Motivation

1. Motivation • Apoptosis is a highly regulated and evolutionary conserved pathway of cell death that plays a critical role in development and maintenance of tissue homeostasis. Formal description of pro- and anti-apoptotic machinery has been enriched significantly in recent years, and a range of mathematical models has been created. But mainly they describe different segments of implicated pathways, and the total model of apoptosis regulation has not been developed yet. • Goals • Development ofthe comprehensive map of pro- and anti-apoptotic pathways for in silico experiments based on the existing mathematical models and information from databases on biological pathways. • Dividing a model into modules to simplify its analysis and processing. • Multi-experimentparametersfittingoftheseparatedmodules. • Simulation andanalysisofthewholemodel. • Methods • The BioUMLplatform was used for the composite model (fig. 1) and individual modules (fig. 2) creation. • All modules were presented in the SBML format with the SBGN notation. • Existing mathematical models were found in the literature and Biomodels database. • Reactom and Transpath databases were used as a source of additional reactions. • BioUML optimization plug-in was developed for the model parameters estimation. • Results • Integrated model of apoptosis includes: • 13 functional modules: • modules resulting activation of caspase-8 by the death stimuli (TRAIL, CD95L, TNF-a); • modules concern of the survival stimuli (p53, EGF, NF-kB); • Mitochondrion level; • modules related to the activation of caspase-3 under the influence of cytochrome C and SMAC; • direct activation of executioner caspases by caspase-8 (type I cells) and caspase-12; • PARP-1 and apoptosis execution phase modules. • 5 different compartments: Nucleus, Cytoplasm, Mitochondria, Extracellular space and Endosomal volume. • 286 species: • proteins and their complexes; • proteins modifications such as different form of the same molecule (e.g. caspases and procaspases); • proteins transformations (e.g. phosphorylation). • 684 reactions including 607 parameters: • Mass action kinetics; • Michaelis-Menten kinetics. • Acknowledgments • Part of this work was partially supported by European Committee grants №037590 “Net2Drug” and №202272 “LipidomicNet”. • References • M. Bentele, et al.The Journal of Cell Biology,2004, 166(6):839-851. • L. Neumann, et al.Molecular Systems Biology, 2010, 6(352). • C. Scaffidi, et al. The EMBO Journal, 1998, 17(6):1675–1687. • Hua F, et al.The Journal of Immunology, 2005, 175:985-995. Modular Approach To Modeling Of The Apoptosis MachineryE. O. Kutumova1,2,*, R. N. Sharipov1,3,2, F. A. Kolpakov1,21Institute of Systems Biology, Novosibirsk, Russia; 2Design Technological Institute of Digital Techniques SB RAS, Novosibirsk, Russia; 3Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia;*Contacts: e.o.kutumova@gmail.com Figure 1. The integrated apoptosis model overview Bentele M et al., 2004 Neumann L et al., 2010 Scaffidi C et al., 1998 Hua F et al., 2005 Figure 2. CD95 module constructed based on the model of M. Benteleet al. [1] and results of its fitting to experimental datasets [1-4] simultaneously.