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2015 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report 2015 Research Interests The DeVos Cardiovascular Research Program is a joint effort between VARI and Spectrum Health. The basic science lab is the Laboratory of Cardiovascular Research at VARI, and a corresponding clinical research unit resides within the Fred Meijer Heart and Vascular Institute. Cardiovascular diseases are among the major causes of death and disability worldwide. While the incidence of ischemic heart diseases has started to decline, congestive heart failure is still rising. Medical treatment is supportive, and the only available replacement therapy is heart transplantation. The regeneration of myocardium after disease or damage is one of the major challenges in medicine. The Jovinge group is working on true heart muscle regeneration along three axes. The most robust source for generating heart muscle cells has been pluripotent stem cells, either from an embryonic stem cell (ESC) system or from reprogrammed pluripotent stem cells (iPSCs). The main drawback to this approach is that all germ layers are generated from the heterogeneous cell population and therefore hold the potential to create tumors. ESCs represent an external source, with the need for lifelong immunosuppressive treatment. iPSCs, however, could be generated from the patient’s own cells. To be able to use these sources, we have developed strategies, like those for bone-marrow cells, to help select homogenous and safe populations to transplant. Although adult human heart muscle cells are to a small extent generated after birth, the internal source for this generation is still unknown. Some data indicate that cardiac progenitors could be involved, and other data suggest that differentiated heart muscle cells might be the source. We have shown that the generation of heart muscle cells is greatly impaired at the time when those cells start to become bi-nucleate. Recent data indicate that in the neonatal phase, when murine heart muscle cells are mono-nucleate, they have a complete regenerative capacity that relies on generation of new heart muscle cells from mature cells. We and our collaborators have rejected the view that adult heart muscle cells are not capable of undergoing a complete cell division. With the use of 14 C dating, the adult heart has been shown to have a regenerative capacity. This has opened a completely new field of induced local generation of heart muscle cells, which is now being explored. Our program’s eventual aims are clinical concept studies of heart muscle cell regeneration in patients, either by cell transplantation or stimulation of endogenous sources. The program’s clinical side involves a multistep process to prepare for these studies. We have been studying the inflammatory response to myocardial infarction and the possibility of new biological anti-inflammatory regimens in order to develop options for enhancing cell endogenous and exogenous survival in myocardial infarction. We have used unique magnetic resonance sequences to identify the threatened ischemic volume of the heart. Indirectly we then can estimate the “hostility” of the local environment: the higher the proportion of threatened volume that actually infarcts, the more hostile the environment. New biological compounds that modify the inflammatory response will be studied to optimize the environment for cell transplantation. Patients with the most severe heart disease, i.e., those needing mechanical support, are being studied to optimize treatments that will be used in later safety studies. Because the studies will enroll fewer than 200 patients, end points other than mortality and myocardial infarction will be identified. These will be based mainly on biomarkers and various imaging technologies. The final phase of patient studies will involve the administration of cells or compounds to stimulate endogenous regeneration. To prepare cells for transplantation into humans, an accredited Good Manufacturing Practice facility will be established, and the first safety studies (Phase II) will be followed by studies evaluating the best route for delivering the treatment and the best timing. In the final stage, randomized prospective clinical trials will be launched. 50

Peter W. Laird, Ph.D. Laboratory of Cancer Epigenetics Dr. Laird earned his B.S. and M.S. from the University of Leiden and his Ph.D. in 1988 from the University of Amsterdam with Piet Borst. He received postdoctoral training from Anton Berns at the Netherlands Cancer Institute and from Rudolf Jaenisch at the Whitehead Institute for Biomedical Research. Dr. Laird was a faculty member at the University of Southern California from 1996 to 2014, where he served as professor of surgery, biochemistry and molecular biology; as Skirball-Kenis Professor of Cancer Research; as a program leader in epigenetics and regulation for the Norris Comprehensive Cancer Center; and as director of the USC Epigenome Center. He joined VARI as a Professor in September 2014. Research Interests Our goal is to develop a detailed understanding of the molecular basis of human disease, with a particular emphasis on the role of epigenetics in cancer. Cancer is often considered to have a primarily genetic basis, with contributions from germline variations in risk and somatically acquired mutations, rearrangements, and copy number alterations. However, it is clear that nongenetic mechanisms can exert a powerful influence on cellular phenotype, as evidenced by the marked diversity of cell types within our bodies, which virtually all contain an identical genetic code. This differential gene expression is controlled by tissue-specific transcription factors and variations in chromatin packaging and modification, which can provide stable phenotypic states governed by epigenetic, not genetic, mechanisms. It seems intrinsically likely that an opportunistic disease such as cancer would take advantage of such a potent mediator of cellular phenotype. Our laboratory is dedicated to understanding how epigenetic mechanisms contribute to the origins of cancer and how to translate this knowledge into more-effective cancer prevention, detection, treatment, and monitoring. One of the best understood epigenetic marks is the covalent modification of DNA as 5-methylcytosine in CpG dinucleotides. We use a multidisciplinary approach to understand the role of DNA methylation in cancer, relying on newly developing technology, mechanistic studies in model organisms and cell cultures, clinical and translational collaborations, genome-scale and bioinformatic analyses, and epidemiological studies. In recent years, we participated in the generation and analysis of high-dimensional epigenetic data sets, including the production of all epigenomic data for The Cancer Genome Atlas (TCGA), and the application of next-generation sequencing technology to single-base-pair-resolution, whole-genome DNA methylation analysis. We are leveraging this epigenomic data for translational applications and hypothesis testing in animal models. A major focus of our laboratory at VARI is to develop mouse models for investigating epigenetic mechanisms and drivers of cancer and to develop novel strategies for single-cell epigenomic analysis. Staff Kelly Foy, B.S. Toshinori Hinoue, Ph.D. KwangHo Lee, Ph.D. JinA Park, M.S. Zhouwei Zhang, M.S. 51

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