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2018 Scientific Report

  • Text
  • Institute
  • Biology
  • Methylation
  • Molecular
  • Mechanisms
  • Epigenetic
  • Michigan
  • Vari
  • Scientific

Center for Epigenetics

Center for Epigenetics STEFAN JOVINGE, M.D., Ph.D. Dr. Jovinge received his M.D. (1991) and his Ph.D. (1997) at Karolinska Institute in Stockholm. Since December 2013 he has been a Professor at VARI and the Medical Director of Research at the Frederik Meijer Heart and Vascular Institute. He also directs the DeVos Cardiovascular Research Program, is a Professor at the MSU College of Human Medicine, and is a Consulting Professor at Stanford University. RESEARCH INTERESTS The DeVos Cardiovascular Research Program is a joint effort between VARI and Spectrum Health. The basic science lab is the Jovinge laboratory at VARI, and a corresponding clinical research unit resides within the Fred Meijer Heart and Vascular Institute. STAFF Lucas Chan, Ph.D. Shelby Compton Paula Davidson, M.S. Lisa DeCamp, M.A., MB(ASCP), RLAT Ellen Ellis Emily Eugster, M.S. Joseph Faski, B.S. Jens Forsberg, Ph.D. Eric Kort, M.D. Olivia Licari Hsiao-Yun Yeh (Christy) Milliron, Ph.D. Matthew Weiland, M.S. To regenerate myocardium after disease or damage is one of the major challenges in medicine. We have shown that endogenous generation of heart muscle cells in humans is continuous throughout life. However, it declines rapidly with age and is far too insufficient to compensate for the large loss of muscle cells seen in most diseased hearts. Our preliminary data support the concept that preexisting cardiomyocytes are the source of this endogenous generation. We have now been able to isolate dividing cardiomyocytes based on their gene expression pattern. Thus, we are working our way toward control of the endogenous generation of cardiomyocytes and thereby toward the possibility of developing strategies to enable the heart to heal itself. “Rare diseases” affect fewer than 200,00 individuals in the USA; while each patient group is small, together rare diseases encompass some 30 million individuals. The generation of drugs for such small populations is very costly, so those who have such diseases are often left without specific treatment. With the use of the NIH database LINCS, which screens all FDA-approved drugs for off-target effects, we have identified a drug that specifically targets the deficiency in patients who have a rare mutation that causes a severe heart muscle disease. By reprogramming blood cells and deriving heart muscle cells from these patients, we have been able to verify the database predictions for the drug, thereby making possible the availability of new drugs for patients with this rare disease at a reasonable cost. Using a sophisticated technology, we have been able to reprogram and derive cardiac pacemaker cells. This year, we were able to use pacemaker cells to create a biological pacemaker in a culture dish. In another study, we have created a large database that allows us to optimize treatment for patients who have severe heart failure and are on mechanical support. We can also create advanced algorithms for predicting the outcome of support selection and for preventing complications. 24 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT

PETER W. LAIRD, Ph.D. Dr. Laird earned his Ph.D. in 1988 from the University of Amsterdam with Piet Borst. He was a faculty member at the University of Southern California from 1996 to 2014, where he was Skirball-Kenis Professor of Cancer Research and directed the USC Epigenome Center. He joined VARI as a Professor in September 2014. STAFF Kelly Foy, B.S. Walid Habib, Ph.D. Toshinori Hinoue, Ph.D. Manpreet Kalkat, Ph.D. Liang Kang, A.S. KwangHo Lee, Ph.D. Amy Nelson Wanding Zhou, Ph.D. STUDENTS Zack Jansen 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 likely that an intrinsically 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. We use a multidisciplinary approach in our research, relying on mechanistic studies in model organisms and cell cultures, clinical and translational collaborations, genome-scale and bioinformatic analyses, and epidemiological studies to advance our understanding of cancer epigenetics. 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 whole-genome DNA methylation analysis at single-base-pair resolution. We are leveraging this epigenomic data for translational applications and hypothesis testing in animal models. A major focus of our laboratory is to develop mouse models for investigating epigenetic mechanisms and drivers of cancer and to develop novel strategies for single-cell epigenomic analysis. Nicole Vander Schaaf, B.S. VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 25

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