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Modeling and Simulation of Signal Transduction Pathways Mark Moeller & Björn Oleson Supervisors: Klaus Prank Ralf Hofestädt Content • Signal Transduction • Modeling and Simulation • Project Signal Transduction is … Biochemical Information Network Transportation Amplification of Information Distribution from Cell to Cell and within Cells Signal transduction pathways • receptor protein (cell surface) transduces • extracellular signal into • intracellular signal initiating –signaling cascade • relaying • amplifying • distributing RELAY AMPLIFICATION DIVERGENCE TO MULTIPLE TARGETS REGULATION CHANGES INOF CYTOSKELETON METHABOLIC GENE EXPRESSION PATHWAY Phosphoinositol Pathway as an Example Phosphoinositol Pathway Ligand Cell Membrane Receptor PLC GDP P P PIP2 P G-Protein GTP P KC Endoplasmic Reticulum Ca2+-Channel-Protein Ca2+ Phosphoinositol Pathway PLC GDP P P P GTP P KC Phosphoinositol Pathway GTP PLC P P P P KC Phosphoinositol Pathway PLC GTP G DP P P DAG P IP3 P KC Phosphoinositol Pathway PLC GDP P KC P P P Phosphoinositol Pathway PLC P KC GDP P P P Complex ? Phosphoinositol Pathway Apoptosis and Growth Network Ca2+ IP3 PIP2 PLC PI3-K Sphingomyeline PC PA DAG PLD PKC- Sphingomyelinase Ceramide CAPP PIP3 PIP2 PI3-K PIP3 PKC- Proteinkinase PKC- PKC- Caspase PKC- Bcl-2 Apoptosis Growth NF-B Pathway Modeling Pathway Cartoons Translated into Differential Equations Parameters Estimated from Measured Data This allows for: • a Quantitative Descrition of Pathways • Testing the Model • Gaining Insight into the Biochemical Principles • Observing Experimentally Unobservable Components • Prediction of new Experiments (in silico Biology) • Identification of Possible Drug Targets Deterministic Model vs. Monte Carlo Modeling Deterministic Approach • Differential Equations – Reaction Rates – Concentrations • Continuous Macroscopic Stochastic Approach • Monte Carlo Simulation – – – – – Reaction Probabilities Molecule Numbers Subcellular Structures Limited Diffusion Cellular Geometry • Discrete Microscopic Existing approaches • Simulators – – – – – – – – MCell StochSim Copasi Gepasi Virtual Cell E-Cell GENESIS NEURON • Companies – Physiome Sciences – Entelos – Cellomics • Databases – – – – TRANSPATH TRANSFAC BIND DIP What I am going to do … molecule database Project biochemical model image data mathematical model other Monte Carlo simulator output visualization pathway database database So, my work includes … 1. Establish Simulator 2. Run Phosphoinositol Pathway 3. Visualize Output 4. Develop Scripting Language 5. Specify Interfaces to Automatization 6. Specify Relational Database Thank you ! Useful in silico Prediction of Signaling Pathways and Networks • Knowledge of all Players • Kinetic Properties, Interaction Partners • Mechanisms of Positive and Negative Regulation • Subcellular Localizations and Concentrations • Incorporation of Kinetic and Particularly Spatial Aspects of Signaling into Models