Modeling endothelial cell behavior using Petri nets: interactions between VE-cadherin and VEGFR-2 during angiogenesis
|Modeling endothelial cell behavior using Petri nets: interactions between VE-cadherin and VEGFR-2 during angiogenesis|
|Student name:||student name::Marta ter Haar|
|Second supervisor:||Anton Feenstra|
|Second reader:||has second reader::Roeland Merks|
The outgrowth of new blood vessels from pre-existing vessels, called angiogenesis, is a crucial step in many physiological and pathological mechanisms, including wound healing and tumor growth. Angiogenesis is a topic of intensive experimental investigation so its phenomenology and many of the molecular signals contributing to it have been well characterized. Yet it is poorly understood how the biological components fit together dynamically to drive the outgrowth of blood vessels. Cell-based simulation models help analyze how cells assemble into embryonic structures, and how cell behavior is guided by signals from neighboring cells.
With such cell-based simulation models, we have identified dynamic cell behaviors by which endothelial cells can form sprouts from existing blood vessels. In one of these, endothelial cells secrete a chemoattractant that attracts other endothelial cells. By itself this mechanism causes cells to aggregate into isolated clusters. But including experimentally observed contact inhibition of chemotaxis in the simulation causes cell aggregates to sprout, using a new stochastic mechanism.
Our current models describe cell behavior phenomenologically, based on experimental observations. In this project, you will build Petri net models of the genetic networks steering endothelial cell behavior and of the pathways responding to cell-cell interations. The models will be based on published interactions between key molecular components, including the receptor VEGFR-2, the cellular adhesion molecule VE-cadherin and the cytokinin CXCL12. The experimentally testable predictions produced by the model will help us unravel the molecular networks responsible for building blood vessels.
- Merks et al. PLoS Comput Biol 2008 4(9): e1000163. doi:10.1371/journal.pcbi.1000163
- Bonzanni et al. Bioinformatics 2009 25(16):2049-2056. doi:10.1093/bioinformatics/btp355