NEMO - an essential modulator of the blood-brain barrier

遗传性疾病色素性失禁是由NEMO基因的失活突变引起的，NEMO基因是NF-κB信号的基本调节器。大约三分之一的患者有神经系统症状。我们以前的研究表明，NEMO缺乏会导致内皮细胞死亡，中枢神经系统小血管稀疏，血脑屏障破坏，所有这些都会导致色素性失禁的神经症状。这些数据提出了我们希望在这项提案中解决的进一步问题。邻近的周细胞是否提供NEMO和NF-κB信号的上游刺激？NEMO缺陷型内皮细胞会死于坏死性下垂吗？为什么在防止内皮细胞死亡时血脑屏障没有完全正常化，血管生成是导致血脑屏障泄漏的原因吗？最后，坏死性下垂抑制剂对治疗色素性失禁有效吗？我们将尝试借助先进的小鼠遗传模型和几种细胞分析来解决这些问题。这些答案可能会影响色素性失禁的治疗。除了这种特定的遗传病，它们可能会提高目前对炎症影响血脑屏障机制的理解。

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.