Van Andel Research Institute

“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.”

“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 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.”

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

“Gain on interest rate swap 11,609,586.”

“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.”

“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 l”

“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”

“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 a”

“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)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.”