The utilisation of computational and mathematical models in analysing experimental data is gaining increasing acceptance. Such approaches enhance the information that can be extracted from data, enabling complex biological hypotheses and conceptual models to be evaluated. We present three theoretical models, of increasing biological complexity, of the early subcellular events following GPVI-receptor-complex activation. These models are direct representations of biological hypotheses and have been built up iteratively, at each stage model simulations being compared quantitatively to experimental data, in turn guiding further experimental design, data collection and model refinement. Platelet activation, central to the formation of blood clots and thrombosis, occurs in response to multiple agonists stimulating subcellular signalling pathways. Our mathematical models capture subcellular signalling events downstream of the GPVI receptor. We compare computational simulations of our models to experimental data of changes in the phosphorylation states of the protein Syk during the initial phases of platelet activation. While it may be tempting to view signalling pathways as linear connections between input and output, in reality they often comprise complex, nonlinear reactions with multiple feedbacks that are difficult to understand by intuition alone. Historically we know less about the involvement of specific PTPases than the kinases in signalling pathways. Computational modelling allows you to ask in silico questions about their possible involvement. Our approach has revealed the central importance of a negative feedback pathway that results in the temporal regulation of a specific class of protein tyrosine phosphatase in controlling the rate and therefore extent of GPVI-stimulated platelet activation.
- CARDIAC PROCEDURES AND THERAPY
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.