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Analysis of inhibition of HER2 signaling to apoptotic transcription factors Marc Fink & Yan Liu & Shangying Wang Student Project Proposal Computational Cell Biology 2012 Goals - Modeling the signaling pathway of HER2 inhibitor, Lapatinib, in Breast Cancer Cells - Analyze the influence factors of cell apoptosis - Explanation of cell survival rate after treatment Outline Brief review Boolean network model and results Modeling with ODEs in VCell and COPASI Analysis of simulation results Summary and outlook Mechanistic (process) diagrams HER2 Lapatinib Death ?????? PI3K Survival PDK1 p AKT (PKB) Protein p Translation ER FoxO p FoxO p 14-3-3 Translocation Translocation FoxO FoxO Transcription Apoptotic genes Apoptosis FoxO FoxO Survival genes 01/13 Flow chart and strategies HER2 Lapatinib IGF1R Lack of experimental parameters AKT RAF => Boolean network MEK Better understanding of FoxO dynamics => ODEs ERK FASL Analysis of survival rate => Stochastic simulation RSK BIM BAD apoptosis 02/13 Boolean network model HER2 Lapatinib IGF1R AKT Apoptosis FoxO Time steps BIM => Average value of apoptosis is around 0.5 with apoptosis simplification. 03/13 Boolean network model HER2 Lapatinib IGF1R AKT Apoptosis FoxO FASL Time steps BIM => Average apoptosis is around 0.6 with additional apoptosis information. 03/13 Boolean network model HER2 Lapatinib IGF1R RAF AKT Apoptosis MEK FoxO ERK FASL RSK Time steps BIM => Results depend on the BAD complexity, adding weights apoptosis not possible. 03/13 Modeling with ODEs => 22 species and 32 reactions, reasonable rates???!!! 04/13 Model reduction and modification Due to the importance of FOXO => Neglect the downstream and add the self regulation 05/13 Model reduction and modification HER2 Lapatinib IGF1R AKT RAF MEK FoxO ERK FASL RSK BIM BAD apoptosis 05/13 Model reduction and modification Due to the importance of FOXO => Neglect the downstream and add the self regulation HER2 Lapatinib HER2_dimer HER2_dimer* PI3K AKT H_PI3K FoxO PIP3 PIP2 Apoptosis AKT AKT* Φ Φ FoxO_gene FoxO_mRNA (x) FoxO (y) FoxO* (z) Model reduction and modification Due to the importance of FOXO => Neglect the downstream and add the self regulation HER2 Lapatinib [Birtwistle et al., 2007] HER2_dimer HER2_dimer* PI3K AKT H_PI3K FoxO PIP3 PIP2 Apoptosis AKT AKT* Φ Φ FoxO_gene FoxO_mRNA (x) FoxO (y) FoxO* (z) Self regulation of FOXO Φ Φ FoxO_gene FoxO_mRNA (x) FoxO (y) FoxO* (z) => Bistability of the positive feedback loop 06/13 Modified model => 14 species and 16 reactions 07/13 Sensitivity analysis in COPASI Binding of Laptinib to HER2 Dimerization of HER2 FOXO => Laptinib is important for cancer cell apoptosis 08/13 Analysis of simulation results Deterministic simulations with parameter scan (Laptinib) FOXO concentration With increasing initial Laptinib concentration 0 -> 400 nM 09/13 Analysis of simulation results Deterministic simulations with parameter scan (Laptinib) Phosphorylation => Laptinib is able to stimulate FOXO, crucial to apoptosis 09/13 Analysis of simulation results Random initial concentrations and constant Laptinib (200nM) FOXO concentration => Initial concentrations influence the effect of Laptinib. 10/13 Analysis of simulation results Stochastic simulation using Gillespie algorithm (in VCell & C) High Laptinib Low Laptinib 11/13 Summary and outlook Inhibition of HER2 signaling to apoptotic transcription factors is studied. Models with different complexities are analyzed. Laptinib induced inhibition of HER2 is simulated. Outlook Improve the stochastic study Improve the pathway model with more details by getting more rates from experiments Measurement of concentrations within small time scale before and after treatment will help to understand the whole signaling process and validate the model. 12/13 Experience with the softwares COPASI vs VCell Writing reactions + +++ Checking parameters + +++ Deterministic simulation +++ + Stochastic simulation ++ + Parameter scan +++ ++ Sensitivity analysis +++ - Visualization - +++ 13/13 Happy Birthday to Nina!
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