27 research outputs found
Systems biology of platelet-vessel wall interactions
Platelets are small, anucleated cells that participate in primary hemostasis by forming a hemostatic plug at the site of a blood vessel's breach, preventing blood loss. However, hemostatic events can lead to excessive thrombosis, resulting in life-threatening strokes, emboli, or infarction. Development of multi-scale models coupling processes at several scales and running predictive model simulations on powerful computer clusters can help interdisciplinary groups of researchers to suggest and test new patient-specific treatment strategies
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Regulation of early steps of GPVI signal transduction by phosphatases: a systems biology approach
We present a data-driven mathematical model of a key initiating step in platelet activation, a central process in the prevention of bleeding following Injury. In vascular disease, this process is activated inappropriately and causes thrombosis, heart attacks and stroke. The collagen receptor GPVI is the primary trigger for platelet activation at sites of injury. Understanding the complex molecular mechanisms initiated by this receptor is important for development of more effective antithrombotic medicines. In this work we developed a series of nonlinear ordinary differential equation models that are direct representations of biological hypotheses surrounding the initial steps in GPVI-stimulated signal transduction. At each stage model simulations were compared to our own quantitative, high-temporal experimental data that guides further experimental design, data collection and model refinement. Much is known about the linear forward reactions within platelet signalling pathways but knowledge of the roles of putative reverse reactions are poorly understood. An initial model, that includes a simple constitutively active phosphatase, was unable to explain experimental data. Model revisions, incorporating a complex pathway of interactions (and specifically the phosphatase TULA-2), provided a good description of the experimental data both based on observations of phosphorylation in samples from one donor and in those of a wider population. Our model was used to investigate the levels of proteins involved in regulating the pathway and the effect of low GPVI levels that have been associated with disease. Results indicate a clear separation in healthy and GPVI deficient states in respect of the signalling cascade dynamics associated with Syk tyrosine phosphorylation and activation. Our approach reveals the central importance of this negative feedback pathway that results in the temporal regulation of a specific class of protein tyrosine phosphatases in controlling the rate, and therefore extent, of GPVI-stimulated platelet activation
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Mathematical techniques for understanding platelet regulation and the development of new pharmacological approaches
Mathematical and computational modeling is currently in the process of becoming an accepted tool in the arsenal of methods utilized for the investigation of complex biological systems. For some problems in the field, like cellular metabolic regulation, neural impulse propagation, or cell cycle, progress is already unthinkable without use of such methods. Mathematical models of platelet signaling, function, and metabolism during the last years have not only been steadily increasing in their number, but have also been providing more in-depth insights, generating hypotheses, and allowing predictions to be made leading to new experimental designs and data. Here we describe the basic approaches to platelet mathematical model development and validation, highlighting the challenges involved. We then review the current theoretical models in the literature and how these are being utilized to increase our understanding of these complex cells