NEMO - an essential modulator of the blood-brain barrier

The genetic disease incontinentia pigmenti is caused by inactivating mutations in NEMO, the gene for the essential modulator of NF-κB signalling. About one third of patients suffer from neurological symptoms. Our previous research has shown that NEMO deficiency leads to endothelial cell death, a rarefaction of small vessels in the CNS, and a disruption of the blood-brain barrier, all of which cause the neurological symptoms of incontinentia pigmenti. The data raise further questions that we want to tackle in this proposal. Do neighbouring pericytes provide the upstream stimulus of NEMO and NF-κB signalling? Do NEMO-deficient endothelial cells die through necroptosis? Why is the blood-brain barrier not completely normalized when endothelial cell death is prevented and does angiogenesis contribute to the leaky blood-brain barrier? Finally, are necroptosis inhibitors useful for the treatment of incontinentia pigmenti? We will try to approach these questions with the help of advanced genetic mouse models and several cellular assays. The answers have the potential to influence the treatment of incontinentia pigmenti. Beyond this specific genetic disease, they may improve current understanding of the mechanisms by which inflammation affects the blood-brain barrier.