1. This project was performed in close collaboration with Dr. Kohn at the Developmental Therapeutics Branch and consists of two lines of study. First, we have developed and released several tools for creating and editing MIM diagrams (Luna, Karac et al. 2011; Luna, Sunshine et al. 2011; Chandan et al., 2012). These tools should make it easier for developers to build MIM-related software, users to create and edit MIM diagrams, and also, help bridge differences between features found in MIM and related notations, such as the BioPAX exchange standard (Demir et al., 2010) and the systems biology graphical notation (SBGN) that is developed by an international consortium with our participation (Le Novere, Hucka et al. 2009; van Iersel et al., 2012). Second, we use MIMs as a basis for mathematical modeling of cellular regulatory networks in an effort to shed light on basic feedback mechanisms that modulate cell proliferation. The first network we have investigated describes the regulation of tumor suppressor p53 by Mdm2 and MdmX in response to DNA damage (Kim, Aladjem et al. 2010). In a separate line of study we have created an extended computational model of a mammalian circadian clock centered on the the nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase SIRT1 (Luna, Aladjem and Kohn, 2013). Development and analysis of this model will provide insights into the regulation of circadian rhythms and the potential role of SIRT1 in cancer biology. We have now published the results of this simulation analysis (PLoS Computational Biology, 11(5):e1004144. 2015) proposing a possible mechanism through which multiple perturbations, each dominant during different points of the circadian cycle, may result in the phase advancement of the circadian clock seen during DNA damage.
| Luna, Augustin; McFadden, Geoffrey B; Aladjem, Mirit I et al. (2015) Predicted Role of NAD Utilization in the Control of Circadian Rhythms during DNA Damage Response. PLoS Comput Biol 11:e1004144 |
| Fried, Jake Y; van Iersel, Martijn P; Aladjem, Mirit I et al. (2013) PathVisio-Faceted Search: an exploration tool for multi-dimensional navigation of large pathways. Bioinformatics 29:1465-6 |
| Chandan, Kumar; van Iersel, Martijn P; Aladjem, Mirit I et al. (2012) PathVisio-Validator: a rule-based validation plugin for graphical pathway notations. Bioinformatics 28:889-90 |
| van Iersel, Martijn P; Villeger, Alice C; Czauderna, Tobias et al. (2012) Software support for SBGN maps: SBGN-ML and LibSBGN. Bioinformatics 28:2016-21 |
| Luna, Augustin; Karac, Evrim I; Sunshine, Margot et al. (2011) A formal MIM specification and tools for the common exchange of MIM diagrams: an XML-Based format, an API, and a validation method. BMC Bioinformatics 12:167 |
| Luna, Augustin; Sunshine, Margot L; van Iersel, Martijn P et al. (2011) PathVisio-MIM: PathVisio plugin for creating and editing Molecular Interaction Maps (MIMs). Bioinformatics 27:2165-6 |
| Kim, Sohyoung; Aladjem, Mirit I; McFadden, Geoffrey B et al. (2010) Predicted functions of MdmX in fine-tuning the response of p53 to DNA damage. PLoS Comput Biol 6:e1000665 |
| Le Novère, Nicolas; Hucka, Michael; Mi, Huaiyu et al. (2009) The Systems Biology Graphical Notation. Nat Biotechnol 27:735-41 |
| Kohn, Kurt W; Aladjem, Mirit I; Weinstein, John N et al. (2009) Network architecture of signaling from uncoupled helicase-polymerase to cell cycle checkpoints and trans-lesion DNA synthesis. Cell Cycle 8:2281-99 |
| Kohn, Kurt W; Aladjem, Mirit I; Weinstein, John N et al. (2008) Chromatin challenges during DNA replication: a systems representation. Mol Biol Cell 19:1-7 |
