Vascular leakage and its role in disease

Blood vessels control the exchange between blood and tissues, regulated by the permeability of the vascular barrier.

Inflammatory cytokines and vascular endothelial growth factor (VEGF) increase permeability by inducing disassembly of endothelial junctions. In diseases such as cancer and retinopathy, chronic, elevated permeability promotes disease progression.

We will use transcriptomic resources combined with high resolution, multiplex imaging to deduce the composition of endothelial junctions and how VEGF-signaling promotes junction disassembly.

We will study vascular leakage in mouse models with gain- or loss-of function for endothelial junction components by live imaging of dynamic events. Vascular leakage will be studied in different organs in the mouse but also in human disease.

Novel, small molecular weight compounds to suppress vascular leakage that have been developed in the group will be analyzed in complex with its target using cryo-EM, and tested in vivo.

The ultimate goals are i) to delineate how the organ-specific composition of the vascular barrier contributes to organ homeostasis and how its breakdown promotes disease progression and ii) to suppress vascular leakage in diseases.

The successful execution of this plan will provide new basic molecular understanding of complex, dynamic control of the vascular barrier.

It will also lay the foundation for development of novel therapy and for improving the delivery of existing therapeutics.