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Bioinformatics Advance Access published online on August 21, 2008
Bioinformatics, doi:10.1093/bioinformatics/btn451
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© The Author (2008). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Novel Pathway Compendium Analysis Elucidates Mechanism of Pro-Angiogenic Synthetic Small Molecule

Kristen A. Wieghaus 1,#, Erwin P. Gianchandani 1,#, Mikell A. Paige 2, Milton L. Brown 2, Edward A. Botchwey 1,3,* and Jason A. Papin 1,4,*

1Department of Biomedical Engineering, University of Virginia, Box 800759, Charlottesville, VA 22908
2Lombardi Comprehensive Cancer Center, Georgetown University, New Research Building, EP 07, 3907 Reservoir Road, Washington, DC 20057
3Department of Orthopaedic Surgery, University of Virginia, Box 800759, Charlottesville, VA 22908
4Cardiovascular Research Center, University of Virginia, Box 800759, Charlottesville, VA 22908

*To whom correspondence should be addressed. Edward A. Botchwey, Jason A. Papin, E-mail: botchwey{at}virginia.edu, papin{at}virginia.edu


  Abstract

Motivation: Computational techniques have been applied to experimental datasets to identify drug mode-of-action. A shortcoming of existing approaches is the requirement of large reference databases of compound expression profiles. Here we developed a new pathway-based compendium analysis that couples multi-timepoint, controlled microarray data for a single compound with systems-based network analysis to elucidate drug mechanism more efficiently.

Results: We applied this approach to a transcriptional regulatory footprint of phthalimide neovascular factor 1 (PNF1)—a novel synthetic small molecule that exhibits significant in vitro endothelial potency—spanning 1-48 h post-supplementation in human microvascular endothelial cells (HMVEC) to comprehensively interrogate PNF1 effects. We concluded that PNF1 first induces tumor necrosis factor-alpha (TNF-{alpha}) signaling pathway function which in turn affects transforming growth factor-beta (TGF-β) signaling. These results are consistent with our previous observations of PNF1-directed TGF- ββ signaling at 24 h (Wieghaus, et al., 2007), including differential regulation of TGF-ββ-induced matrix metalloproteinase 14 (MMP14/MT1-MMP) which is implicated in angiogenesis (Wieghaus, et al., 2008a). Ultimately, we illustrate how our pathway-based compendium analysis more efficiently generates hypotheses for compound mechanism than existing techniques.

Availability: The microarray data generated as part of this study will be deposited into the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) (Wieghaus, et al., 2008a).

Contact: botchwey{at}virginia.edu; papin{at}virginia.edu

Supplementary information: Supplementary data are available at Bioinformatics online.

Associate Editor: Prof. Alfonso Valencia

#These authors contributed equally to this work.

Received on May 27, 2008; revised on August 14, 2008; accepted on August 19, 2008

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