR. THE RESULTS SUGGEST AN ACTIVATION MECHANISM AND PROVIDE A RATIONAL FRAMEWORK FOR IMPROVING THE SAFETY PROFILES OF FENTANYL-BASED ANALGESICS (DE WAAL ET AL., PLOS COMPUTATIONAL BIOLOGY 16(4): E1007394). THE MELCHER LAB ALSO STUDIED TWO G-PROTEIN-COUPLED RECEPTORS (GPCRS) CALLED CFR1R AND CFR2R, WHICH ARE ACTIVATED BY ENDOCRINE HORMONES AND ARE INVOLVED IN THE BODY'S STRESS RESPONSES. THE PEPTIDE-BINDING AMINO ACIDS IN THESE TWO RECEPTORS DIFFER FROM THOSE IN OTHER CLASS B GPCRS, AND BOTH STRUCTURES HAD BOUND CHOLESTEROL MOLECULES. THIS WORK PROVIDES A MODEL FOR STUDYING THE MEMBRANE PROTEIN-LIPID INTERACTIONS OF CLASS B GPCRS (MA ET AL., MOLECULAR CELL 77(3): 669-680.E4). FINALLY, THEY STUDIED THE CANNABINOID RECEPTOR CB2 AS A TARGET FOR TREATING NEURODEGENERATIVE DISORDERS AND FOR TREATING PAIN WITH FEWER SIDE EFFECTS. THE STRUCTURE OF THE HUMAN CB2-G(I) SIGNALING COMPLEX WAS SOLVED WITH A BOUND AGONIST, SHOWING THE BINDING MODE AND HOW CB2 DISTINGUISHES AGONISTS FROM ANTAGONISTS. THIS KNOWLEDGE SHOULD AID IN DEVELOPING MORE-EFFECTIVE DRUGS THAT TARGET THE CANNABINOID SYSTEM (XING ET AL., CELL 180(4): 645-654.E13). IN THE METABOLISM PROGRAM, THE RUSSELL JONES LAB INVESTIGATED THE METABOLIC ADAPTATION OF CANCER CELLS THROUGH THE LIVER KINASE B1-AMPK PATHWAY. THE MICRORNA MIR-17 SENSITIZED LYMPHOMA CELLS TO TREATMENT WITH BIGUANIDES, WHICH STRESS THE CELLS BY INHIBITING THE KREBS CYCLE AND MITOCHONDRIAL RESPIRATION. MIR-17 EXPRESSION MAY BE A BIOMARKER FOR BIGUANIDE SENSITIVITY IN CANCERS (IZREIG ET AL., CELL REPORTS MEDICINE 1(2): 100014). THE LAB ALSO INVESTIGATED THE REASONS FOR AND EFFECTS OF HIGH SERUM ACETATE AT SITES OF INFECTION. THEY FOUND THAT AN ABUNDANCE OF ACETATE IMPROVED PATHOGEN CLEARANCE WHILE REDUCING IMMUNOPATHOLOGY. OVERALL, THE WORK SHOWED THAT AT DIFFERENT STAGES OF THE IMMUNE RESPONSE, ACETATE HAS DISTINCTLY DIFFERENT EFFECTS WITHIN THE SAME CELL TYPE (BALMER ET AL., CELL METABOLISM 32(3): 457-467.E5). A THIRD PAPER REPORTED THE EFFECTS OF METHOTREXATE ON CELLULAR METABOLISM, ONE OF WHICH WAS AMPK ACTIVATION. THAT ACTIVATION WAS NECESSARY FOR BOTH THE ANTI-PROLIFERATIVE AND PRO-RESPIRATORY EFFECTS OF METHOTREXATE. COMBINING METHOTREXATE WITH THE AMPK ACTIVATOR PHENFORMIN POTENTIATES THE ANTI-PROLIFERATIVE ACTIVITY IN CANCER CELLS (PAPADOPOLI ET AL., SCIENTIFIC REPORTS 10(1): 7838). THE JONES AND KRAWCZYK LABS COLLABORATED IN A STUDY OF MICRORNA-9 IN THE DENDRITIC CELLS OF THE INNATE IMMUNE SYSTEM. THE RESULTS SHOWED THAT MIR-9 AIDED THE TRANSITION OF DENDRITIC CELLS FROM STEADY STATE TO A MATURE STATE BY AFFECTING THE EXPRESSION OF SEVERAL NEGATIVE REGULATORS OF CELL TRANSCRIPTION, INCLUDING POLYCOMB GROUP FACTOR 6 (CORDEIRO ET AL., CELL REPORTS 21(5): 107585). METHIONINE IS A KEY NUTRIENT AFFECTING EPIGENETIC REPROGRAMMING IN CD4+ T HELPER (TH) CELLS. A COLLABORATION AMONG THE R. JONES, KRAWCZYK, AND POSPISILIK LABS SHOWED THAT A LACK OF METHIONINE AFFECTED THE PROMOTER REGIONS OF GENES INVOLVED IN THE PROLIFERATION OF INFLAMMATORY TH17 CELLS AND CYTOKINE PRODUCTION. IN A MOUSE MODEL OF MULTIPLE SCLEROSIS, LACK OF DIETARY METHIONINE LED TO REDUCED T CELL-MEDIATED NEUROINFLAMMATION AND DISEASE ONSET. METHIONINE RESTRICTION MAY BE A USEFUL INTERVENTION FOR TREATING AUTOIMMUNE CONDITIONS SUCH AS MS (ROY ET AL., CELL METABOLISM 31(2): 250-266.E9). FINALLY, THE STEENSMA LAB STUDIED KINASE ENZYME INHIBITION IN MALIGNANT PERIPHERAL NERVE SHEATH TUMORS USING CAPMATINIB, TRAMETINIB, OR DOXORUBICIN TREATMENT. THEY FOUND BROAD AND REDUNDANT KINOME ADAPTATIONS, SHOWING THAT THESE TUMORS ARE CAPABLE OF PROFOUND SIGNALING PLASTICITY IN THE FACE OF SUCH TREATMENTS. SOME OF THE DATA SUGGEST THAT TARGETING AXL OR MFKB MAY LESSEN THE RESISTANCE TO THESE THERAPIES (GRIT ET AL., GENES 11(3): 331). |
| FORM 990, PART III, LINE 4B | LINE 4B - PROGRAM SERVICE ACTIVITY #2 CENTER FOR EPIGENETICS THE CENTER, ESTABLISHED IN 2014 AND NOW DIRECTED BY J. ANDREW POSPISILIK, PH.D., HAS 10 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 AN R01 AND AN R21 FROM THE NATIONAL INSTITUTES OF HEALTH, AS WELL AS AN NIH GRANT SUB-AWARD. THE LAB OF PETER JONES CONDUCTED A STUDY OF THE WHOLE-GENOME SEQUENCES OF 53 ORGANISMS, AND THEY SHOWED A POSITIVE CORRELATION BETWEEN THE SIZE OF A GENOME AND THE PERCENTAGE OF TRANSPOSABLE ELEMENTS (TES) IT CONTAINS. THE METHYLATION OF THE DNA OF SUCH ELEMENTS ALLOWS FOR THEIR LONG-TERM RESIDENCE IN THE GENOME, AND THEIR ACCUMULATION LEADS TO AN INCREASE IN GENOME SIZE. IT ALSO LEADS TO NEW OPPORTUNITIES FOR GENE CONTROL BY TE-BASED REGULATORY SITES (ZHOU ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES USA 117(32): 19359-19366). ANOTHER PROJECT LOOKED AT THE USE OF DNA METHYLTRANSFERASE INHIBITORS AS DRUGS FOR TREATING HEMATOLOGIC CANCERS. IN RESPONSE TO THIS TREATMENT, MALIGNANT CELLS SHOWED THE ACTIVATION OF NEWER TRANSPOSABLE ELEMENTS OF SEVERAL KINDS, AND CELL CULTURES SHOWED THE ACTIVATION OF SIX GENES IN THE TYPE I IFN PATHWAY. THUS, THE TES ELICITED AN IMMUNE REACTION THAT MAY BE IMPORTANT IN THE PATIENT'S RESPONSE TO THERAPY (OHTANI ET AL., CANCER RESEARCH 80(12): 2441-2450). THE ROTHBART LAB'S RESEARCH INVOLVES THE GAIN AND LOSS OF METHYL GROUPS ADDED TO DNA AND THE FUNCTION OF THOSE CHANGES. THE LIGASE UHRF1 IS KNOWN TO HELP MAINTAIN ABNORMAL DNA METHYLATION IN CANCER CELLS. THE LAB INVESTIGATED THIS ENZYME'S ACTIVITY AND THE PATTERN OF DNA METHYL GROUPS IN A VARIETY OF EXPERIMENTS, WHICH SHOWED THAT UHRF1 SELECTIVELY IDENTIFIES SPECIFIC METHYLATION POSITIONS ON BOTH DNA AND HISTONE PROTEINS. THEY ALSO FOUND THAT THE READER ACTIVITY OF THE UHRF1 TANDEM TUDOR DOMAIN IS DISPENSABLE FOR MAINTAINING DNA METHYLATION IN CANCER CELLS (VAUGHAN ET AL., EPIGENETICS AND CHROMATIN 13: 44). THE LAB HAS DEVELOPED A HIGH-THROUGHPUT BINDING ASSAY TO SHOW THE SEQUENCE DETERMINANTS OF METHYLLYSINE-DRIVEN PROTEIN INTERACTIONS. THEY ALSO USED IT TO IDENTIFY THE BINDING LOCALES OF HISTONE ANTIBODIES AND FOUND THAT ONLY A FEW AMINO ACIDS DRIVE EPITOPE RECOGNITION. THIS ASSAY WILL BE A VALUABLE RESOURCE FOR FUTURE STUDIES OF METHYLLYSINE-DRIVEN PROTEIN INTERACTIONS (KUPAI ET AL., FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY 8: 241). IN A THIRD PAPER, THE LAB DESCRIBED A NEW MODEL DEFINING CHROMATIN IMMUNOPRECIPITATION (CHIP-SEQ) TECHNOLOGY, AND THEY EXPLORED THE MODEL'S IMPLICATIONS FOR THE USE OF EXOGENOUS ADDITIVES (SPIKE-INS) WITH CHIP-SEQ. THEY IDENTIFIED A NEW SENSITIVITY ISSUE THAT LIMITS THE UTILITY AND TRUSTWORTHINESS OF SPIKE-INS. THIS PROMISES TO BE A VALUABLE STEP IN IMPROVING THE WIDELY USED CHIP-SEQ TECHNOLOGY (DICKSON ET AL., JOURNAL OF BIOLOGICAL CHEMISTRY 295(47): 15826-15837). FINALLY, THEY COLLABORATED IN A PROJECT LOOKING AT THE RAPID TRANSCRIPTION OF SELECT GENES IN RESPONSE TO CUES SUCH AS THE SENSING OF PATHOGENS BY MACROPHAGES. THE AUTHORS PROPOSE THAT FEATURES OF THE HISTONE H3.3 PROVIDE PREFERENTIAL ACCESS TO THE TRANSCRIPTIONAL MACHINERY, AND THAT DEDICATED MECHANISMS ENABLE RAPID TRANSCRIPTION INVOLVING H3.3, ITS PHOSPHORYLATION, AND BOTH THE RECRUITMENT AND EJECTION OF CHROMATIN REGULATORS (ARMACHE ET AL., NATURE 583(7818): 852-857). THE SHI LAB TOOK PART IN A STUDY REPORTING THAT WNT ACTIVATION STABILIZES THE EPIGENETIC REGULATOR PROTEIN KDM4C, WHICH PROMOTES TUMORIGENESIS AND AIDS THE SURVIVAL OF HUMAN GLIOBLASTOMA CELLS. WNT-KDM4C-BETA-CATENIN SIGNALING REPRESENTS A NEW MECHANISM FOR THE TRANSCRIPTION OF WNT TARGET GENES AND THE REGULATION OF TUMORIGENESIS, AND IT HAS IMPORTANT CLINICAL IMPLICATIONS FOR THIS CANCER (CHEN ET AL., CANCER RESEARCH 80(5): 1049-1063). A SECOND PAPER LOOKED AT THE HUMAN ENZYME HERC2, WHICH IS LINKED TO NEUROLOGICAL DISEASES AND CANCER. A DETAILED STRUCTURE OF THE ENZYME'S ZZ DOMAIN WAS SOLVED, SHOWING THE NEGATIVELY CHARGED SITE OF THAT DOMAIN HAS A CRUCIAL ROLE IN THE ENZYME'S INTERACTIONS. THE ZZ DOMAIN MAY PLAY A ROLE IN THE ASSOCIATION OF HERC2 WITH CHROMATIN (LIU ET AL., STRUCTURE 28(11): 1225-1330.E3). ANOTHER PAPER FROM THE LAB LOOKED INTO CHANGES FOUND IN AN AGGRESSIVE FORM OF ACUTE MYELOID LEUKEMIA. THE DATA SUPPORT A CRUCIAL ROLE OF THE FUSION PROTEIN NUP98-PHF23 IN DRIVING LEUKEMOGENESIS. THEY HIGHLIGHT A DIRECT CORRELATION BETWEEN LEUKEMIC TRANSFORMATION AND THE ABILITIES OF NUP98-PHD FINGER CHIMERAS TO ASSOCIATE WITH H3K4ME3 METHYLATION SITES ON CHROMATIN (ZHANG ET AL., NATURE COMMUNICATIONS 11: 3339). THESE STUDIES ALL ADD TO OUR KNOWLEDGE OF THE MOLECULAR BASIS OF CANCER. THE LAIRD LAB CONTRIBUTED TO A PHASE 1 TRIAL OF TRC102 IN COMBINATION WITH TEMOZOLOMIDE FOR PATIENTS WHO HAD REFRACTORY SOLID TUMORS. OF 52 PATIENTS, FOUR HAD PARTIAL RESPONSES AND 13 HAD A BEST RESPONSE OF STABLE DISEASE. THE COMBINATION TREATMENT IS ACTIVE, AND THE SIDE-EFFECT PROFILE IS MANAGEABLE (COYNE ET AL., ONCOTARGET 11(44): 3959-3971). ANOTHER PAPER STUDIED TEN ESTIMATION METHODS FOR TUMOR PURITY IN A COHORT OF 333 PROSTATE CANCER PATIENTS. THE DATA SHOWED POOR CONCORDANCE BETWEEN PATHOLOGIC AND MOLECULAR PURITY ESTIMATES. THUS, THE CHOICE OF TUMOR PURITY ESTIMATION METHOD MAY HAVE A PROFOUND IMPACT ON THE INTERPRETATION OF GENOMIC ASSAYS, HIGHLIGHTING A NEED FOR IMPROVED WAYS TO ASSESS TUMOR PURITY (HAIDER ET AL., JCO PRECISION ONCOLOGY 4: 995-1005). THE SHEN LAB TOOK PART IN A PHASE II CLINICAL TRIAL OF METFORMIN AGAINST EPITHELIAL OVARIAN CANCER. METFORMIN WAS WELL TOLERATED, AND TREATED TUMORS SHOWED INCREASED SENSITIVITY TO CISPLATIN EX VIVO. IT ALTERED THE METHYLATION SIGNATURE OF CARCINOMA-ASSOCIATED MESENCHYMAL STEM CELLS, PREVENTING CHEMORESISTANCE IN VITRO. THE STUDY SUPPORTS THE USE OF METFORMIN IN PHASE II STUDIES (BROWN ET AL., JCI INSIGHT 5(11): E1332247). THE SHEN AND TRICHE LABS BOTH CONTRIBUTED TO A STUDY OF UTERINE FIBROIDS. SIGNIFICANT OVERLAP OF DIFFERENTIALLY EXPRESSED GENES WAS OBSERVED FOR CERVICAL STROMA OR UTERINE FIBROIDS COMPARED WITH NORMAL MYOMETRIUM. THESE ANALYSES SHOW A POSSIBLE ROLE OF DNA METHYLATION IN FIBROID BIOLOGY, AND THEY SUGGEST THAT HOMEOTIC TRANSFORMATION OF MYOMETRIAL CELLS TO A MORE CERVICAL STROMA PHENOTYPE COULD BE AN IMPORTANT MECHANISM IN THE DISEASE (GEORGE ET AL., CELL REPORTS 29(12): 4069-4085.E6). STEFAN JOVINGE'S LAB HELPED EVALUATE THE EFFECT OF S100A9 BLOCKADE ON POST-ISCHEMIC CARDIAC REPAIR. SEVEN DAYS OF TREATMENT WERE BENEFICIAL, BUT 21 DAYS OF BLOCKADE LED TO DETERIORATION OF CARDIAC FUNCTION IN MICE. THUS, THERE IS A THERAPEUTIC WINDOW FOR OPTIMAL EFFECT OF THIS TREATMENT IN ACUTE MYOCARDIAL INFARCTION (MARINKOVIC ET AL., CIRCULATION RESEARCH 127(5): 664-676). IN ANOTHER STUDY, THE LAB COLLABORATED IN A STUDY OF THE CO-CULTURE OF CARDIOMYOCYTES AND SYMPATHETIC NEURONS, BOTH DERIVED FROM HUMAN-INDUCED PLURIPOTENT STEM CELLS. THE DATA SHOWED THE DEVELOPMENT OF ELECTROPHYSIOLOGICALLY FUNCTIONAL SYMPATHETIC NEURONS THAT ARE CAPABLE OF MODULATING THE BEATING RATE OF THE CARDIOMYOCYTES IN VITRO. THESE HUMAN CELL CO-CULTURES PROVIDE A NOVEL MULTICELLULAR MODEL FOR THE STUDY OF NEUROCARDIAC MODULATION UNDER PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS (WINBO ET AL., AMERICAN JOURNAL OF PHYSIOLOGY - HEART AND CIRCULATORY PHYSIOLOGY 319(5): H927-H937). THE POSPISILIK LAB COAUTHORED A PAPER SHOWING THAT MACROPHAGES CAN MAINTAIN INSULIN SECRETION IN VIVO FOLLOWING BETA-CELL DEATH, WITH NO EFFECTS ON ISLET CELL TURNOVER. IGF-1 NEUTRALIZATION DURING STREPTOZOTOCIN TREATMENT DECREASED INSULIN SECRETION WITHOUT AFFECTING ISLET CELL APOPTOSIS OR PROLIFERATION. A HIGH-FAT DIET PLUS STZ FURTHER SKEWED ISLET MACROPHAGES TO A REPARATIVE STATE (NACKIEWICZ ET AL., ISCIENCE 23(1): 100775). THE LAB ALSO COLLABORATED IN RESEARCH INTO ADHESION G-PROTEIN-COUPLED RECEPTORS IN ADIPOSE TISSUE. THE PROJECT CONCLUDED THAT ADHESION GPCRS ARE SIGNIFICANTLY INVOLVED IN QUALITATIVE AND QUANTITATIVE LIPID ACCUMULATION IN ADIPOCYTES AND CAN CONTROL LIPOLYSIS. FACTORS DRIVING ADIPOCYTE FORMATION AND FUNCTION ARE GOVERNED BY SIGNALING PATHWAYS INDUCED BY ADHESION GPCRS, SUGGESTING THAT THESE RECEPTORS ARE POTENTIAL TARGETS FOR TREATING OBESITY (SUCHY ET AL., INTERNATIONAL JOURNAL OF OBESITY 44(10): 2124-2136). |
| FORM 990, PART III, LINE 4C | LINE 4C - PROGRAM SERVICE ACTIVITY #3 CENTER FOR NEURODEGENERATIVE SCIENCE THE CENTER WAS ESTABLISHED IN 2012 UNDER DIRECTOR PATRIK BRUNDIN, M.D., PH.D. IN 2020, IT HAD NINE LABORATORIES STUDYING PARKINSON'S DISEASE, ALZHEIMER'S DISEASE, AND THE RELATIONSHIPS BETWEEN DEPRESSION, SUICIDE, AND BRAIN INFLAMMATION. THE NEWEST LABORATORY, THAT OF MICHAEL HENDERSON, PH.D., FOCUSES ON THE PATHOGENESIS AND POTENTIAL THERAPIES FOR PARKINSON'S DISEASE AND DEMENTIA WITH LEWY BODIES. CENTER RESEARCHERS AND TRAINEES DURING THIS FISCAL YEAR RECEIVED FIVE R01S AND AN R21 FROM THE NATIONAL INSTITUTES OF HEALTH, TWO AWARDS FROM THE MICHAEL J. FOX FOUNDATION AND THREE FROM THE ASAP COLLABORATIVE RESEARCH NETWORK, AND A SUBAWARD FROM THE PARKINSON'S FOUNDATION. A POSTDOCTORAL FELLOWSHIP WAS ALSO RECEIVED FROM THE PARKINSON'S FOUNDATION. THE LENA BRUNDIN LAB EXPLORED THE INCREASED INFLAMMATION REPORTED IN MAJOR DEPRESSIVE DISORDER (MDD), WHICH MAY BE DRIVEN BY VITAMIN D DEFICIENCY. WHILE 25(OH)D LEVELS DID NOT SIGNIFICANTLY DIFFER IN MDD VS. CONTROLS, LOWER 25(OH)D WAS ASSOCIATED WITH INDICES OF IMMUNE ACTIVATION IN MDD, ESPECIALLY IN CASES WITH SUICIDAL IDEATION. THE FINDINGS ARE CONSISTENT WITH RELATIVELY LOW 25(OH)D LEVELS IN MDD BEING ASSOCIATED WITH A PRO-INFLAMMATORY STATE (GRUDET ET AL., JOURNAL OF AFFECTIVE DISORDERS 267: 33-41). ANOTHER STUDY FOCUSED ON TRYPTOPHAN (TRP) METABOLITES IN THE CEREBROSPINAL FLUID (CSF), WHICH MAY BE MODULATORS OF PSYCHIATRIC DISEASE. THE LAB SHOWED THE FEASIBILITY OF BIOCHEMICAL ANALYSIS OF CSF TRP METABOLITES, INCLUDING THE SEPARATION OF PICOLINIC ACID FROM NICOTINIC ACID. THEY ALSO CONFIRMED PRIOR FINDINGS OF ABERRANT CSF QUINOLINIC ACID AND PICOLINIC ACID IN SUICIDE ATTEMPTERS (SCHWIELER ET AL., BIOANALYSIS 12(6): 379-392). THE LABS OF PATRIK AND LENA BRUNDIN COLLABORATED IN LOOKING AT TRYPTOPHAN METABOLITES IN PARKINSON'S DISEASE PATIENTS. PD SUBJECTS HAD OVER 100% HIGHER 3-HYDROXYKYNURENINE AND 14% LOWER 3-HYDROXYANTHRANILIC ACID CONCENTRATIONS IN THEIR PLASMA. OVERALL, KYNURENINE PATHWAY METABOLITES WERE ALTERED IN PD PATIENTS IN BOTH THE PERIPHERY AND THE CENTRAL NERVOUS SYSTEM, AND THESE CHANGES ASSOCIATED WITH SYMPTOM SEVERITY (HEILMAN ET AL., MOVEMENT DISORDERS 35(11): 2028-2037). THE PATRIK BRUNDIN LAB EVALUATED THE SMELLING FUNCTION OF MICE AFTER INJECTING ALPHA-SYNUCLEIN PREFORMED FIBRILS INTO THE OLFACTORY BULB. NO OVERT IMPAIRMENTS IN SNIFFING ABILITY WERE EVIDENT. AT ALL TIME POINTS, FEMALES HAD A REDUCED ABILITY TO DETECT ODORS IN A PLETHYSMOGRAPHY TEST. THIS SENSITIVE METHOD COULD BE USED TO DEFINE HOW ALPHA-SYNUCLEIN PATHOLOGY AFFECTS OTHER ASPECTS OF OLFACTORY PERCEPTION AND TO CLARIFY THE NEUROPATHOLOGICAL BASIS OF THESE DEFICITS (JOHNSON ET AL., SCIENTIFIC REPORTS 10(1): 9242). A SECOND SET OF EXPERIMENTS FOUND PATHOLOGY IN BOTH THE OLFACTORY BULB AND THE PIRIFORM CORTEX OF MICE INJECTED WITH ALPHA-SYNUCLEIN FIBRILS. THE MICE DISPLAYED ABERRANTLY HIGH ODOR-EVOKED POWER IN THE BETA SPECTRAL RANGE. NO SIMILAR CHANGE WAS FOUND IN THE PIRIFORM CORTEX, DESPITE HIGH LEVELS OF PATHOLOGY. THESE RESULTS PROVIDE EVIDENCE THAT SYNUCLEINOPATHY AFFECTS NEURAL ACTIVITY IN THE OLFACTORY SYSTEM AT THE NETWORK LEVEL (KULKARNI ET AL., JOURNAL OF PARKINSON'S DISEASE 10(4): 1411-1427). A THIRD PAPER REPORTED THE INJECTION OF FIVE CONFORMATIONAL STRAINS OF ALPHA-SYNUCLEIN INTO THE OLFACTORY BULB OF FEMALE MICE. EACH STRAIN PROPAGATED PATHOLOGY THROUGH THE CENTRAL NERVOUS IN DISTINCT PATTERNS. THE DATA SUPPORT THE VIEW THAT THE CONFORMATIONS OF ALPHA-SYNUCLEIN ASSEMBLIES MAY UNDERLIE DIFFERENT PROPAGATION PATTERNS WITHIN THE HUMAN BRAIN (REY ET AL., ACTA NEUROPATHOLOGICA COMMUNICATIONS 7:221). THE MOORE LAB STUDIED THE LRRK2 KINASE ENZYME AND IDENTIFIED ITS FUNCTION IN REGULATING MEMBRANE FUSION AT THE TRANS-GOLGI NETWORK, INFLUENCING BOTH RETROGRADE AND POST-GOLGI TRAFFICKING PATHWAYS. ITS ACTION IS EXAGGERATED BY MUTATIONS ASSOCIATED WITH PARKINSON'S DISEASE AND CAN BE BLOCKED BY KINASE INHIBITORS. DISRUPTION OF THE GARP PROTEIN COMPLEX SENSITIZES DOPAMINERGIC NEURONS TO MUTANT LRRK2 TOXICITY IN C. ELEGANS, SHOWING THAT THESE PATHWAYS ARE INTERLINKED IN VIVO AND SUGGESTING A LINK IN PD (BEILINA ET AL., CELL REPORTS 31(5): 107614). THE LAB ALSO DEVELOPED A ROBUST PRECLINICAL MODEL OF PARKINSON'S DISEASE IN ADULT RATS HAVING NEURON-SPECIFIC EXPRESSION OF HUMAN LRRK2 BEARING THE G2019S MUTATION, WHICH INDUCES ROBUST DEGENERATION OF SUBSTANTIA NIGRA DOPAMINERGIC NEURONS. THIS MODEL SHOWED THAT SUCH NEURODEGENERATION REQUIRES NORMAL GTPASE AND KINASE ACTIVITY. INHIBITION OF THE KINASE AND ALTERATION OF GTPASE ACTIVITY MAY BE PROMISING AS DISEASE-MODIFYING TARGETS (NGUYEN ET AL., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES USA 117(29): 17296-17307). THE LAB ALSO PUBLISHED TWO REVIEWS, ONE ON THE FUNCTIONS OF LRRK2 WITH THE ENDOLYSOSOMAL PATHWAY (ERB AND MOORE, JOURNAL OF PARKINSON'S DISEASE 10(4): 1271-1291) AND ANOTHER ON THE LINKAGE BETWEEN LRRK2 AND PROTEIN AGGREGATION IN ANIMAL MODELS OF PARKINSON'S DISEASE (DUES AND MOORE, FRONTIERS IN NEUROSCIENCE 14:719). THE GUERREIRO AND BRAS LABS COLLABORATED ON PROJECTS IN SEVERAL DIVERSE AREAS. THE KCNN2 GENE IS HIGHLY EXPRESSED IN THE HUMAN BRAIN. ONE OF THEIR PAPERS REPORTED A MISSENSE MUTATION IN THAT GENE WHICH TRACKED WITH THE CHILDHOOD-ONSET TREMORS CHARACTERISTIC OF MYOCLONUS-DYSTONIA. THIS IS THE FIRST SUGGESTION THAT KCNN2 MUTATIONS COULD BE A PLAUSIBLE CAUSE OF THIS DISEASE (BALINT ET AL., EUROPEAN JOURNAL OF NEUROLOGY 27(8): 1471-1477). THE LABS ALSO PUBLISHED THE RESULTS OF WHOLE-EXOME SEQUENCING OF A COHORT OF 1118 CAUCASIAN PATIENTS WHO HAD DEMENTIA WITH LEWY BODIES (DLB); THEY FOCUSED ON GENES THAT CAUSE MONOGENIC NEURODEGENERATIVE DISEASES. THE RARITY OF PREVIOUSLY REPORTED PATHOGENIC MUTATIONS IN THIS COHORT SUGGESTS THAT THE GENETIC OVERLAP BETWEEN OTHER NEURODEGENERATIVE DISEASES AND DLB IS NOT SUBSTANTIAL (ORME ET AL. ACTA NEUROPATHOLOGICA COMMUNICATIONS 8(1): 5). A THIRD PAPER IDENTIFIED A NOVEL HOMOZYGOUS MISSENSE MUTATION OF THE MYELIN-ASSOCIATED GLYCOPROTEIN (MAG) IN A PORTUGUESE FAMILY WITH EARLY-ONSET, AUTOSOMAL RECESSIVE, CEREBELLAR ATAXIA WITH NEUROPATHY AND OCULOMOTOR APRAXIA. THE MUTATION REDUCED PROTEIN STABILITY, IMPAIRED THE PROTEIN'S GLYCOSYLATION, AND CHANGED ITS SUBCELLULAR LOCATION. THIS MUTATION THUS PROVIDES A NEW DIAGNOSTIC MARKER FOR HEREDITARY OCCURRENCES OF THIS DISEASE (SANTOS ET AL., JOURNAL OF CLINICAL MEDICINE 9(4): 1212). THEY ALSO WORKED ON A STUDY OF GENETIC FRONTOTEMPORAL DEMENTIA, USING AN INTERNATIONAL, RETROSPECTIVE COHORT OF 3403 INDIVIDUALS FROM 1492 FAMILIES. IT SHOWED THAT THE AGE AT SYMPTOM ONSET AND AT DEATH OF PATIENTS IS INFLUENCED BY THEIR GENETIC GROUP, BY THE SPECIFIC MUTATION CARRIED, AND BY FAMILY MEMBERSHIP. THE DATA SUGGEST THAT STUDYING OTHER MEMBERS OF A FAMILY WILL BE HELPFUL ONLY FOR INDIVIDUALS WITH MUTATIONS OF THE MAPT GENE. (MOORE ET AL., LANCET NEUROLOGY 19(2): 145-156). THE LABRIE LAB REPORTED THAT NEURONS IN THE HUMAN PREFRONTAL CORTEX HAVE HEMISPHERIC DIFFERENCES IN DNA METHYLATION LARGELY MEDIATED BY DIFFERENTIAL CPH METHYLATION. THE ASYMMETRY IS GREATER IN NEURONS OF PARKINSON'S DISEASE PATIENTS THAN IN HEALTHY CONTROLS. THESE DIFFERENCES MAY AFFECT THE PROGRESSION AND SYMPTOMS OF PARKINSON'S DISEASE (LI ET AL., GENOME BIOLOGY 21: 61). IN ANOTHER PAPER, THE LABRIE, COETZEE, AND JOVINGE LABS FOUND A WIDESPREAD INCREASE IN CYTOSINE METHYLATION AT THE ENHANCER LOCI IN PARKINSON'S DISEASE NEURONS. PARKINSON'S PATIENTS SHOWED AN INCREASE IN TET2 GENE ACTIVITY, WHICH IS A MASTER REGULATOR OF CYTOSINE MODIFICATIONS. DECREASED TET2 ACTIVITY IS NEUROPROTECTIVE IN MICE AND MAY BE A NEW THERAPEUTIC AVENUE AGAINST PARKINSON'S DISEASE (WEILAND ET AL., NATURE NEUROSCIENCE 23(10): 1203-1214). |
| 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 $1,635,281,000 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: |