NR AXRA
AU Lee,I.; Hwang,D.; Yoo,H.; Baxter,D.; Gehlenborg,N.; Price,N.; Ogata,B.; Pitstick,R.; Spicer,D.; Young,R.; Hohmann,J.; DeArmond,S.; Carlson,G.; Hood,L.
TI Prion Disease Database: An On-line Systems Biology Resource for Hypothesis Building and Testing
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Pathology and Pathogenesis P03.114
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB
Systems approaches to disease have two cardinal features: 1) global analyses to generate comprehensive data sets (e.g., changes levels of mRNAs or proteins) and 2) the integration of different levels of biological information (DNA, mRNA, protein, interactions, networks, tissues, and organism) to generate coherent hypotheses about fundamental principles of disease. We integrated multiple layers of data to build hypothetical protein network models describing fundamental processes in prion infection. Changes in global gene expression in the brain were tracked in 8 different prion-host combinations involving two prion strains and six lines of mice that exhibited different prion disease phenotypes. Using a novel statistical method, we identified differentially expressed genes (DEGs) showing consistent temporal patterns that were shared by the five mouse-prion combinations that expressed PrP from both copies of their endogenous Prnp gene. Hypothetical protein networks based on the shared DEGs then were constructed using known protein interactions, temporal gene expression patterns, and pathological changes in prion disease. The hypothetical protein networks and pathways were then integrated or tested with cell-type and brain region specific gene expression information available in the Allen Brain Atlas and other databases to discriminate processes occurring in neurons, astrocytes, and microglia with clinical signs, pathological changes, and regional deposition of proteinase Kresistant PrPsc as the disease progresses. Networks were tested for involvement in specific pathogenic processes by comparison with temporal DEG profiles from transgenic mice overexpressing PrP and gene-targeted mice expressing lower levels of PrP and by grouping prion-host combinations according to incubation time or prion strain. We have developed a database and web interface as a repository for data collected in this project. The PDDB provides access to the roughly 20 million data points in our transcriptomic time-course. Subsets of genes from each of the 8 prionhost combinations can be extracted and visualized along with time-course and endpoint histoblots. The PDDB also presents our hypothetical networks and provides access to the tools and methods that we used to build them.
Supported by National Prion Research Program of the US Dept of Defense and by USPHS grant NS041997.
AD I. Lee, D. Hwang, H. Yoo, D. Baxter, N. Gehlenborg, N. Price, B. Ogata, L. Hood, Institute for Systems Biology, USA; R. Pitstick, D. Spicer, R. Young, G. Carlson, McLaughlin Research Institute, USA; J. Hohmann, Allen Brain Institute, USA; S. DeArmond, University of California, Department of Pathology, USA
SP englisch
PO Schottland