功能丧失的RNF213通过Hippo路径促进莫亚莫亚病的病态血管生成
Fei Ye1,2, Xingyang Niu1, Feng Liang3
1Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
Brain : a journal of neurology
|July 3, 2023
概括
失去RNF213功能通过激活Hippo路径促进莫亚莫亚疾病. 这导致血管形成增加和细胞行为改变,为这种罕见的脑血管疾病提供了新的治疗点.
科学领域:
- 脑血管生物学 脑血管生物学
- 罕见疾病的遗传学
- 内皮细胞的功能是内皮细胞功能.
背景情况:
- 莫亚莫亚病是一种罕见的脑血管疾病,病因不明.
- 环指蛋白213 (RNF213) 是一个关键的易感基因,特别是在亚洲人群中.
- RNF213突变在莫亚莫亚病发展中的确切作用需要进一步阐明.
研究的目的:
- 调查RNF213突变对莫亚莫亚病病原发生的功能影响.
- 探索RNF213功能丧失影响血管发育的分子机制.
- 通过分析RNF213在内皮细胞信号传递中的作用来确定潜在的治疗点.
主要方法:
- 患者样本的全基因组测序和RNF213突变分析.
- 在RNF213缺乏的小鼠和斑马鱼模型的体内研究.
- 在体外实验中,RNF213在人类大脑的微血管内皮细胞中被淘汰.
- 对RNA-seq数据的生物信息学分析和信号通路的验证.
主要成果:
- 致病性RNF213突变与莫亚莫亚病组织病理学相关.
- 在动物模型和细胞培养中,RNF213缺乏会加剧病理性血管生成.
- 减少RNF213的表达增强了内皮细胞的增殖,迁移和管形成.
- RNF213 Knockdown 激活了Hippo通路 (YAP/TAZ),并对VEGFR2进行上调,从而促进血管生成.
结论:
- 在RNF213中的功能丧失突变与莫亚莫亚病的发病有关.
- 河马通路和VEGFR2信号传递是RNF213在血管生成中的作用的关键调解者.
- 通过Hippo通路调节内皮细胞行为的RNF213,为莫亚莫亚病提供了潜在的治疗途径.
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