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- Title
Novel pathway compendium analysis elucidates mechanism of pro-angiogenic synthetic small molecule.
- Authors
Kristen A. Wieghaus; Erwin P. Gianchandani; Mikell A. Paige; Milton L. Brown; Edward A. Botchwey; Jason A. Papin
- 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 micro-vascular endothelial cells (HMVEC) to comprehensively interrogate PNF1 effects. We concluded that PNF1 first induces tumor necrosis factor-alpha (TNF-α) 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-β signaling at 24 h, including differential regulation of TGF-β-induced matrix metalloproteinase 14 (MMP14/MT1-MMP) which is implicated in angiogenesis. 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 are available in the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/). Contact: botchwey@virginia.edu; papin@virginia.edu Supplementary information: Supplementary data are available at Bioinformatics online.
- Subjects
VASCULAR endothelial growth factors; TUMOR necrosis factors; MOLECULES; GENE expression
- Publication
Bioinformatics, 2008, Vol 24, Issue 20, p2384
- ISSN
1367-4803
- Publication type
Article
- DOI
10.1093/bioinformatics/btn451