Van Andel Research Institute

“Vari, vai, vaei, and vaigs share common management. David van andel, dr. Jana hall, timothy myers and david whitescarver are also officers of vai, and david van andel, timothy myers and david whitescarver (through 8/31/16) are officers of vaei and vaigs.”

“The trustees of van andel institute have the authority to elect one or more members of vari's governing body.”

“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.”

“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.”

“Comparability data from expert third party is obtained and reviewed by the independent, joint compensation committee of van andel research institute and related organizations to determine appropriate compensation for the ceo, executive management officials, officers, and key employees, on behalf of van andel research institute.”

“All documents required to be made available to the public are available for public inspection upon written request.”

“Gain on interest rate swap 3,856,298.”

“Van andel research institute (vari) is dedicated to determining the epigenetic, genetic, molecular, and cellular origins of cancer, parkinson's disease, and other illnesses and to translating those findings into effective therapies. The institute's scientists work in on-site laboratories and participate in collaborations that span the globe. With epigenetics as its common thread, vari is organized into three centers-the center for cancer and cell biology, the center for epigenetics, and the center for neurodegenerative science-as well as a core technologies and services group, which provides a vivarium, a biorepository, and valuable on-site capabilities in cryo-electron microscopy (cryo-em), imaging, pathology, bioinformatics, genomics, and flow cytometry. Research by vari scientists is published in major peer-reviewed journals, including, in 2016, cell, cell discovery, molecular cell, new england journal of medicine, science translational medicine, nature reviews genetics, scientific reports, cancer, cancer cell, genome biology, bone research, cancer research, proceedings of the national academy of sciences usa, clinical cancer research, journal of bone and mineral research, journal of biological chemistry, molecular biology of the cell, journal of affective disorders, oncogene, journal of chemical physics, neuropathology and applied neurobiology, sarcoma, molecular cancer research, journal of medicinal chemistry, plos one, bmj open, journal of experimental medicine, epigenetics and chromatin, cellular and molecular gastroenterology and hepatology, febs journal, journal of parkinson's disease, virology journal, pediatric cardiology, and psychoneuroendocrinology.”

“Line 4a - program service activity #1 center for cancer and cell biology the center for cancer and cell biology, directed by bart williams, ph.d., comprises 12 laboratories engaged in basic research in molecular and structural biology and in translational research on cancers, the tumor microenvironment, and skeletal diseases. Dr. H. Eric xu, a structural biologist in the center, received the prestigious hans neurath award from the protein society in august of 2016 for contributions of exceptional merit to protein research. Center investigators received three nih awards in 2016. Additonal awards and license revenue were received from the department of defense, the tuberous sclerosis alliance, the american asthma foundation, the breast cancer research foundation, the michael j. Fox foundation, and bolaatu medicine. Two new research contracts were signed in 2016. Studies of three-dimensional molecular structures and their physical interactions have been proceeding on several fronts in 2016. The xu and melcher laboratories designed and developed a highly potent glucocorticoid, vsgc12, that demonstrated a higher efficacy and potency than fluticasone furoate, a common asthma treatment, in repressing most asthma symptoms. Vsgc12 also showed a better side-effect profile at the effective doses, giving this new molecule promise as a new asthma treatment (he et al., cell discovery 1: 15035). Another study involved the amyloid precursor protein and its association with alzheimer's disease. Mutations in this protein can change its susceptibility to cleavage into an aggregation-prone form, which is found in alzheimer's patients. This work identified which mutations increase the tendency toward aggregation, and this result can be extended to the cleavage of the proteins called notch" receptors, which are cell-surface signaling proteins (xu et al., cell discovery 2: 16026). In structural work addressing more basic questions, the xu and melcher labs studied nanobodies, which are fragments of human antibodies, specifically the variable antibody domain. They isolated a nanobody called ntv1 against vegfr2, a cellular receptor important in blood vessel growth and development, and also in the growth of tumors. The ntv1 nanobody has potential as a blocker of vegrf2 and thus as a cancer therapeutic (ma et al., acta pharmacologica sinica 37(6): 857-864). The two labs also studied class b g-protein-coupled receptors (gpcrs), which play an intergral role in cellular communication and are major drug targets; an estimated one-third to one-half of drugs currently on the market work by interacting with gpcrs. Xu and melcher showed that such receptors vary widely in their need for the receptor's extracellular domain in order to activate the receptor. This work suggests a new model of how these receptors function and how they can be further targeted to treat disease (zhao et al., journal of biological chemistry 291(29): 15119-15130). The xu and melcher labs have shown a dominant role for the extracellular domain of the glucagon-like peptide-1 receptor, which is a major target for diabetes therapy. The data support a model in which binding of a peptide to the receptor switches it from autoinhibited to autoactivated, by releasing the intrinsic agonist activity of the extracellular domain (yin et al., cell discovery 2: 10642). Progress continues in studies of pancreatic cancer. The haab laboratory has identified sugar molecules that attach to muc5ac, a protein found in precancerous (mucinuous cysts), in a characteristic way, providing a means to determine whether pancreatic cysts carry a future risk of cancer (sinha et al., plos one 11(12): e0167070). The lab also developed a new method of obtaining data on sugar-modified proteins using as little as 11 nanograms of protein. This method was effective in analyzing the sugars attached to the muc5ac protein from a sample of only 20 microliters of plasma (reatini et al., analytical chemistry 88(23): 11584-11592). A t”

“Line 4b - program service activity #2 center for epigenetics the center, established in 2014 and directed by the institute's chief scientific officer peter jones, ph.d., d.sc., comprises nine laboratories studying epigenetics and epigenomics and the role of epigenetic dysfunction in cancer and neurodegenerative disease, cardiovascular disease, and viral transcription. Stephen baylin, m.d., a professor at johns hopkins university, holds a 25% appointment in the center. Huilin li, ph.d., was recruited to the center in 2016 as a professor. In 2016, center researchers received three nih awards as well as awards from the michael j. Fox foundation and the ovarian cancer research fund. The vari-su2c epigenetics dream team, led by peter jones and stephen baylin, continued its work in 2016, with the 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. One study, led by peter jones and university of copenhagen's kirsten gronbaek, m.d., d.msc., showed that many patients with blood cancers (myeloid dysplastic syndrome and acute myeloid leukemia) are markedly deficient in vitamin c. The data suggests that correction of vitamin c deficiency in patients with hematological and other cancers may improve their response to epigenetic therapy combined with the use of inhibitors of dna methyltransferases (liu et al., proceedings of the national academy of sciences usa 113(37): 10238-10244). Another study by team members at johns hopkins univeristy and university of maryland describes a mechanism to enhance the anticancer efficacy of inhibitors of poly(adp-ribose) polymerase (parp), which are effective agents against some breast cancers. Low doses of dna methyltransfersase inhibitors plus parp inhibitors can increase parpi efficacy in terms of increased dna damage and other anticancer effects. Such treatment may be useful against some subtypes of acute myeloid leukemia and of breast cancers (muvarak et al., cancer cell 30(4): 637-650). At the end of 2016, four vari -su2c epiegnetics dream team-supported clinical trials were underway at sites across the country and in copenhagen, denmark. Peter jones and collaborator gangning liang, m.d., ph.d., reported the development of a cost-effective and computationally simple assay called "accesssible" to simultaneously determine dna methylation and chromatin accessibility changes in primary human clear cell renal cell carcinoma. This assay found significant changes to the epigenome of clear cell renal cell carcinoma as well as gene expression changes specifically attributed to chromatin accessibility (becket et al., cancer research 76(7) 1954-1964). The laird laboratory is heavily involved in the work of the cancer genome atlas research network, a nih-funded multi institutional effort to molecularly map cancer. Among the several publications produced in 2016 was a comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas. Type 1 and type 2 papillary renal-cell carcinomas are clinically and biologically distinct, and type 2 consists of at least three subtypes. This knowledge may aid in selecting appropriate treatments for individual patients based on disease subtype (cancer genome atlas research network, new england journal of medicine 374(2): 135-145). Other research defined the complete set of genes associated with diffuse grade ii-iii-iv gliomas (1122 samples) from the cancer genome atlas. The molecular profiles defined will be used to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease (ceccarelli et al., cell 164(3): 550-563). The rothbart laboratory reported the first demonstration of a dna-protein interaction and an epigenetic modification directly regulating the enzyme activity of”

“Line 4c - program service activity #3 center for neurodegenerative science the center was established in 2011 under patrik brundin, m.d., ph.d., who is also vari's associate director. The center has seven laboratories studying parkinson's disease, aging, prions, alzheimer's disease, and the relationship between depression, suicide, and brain inflammation. Jeffrey kordower, ph.d., a professor at rush university, holds a 25% appointment in the center. Viviane labrie, ph.d., joined the center in 2016 as an assistant professor. Center researchers in 2016 received r01 and r21 awards from nih as well as awards from the brain and behavior research foundation, the east tennessee foundation, five grants from the michael j. Fox foundation, one grant from pine rest christian mental health services, and an industry contract award from hoffman-la roche. Prions, which cause neurodegenerative diseases, are the main focus of research in the laboratory of jiyan ma, ph.d. One study explored the role of a string of four threonines in the conversion of normal prion protein into the disease-causing form. The results suggested a theory for the contradictory research results that have been previously published. They also gave new insights into the relationships between prion stability, structure, and seeded conformational changes, which will aid in understanding prion infectivity (abskharon et al., scientific reports 6:38877). Another study found that prion protein expression in gastric cancer was significantly less frequent than in noncancerous gastric tissue and was associated with tnm stage, survival status, and survival time. Patients at higher tnm stages had significantly lower expression of prion protein in their tumors (tang et al., journal of cancer 7(8): 984-990). In a separate project on parkinson's disease, the lab found that hydroxytyrosol (ht), a major component of olive oil, protected dopaminergic sh-sy5y cells against dopamine-induced cell death. It also efficiently induced expression of detoxifying enzymes such as nad(p)h quinone oxidoreductase 1, which contributed to the protective effect against cell death. This result supports the beneficial effect of olive oil on dopaminergic neurons (yu, et al., neurochemistry international 96: 113-120). The question of whether parkinson's disease spreads in a prion like manner was addressed in 2016 in two reviews. One review focused on the possible mechanisms by which alpha-synuclein misfolding might propagate throughout the brain via a prion-like spreading (tyson et al., journal of neurochemistry 139(s1): 275-289). A second review describes evidence of alpha-synuclein's disease-propagating properties. The finding that alpha-synuclein pathology can spread between brain regions in neurodegenerative disease has expanded our thinking about new diagnostic tools and therapies that may benefit patients suffering from parkinson's disease (brundin et al., current opinion in neurology 29(4): 459-466). The coetzee laboratory assessed genetic risk for parkinson's disease in 77 cell types. The findings showed risk loci unexpectedly present in non-neuronal cell types including lymphocytes, mesendoderm, liver cells, and fat cells, indicating that cell types outside the brain are involved in the genetic predisposition to parkinson's disease (coetzee et al., scientific reports 6: 30509). Another study involving the laboratory of patrik brundin identified genetic loci that linked susceptibility to parkinson's-like neurodegenerative changes to the loss of one allele of the en1 gene. These loci should be of prime interest for studies of parkinson's-like damage in rodent models and in clinical association studies of parkinson's disease (kurowska et al., scientific reports 6: 31701). A study found that alpha-synuclein fibrils injected into the olfactory bulb of mice recruited endogenous alpha-synuclein into aggregates that subsequently spread through the olfactory network and then to distant brain regions. The spre”

“Fundraising expenses at vari were incurred to support the mission of the research institute through donor solicitation, grant solicitation and extramural proposal preparation.”

“Vari net assets are considered on a consolidated basis with van andel institute (vai), van andel education institute (vaei), and related parties. On a consolidated basis, net assets are $1,417,500,000 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.”