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2008 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report James H. Resau, Ph.D. Division of Quantitative Sciences Laboratory of Analytical, Cellular, and Molecular Microscopy Laboratory of Microarray Technology Laboratory of Molecular Epidemiology Dr. Resau received his Ph.D. from the University of Maryland School of Medicine in 1985. He has been involved in clinical and basic science imaging and pathology-related research since 1972. Between 1968 and 1994, he was in the U.S. Army (active duty and reserve assignments) and served in Vietnam. From 1985 until 1992, Dr. Resau was a tenured faculty member at the University of Maryland School of Medicine, Department of Pathology. Dr. Resau was the Director of the Analytical, Cellular and Molecular Microscopy Laboratory in the Advanced BioScience Laboratories–Basic Research Program at the National Cancer Institute, Frederick Cancer Research and Development Center, Maryland, from 1992 to 1999. He joined VARI as a Special Program Senior Scientific Investigator in June 1999 and in 2003 was promoted to Deputy Director. In 2004, Dr. Resau assumed as well the direction of the Laboratory of Microarray Technology to consolidate the imaging and quantification of clinical samples in a CLIAtype research laboratory program. In 2005, Dr. Resau was made the Division Director of the quantitative laboratories (pathology-histology, microarray, proteomics, epidemiology, and bioinformatics), and in 2006 he was promoted to Distinguished Scientific Investigator. Staff Eric Kort, M.D. Brendan Looyenga, Ph.D. Bree Berghuis, B.S., HTL (ASCP), QIHC Eric Hudson, B.S. Angie Jason, B.S. Paul Norton, B.S. Ken Olinger, B.S. David Satterthwaite, B.S. Kristin VandenBeldt, B.S. JC Goolsby 42 Students Pete Haak, B.S. Heather Born Danielle Burgenske Janell Carruthers Halley Crissman Sara Herman Wei Luo Bryan Mendez Tarrick Mussa Sara Ramirez Aleesa Schlientz Huong Tran Yarong Yang Visiting Scientist Yair Andegeko

VARI | 2008 Research Interests The Division of Quantitative Sciences includes the laboratories of Analytical, Cellular, and Molecular Microscopy (ACMM), the Laboratory of Microarray Technology, the Laboratory of Computational Biology, the Laboratory of Molecular Epidemiology, and the Laboratory of Mass Spectrometry and Proteomics. The Division’s laboratories use objective measures to define pathophysiologic events and processes. The ACMM laboratory has programs in pathology, histology, and imaging to describe and visualize changes in cell, tissue, or organ structure. Our imaging instruments allow us to visualize cells and their components with striking clarity, and enable researchers to determine where in a cell specific molecules are located. An archive of pathology tissues in paraffin blocks (Van Andel Tissue Repository) is being accumulated with the cooperation of local hospitals, and the data on the samples is being converted to computerized files in collaboration with Tom Barney from VAI-IT. The lab also carries out research that will improve our ability to quantify images. We are able to image using either fluorescent (e.g., FITC, GFP) or chromatic agents (e.g., DAB, H&E) and separate the components using our confocal, Nuance, or Maestro instruments. The Laboratory of Microarray Technology provides gene expression analysis using Agilent commercially prepared arrays as well as “home-brewed” cDNA microarrays. In 2007 we produced and used 305 cDNA microarrays and 150 custom protein microarrays. We also used 107 Agilent arrays to genomically characterize a variety of tissues and samples, including archived human blood samples from newborns. Hauenstein Parkinson’s Center Throughout 2007 we continued our collaboration with the Hauenstein Parkinson’s Center, collecting blood samples and controls from 154 individuals. Mutations in the parkin gene in a set of families with more than one generation affected by Parkinson disease are being studied by DNA sequence analysis and will be correlated to gene expression data from microarray analysis. Identification of novel Parkinson-modifying genes with siRNA screening Small interfering RNA (siRNA) technology allows the specific knockdown of any mRNA/protein pair. Combined with information from the human genome, this technology has given rise to libraries of siRNAs targeted to every known or predicted gene in the genome. Under the direction of VARI’s Jeff MacKeigan, postdoctoral fellow Brendon Looyenga has begun to use a subset of the siRNA library developed by Qiagen to individually target several classes of enzymes having pharmaceutical potential. We are searching for genes involved in Parkinson disease that may be drug targets for rationally designed therapies. We are attempting to identify molecules that attenuate oxidative stress–induced toxicity in dopaminergic neurons; our initial focus is on phosphatases and kinases. To date we have screened all of the phosphatases in the human genome and have identified several potential candidates that regulate neuronal cell death in response to 6-hydroxydopamine, a toxic compound used to induce oxidative stress in Parkinson research. We are validating these initial screening studies and are planning the assays required to screen all kinases in the human genome as well. We hope to extend these studies to include nuclear hormone receptors and G protein–coupled receptors. Mouse models of Parkinson disease James Resau and Brendan Looyenga are generating novel rodent models of dopaminergic cell loss in the brain in collaboration with VARI’s Bart Williams. A key tool for these studies is the transgenic dopamine-transporter/cre (DAT-cre) mouse line, which specifically expresses the cre recombinase in dopaminergic neurons of the brain. The DAT-cre mice will allow us to address the response of such neurons to specific gene deletions and additions; projects based on the DAT-cre mouse model include the following. 43

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