Computational modelling of the angiopoietin and tie interactions

Angiopoietins have been shown to regulate the vascular states of development and quiescence. Activation of this signalling pathway through their receptor tyrosine kinase, Tie2, is involved in angiogenesis and vascular protection. Regulation of this pathway is under tight control and has many complex factors which regulate its activation, defects in which cause many pathological conditions such as; vascular disease, sepsis and cancer. There are several factors which are integrated to control the Tie2 signalling pathway at the level of the receptor and these mechanisms are poorly understood. Computational and mathematical modelling can be used to understand the regulation of this pathway. The aim of this project was to construct a quantitative model of the angiopoietin and Tie interactions at the endothelial cell surface. A schematic representation of the interactions was produced in the CellDesigner modelling program. Ordinary differential equations were used to describe the system and change of states over time. Parameters required for the simulation of the model were identified and most were obtained from the literature, while others were quantified through experiments. The model was converted for use in MATLAB to simulate the angiopoietin time-courses and concentration-dependent studies. Quantitative Western blotting was used to measure the relative levels of receptor activation in endothelial cells stimulated with angiopoietin(s). Subsequently simulation results were compared to experimental data to validate the model. In summary this project has established a model similar to physiological conditions which is valid for Ang1 and potentially for Ang2 interactions. This simplified model of Ang1 and Ang2 interactions with Tie2 on the endothelial cell surface provides a foundation on which further analysis, and additional receptor modelling can be performed and expanded. The model can also be used to test hypotheses, generate new predictions, and identify new therapeutic targets for many diseases.