NR AWIU
AU Lee,I.; Hwang,D.; Yoo,H.; Baxter,D.; Gehlenborg,N.; Giri,R.K.; Kumar,R.; Ogata,B.; Orr,M.; Pitstick,R.; Spicer,D.; Young,R.; DeArmond,S.J.; Hood,L.E.; Carlson,G.A.
TI Systems biology approach to prion disease pathogenesis
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Oral sessions ORAL-40
PT Konferenz-Vortrag
AB A systems view of disease attempts to understand disease initiation and progression in terms of specific perturbations and their dynamic transitions. The unusual nature of prion disease and the variety of strains and pathologies prompted exploration of a systems approach to identify networks perturbed by infection and to determine which perturbations are essential for various aspects of pathogenesis. Using the Affymetrix GeneChip mouse array 430 2.0, we tracked changes in gene expression for two prion strains (RML and 301V) and five lines of mice over their entire incubation periods; PrP null mice also were inoculated. Differentially expressed genes (DEGs) with consistent temporal patterns across multiple mouse-prion groups were considered likely to be associated with fundamental prion disease processes. However, the goal of this study was not to compile a list of DEGs, but rather to integrate multiple types of data to provide a new perspective on disease for hypothesis building and testing. Array data were used in conjunction with gene ontology, protein interaction and gene regulatory databases to construct hypothetical pathways and gene regulatory networks associated with major pathological events, including glial activation, synaptic degeneration, cell death, and protein degradation. These pathways were integrated with temporal changes in regional PrPsc distribution, pathology, and regional gene expression among the different host-agent combinations. The mismatch between rate of PrPsc accumulation and disease onset and differences in DEGs in specific combinations were used to formulate and test hypotheses on the involvement of specific pathways in disease. For example, lack of changes in a pathway involved in generation of reactive oxygen species (ROS) in transgenic mice with short incubation times suggested that ROS might not be an essential component of neurological dysfunction. In accord with this prediction, overexpression of SOD1, shown to be effective in our Alzheimer's disease models, had no effect on prion incubation time. Data and analysis tools are available on the internet in our searchable Prion Disease Database.
AD I. Lee, D. Hwang, H. Yoo, D. Baxter, N. Gehlenborg, B. Ogata, L.E. Hood: Institute for Systems Biology, Seattle, Washington USA. E-mail: lhood@systemsbiology.org; R.K. Giri, R. Kumar, M. Orr, R. Pitstick, D. Spicer, R. Young, G.A. Carlson: McLaughlin Research Institute, Great Falls, Montana, USA. E-mail: gac@po.mri.montana.edu; S.J. DeArmond: Department of Pathology, University of California, San Francisco, California, USA. E-mail: stephen.dearmond@ucsf.edu
SP englisch
PO Italien