Cellulär och molekulär mekanism för CCM-sjukdom

Cerebral Cavernous Malformations (CCM) is a disease that leads to the development of vascular malformations in the brain. CCM lesions can measure several cm in size and impose a direct threat as the affected blood vessels are prone to leak. While CCM is a rare disease, it can be devastating. Symptoms include severe headaches, vision and hearing loss, seizures and paralysis.

At present, there is no pharmacological treatment available and mechanisms that lead to lesion formation remain poorly understood.

We have recently shown that the small GTPase CDC42 plays a key role in the pathophysiology of CCM and have developed a CDC42 based animal model to study this disease.

Our results suggest that endothelial cell migration defects initiate the formation of malformations and that other processes subsequently contribute to lesion expansion and growth.

The experiments outlined in this application aim to specifically investigate if cell migration defects also contribute to lesion formation in other CCM mouse models and to characterize the cellular and molecular mechanisms that underlay the subsequent lesion expansion.

Using single-cell RNA sequencing experiments we will map the transcriptional changes in Cdc42 depleted endothelial cells and hope to identify potential therapeutic targets as well as useful biomarkers that can help to diagnose the initial steps of lesion formation. We will also study the morphogenetic events and dynamics of lesion formation using intravital imaging.