Comparative modeling of signaling in thrombocytes - Modeling thrombocyte signaling
Activatory and inhibitory signalling cascades in the human thrombocyte were modelled (models and data bank) and validated by proteomics and functional experiments. The influence of further signaling cascades (Ca2+- and Mg2+-modulation) will now be studied and compared to murine thrombocytes and mutations. Including validation by experimental SFB groups we want to better understand activation and inhibition of the thrombozyte (Fig. 1; data from plateletweb databank http://plateletweb.bioapps.biozentrum.uni-wuerzburg.de/plateletweb.php). This leads to new tools and models (comparative thrombocyte databank, Ca2+ activating cascade, Mg2+ modulation) which will be available also beyond the SFB.
Fig. 1 Network around ITAM-GPVI-ADAM10. The complex regulation by phosphorylation (red arrows) is illustrated for this part of the activation cascade. Kinases (triangles) and protein substrates (circles) are either reported to be unphosphorylated (yellow), reported to be phosphorylated in some tissue (red) or it is even known that they are phosphorylated in the platelet (blue). For some of the phosphorylations we have even detailed information or will require this during our project. Each phosphorylation is the result of a molecular switching process. Network graphs as the one shown here provide a basis for our Boolean Modelling. They can be used for and analysed by semiquantitative modelling. Thus system states, feed-back loops, resulting platelet activation and inhibition as well as signal activation and relative strength can be determined (semi-quantiative model, Mischnik et al., 2013;2014).
Mischnik M, Gambaryan S, Subramanian H, Geiger J, Schütz C, Timmer J, Dandekar T. A comparative analysis of the bistability switch for platelet aggregation by logic ODE based dynamical modeling. Mol Biosyst. 2014 Jul 1;10(8):2082-2089.
PubMed PMID: 24852796.
Mischnik M, Boyanova D, Hubertus K, Geiger J, Philippi N, Dittrich M, Wangorsch G, Timmer J, Dandekar T. A Boolean view separates platelet activatory and inhibitory signalling as verified by phosphorylation monitoring including threshold behaviour and integrin modulation. Mol Biosyst. 2013 Jun;9(6):1326-39.