2. Modeling and Simulation of Signal Transduction Pathways Mark Moeller & Björn Oleson Supervisors: Klaus Prank Ralf Hofestädt

3. Content Signal Transduction Modeling and Simulation Project

4. Biochemical Information Network Transportation Amplification Distribution of Information from Cell to Cell and within Cells Signal Transduction is …

5. REGULATION OF GENE EXPRESSION Signal transduction pathways receptor protein (cell surface) RELAY AMPLIFICATION DIVERGENCE TO MULTIPLE TARGETS REGULATION OF METHABOLIC PATHWAY CHANGES IN CYTOSKELETON transduces extracellular signal into intracellular signal –signaling cascade relaying amplifying distributing initiating

6. Phosphoinositol Pathway as an Example

7. Phosphoinositol Pathway Ligand Receptor G-Protein PIP 2 Ca 2+ -Channel-Protein Ca 2+ Cell Membrane Endoplasmic Reticulum

8. Phosphoinositol Pathway

10. DAG IP 3

11. Phosphoinositol Pathway

13. Complex ?

14. Apoptosis and Growth Network Ca 2+ IP 3 PIP 2 PLC DAG PKC-  PI3-K PIP 3 PKC-  Sphingomyeline Sphingomyelinase Ceramide Proteinkinase Caspase PKC-  Apoptosis Growth PIP 2 PI3-K PIP 3 PKC-  NF-  B PC PA PLD PKC-  CAPP Bcl-2 Phosphoinositol Pathway

15. 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

16. Deterministic Model vs. Monte Carlo Modeling Deterministic Approach Differential Equations –Reaction Rates –Concentrations Stochastic Approach Monte Carlo Simulation –Reaction Probabilities –Molecule Numbers –Subcellular Structures –Limited Diffusion –Cellular Geometry Discrete Continuous MacroscopicMicroscopic

17. Existing approaches Simulators –MCell –StochSim –Copasi –Gepasi –Virtual Cell –E-Cell –GENESIS –NEURON Companies –Physiome Sciences –Entelos –Cellomics Databases –TRANSPATH –TRANSFAC –BIND –DIP

18. What I am going to do …

19. other Project Monte Carlo simulator mathematical model output biochemical model molecule database pathway database image data visualization

20. 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

21. Thank you !

22. 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