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Pathway analysis of dilated cardiomyopathy using global proteomic profiling and enrichment maps

Authors

  • Ruth Isserlin,

    1. Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, Canada
    2. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
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  • Daniele Merico,

    1. Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, Canada
    2. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
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  • Rasoul Alikhani-Koupaei,

    1. Department of Physiology, University of Toronto, Toronto, ON, Canada
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  • Anthony Gramolini,

    1. Department of Physiology, University of Toronto, Toronto, ON, Canada
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  • Gary D. Bader,

    1. Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, Canada
    2. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
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  • Andrew Emili

    Corresponding author
    1. Banting and Best Department of Medical Research, University of Toronto, Toronto, ON, Canada
    2. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
    • Donnelly Centre for Cellular and Biomedical Research, 160 College St. Toronto, ON, M5S 3E1 Canada Fax: +1-416-978-8287
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Abstract

Global protein expression profiling can potentially uncover perturbations associated with common forms of heart disease. We have used shotgun MS/MS to monitor the state of biological systems in cardiac tissue correlating with disease onset, cardiac insufficiency and progression to heart failure in a time-course mouse model of dilated cardiomyopathy. However, interpreting the functional significance of the hundreds of differentially expressed proteins has been challenging. Here, we utilize improved enrichment statistical methods and an extensive collection of functionally related gene sets, gaining a more comprehensive understanding of the progressive alterations associated with functional decline in dilated cardiomyopathy. We visualize the enrichment results as an Enrichment Map, where significant gene sets are grouped based on annotation similarity. This approach vastly simplifies the interpretation of the large number of enriched gene sets found. For pathways of specific interest, such as Apoptosis and the MAPK (mitogen-activated protein kinase) cascade, we performed a more detailed analysis of the underlying signaling network, including experimental validation of expression patterns.

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