Endothelial Dynamics

The endothelial barrier lines our entire vascular tree, acting as a vital gatekeeper that regulates fluid balance, immune cell trafficking, and tissue homeostasis. When this barrier fails, uncontrolled vascular leakage drives life-threatening conditions such as acute inflammation, sepsis, pulmonary edema, and cancer metastasis.

At the cellular level, barrier integrity depends on a tight balance between mechanical forces and cell–cell junctions, dynamically coordinated by intracellular signalling networks. This project aims to build a multiscale computational model that connects intracellular RhoA and RhoB signalling dynamics to multicellular biomechanics, uncovering how their interplay preserves or destabilizes vascular barrier function.

Objectives

1. Build a spatial Cellular Potts Model (CPM) to simulate endothelial monolayer dynamics, capturing cell deformation, VE-cadherin-mediated adhesion, and paracellular gap formation under mechanical tension.
2. Formulate a dynamic intracellular signalling model using ordinary differential equations to describe the activation kinetics, antagonistic crosstalk, and endosomal trafficking of RhoA and RhoB in resting and inflamed endothelial states.
3. Couple the intracellular signalling network directly to the multicellular CPM framework to predict tissue-level permeability changes, benchmarking the simulation against experimental knockdown and drug perturbation data.

References

1. Buttenschön, A., and Edelstein-Keshet, L. "Bridging from single to collective cell migration: A review of models and links to experiments." PLoS Computational Biology 16.12 (2020): e1008411.
2. Marcos-Ramiro, B., et al. "RhoB controls endothelial barrier recovery by inhibiting Rac1 trafficking to the cell border." Journal of Cell Biology 213.3 (2016): 385–402.
3. Pronk, M. C. A., et al. "RhoA, RhoB and RhoC differentially regulate endothelial barrier function." Small GTPases 10.6 (2019): 466–484.

Expectations

A background in biology is advantageous, but not strictly required.

Work environment

The student will join an interdisciplinary research team spanning the Informatics Institute (IvI) and Amsterdam UMC, bringing together expertise in computational biology, physics, and vascular medicine. You will work closely with both modellers and experimentalists, gaining practical experience in multiscale simulation and biological data integration.