NEMO - an essential modulator of the blood-brain barrier

NEMO - 血脑屏障的重要调节剂

• 批准号: 31660076
• 负责人: Professor Dr. Markus Schwaninger
• 金额: --
• 依托单位: Institut für experimentelle und klinische Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/31660076?language=en
• 关键词: NEMO; essential; modulator; blood; brain

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.

遗传性疾病色素失禁是由NEMO基因突变失活引起的，NEMO基因是NF-κB信号传导的重要调节因子。大约三分之一的患者患有神经系统症状。我们之前的研究表明，NEMO缺乏导致内皮细胞死亡，中枢神经系统小血管稀少，血脑屏障破坏，所有这些都会导致色素失禁的神经系统症状。这些数据提出了我们希望在本提案中解决的进一步问题。邻近周细胞是否提供NEMO和NF-κB信号传导的上游刺激？nemo缺陷内皮细胞会死于坏死坏死吗？当内皮细胞死亡被阻止时，为什么血脑屏障没有完全正常化？血管生成是否导致了血脑屏障的渗漏？最后，坏死性上睑下垂抑制剂对治疗色素失禁有用吗？我们将尝试在先进的遗传小鼠模型和几种细胞分析的帮助下接近这些问题。这些问题的答案有可能影响到色素失禁的治疗。除了这种特殊的遗传疾病，他们可能会提高目前对炎症影响血脑屏障机制的理解。