2009 Scientific Report

Van Andel Research Institute | Scientific Report
Research Interests
The Division of Quantitative Sciences includes the laboratories of Analytical, Cellular, and Molecular Microscopy (ACMM),
Microarray Technology, Computational Biology, Molecular Epidemiology, and Mass Spectrometry and Proteomics. The Division’s
laboratories use objective measures to define pathophysiologic events and processes.
The ACMM laboratory prepares samples by either paraffin or frozen methods and 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 they enable researchers to determine where in a cell particular molecules
are located. An archive of pathology tissues in paraffin blocks (Van Andel Tissue Repository, or VATR) is being accumulated
with the cooperation of local hospitals. The archive currently has approximately 250,000 paraffin blocks representing 150,000
cases. In collaboration with Tom Barney from VAI-IT, clinical data is being added into VATR for hundreds of the samples each
week by digital parsing of pathology report texts sent electronically from the hospital files. VATR is used to track samples
coming from the hospitals, along with all of the data and images generated from research. Images from the Aperio ScanScope
are automatically imported into VATR and associated with the appropriate sample. The ACMM 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 arrays, miRNA arrays, and array CGH using the Agilent
microarray platform and cDNA platform capability. Samples can be prepared from a variety of species. Genomic DNA or total
RNA from a wide range of tissues including blood and fresh or frozen tissues have been analyzed. A recent gene expression
discovery was made using archived newborn blood spots, in collaboration with Dr. Nigel Paneth at MSU. We showed that
thousands of gene signatures can be obtained using low-resolution gene expression arrays, enabling clinical research into
the origins, epidemiology, and diagnosis of human pediatric diseases. Feature extraction software reads and processes the
raw microarray image files in an automated mode. Application-specific QC reports summarize the results and provide an
accurate quality assessment. The output files are compatible with statistical analysis packages such as R and GeneSpring.
Microarray technology plays an important part in the discovery of genetic signatures, copy number variations, and biomarkers
for therapeutic purposes.
Hauenstein Parkinson’s Center
Throughout 2008 we continued our collaboration with the Hauenstein Parkinson’s Center, collecting blood samples and control
samples from 216 individuals. Mutations/polymorphisms in the NR4A2 gene are being studied by DNA sequence analysis,
motivated by our previous identification of this gene in a genomic screen for neuroprotective factors. We are particularly
interested in polymorphisms in the DNA-binding domain of NR4A2, as changes to this region of the gene are most likely to
affect its function.
Identification of novel Parkinson-modifying genes with siRNA screening
Small interfering RNA (siRNA) technology allows the specific knockdown of any mRNA/protein pair. Under the direction of
VARI’s Jeff MacKeigan, postdoctoral fellow Brendan Looyenga has begun to use a subset of the siRNA library developed by
Qiagen to individually target several classes of enzymes having pharmaceutical potential. Specifically, we are continuing a
project to identify molecules that attenuate oxidative stress–induced toxicity in dopaminergic neurons; our initial focus is on
phosphatases and kinases. We are validating the initial screening studies and we hope to extend these studies to include
nuclear hormone receptors and G protein–coupled receptors.
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