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在大脑内皮原始体中mTORC1信号传递有助于CCM病变发生

Wang Min^1,2, Lingfeng Qin¹, Haifeng Zhang¹

¹Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, CT (W.M., L.Q., H.Z., N.J., Y.K., V.K.M., M.S., J.H.Z.).

Circulation research

|July 3, 2024

概括

CCM3的损失破坏了血脑屏障,激活了脑内皮前体细胞 (EPC) 中的mTORC1信号传递. 这种信号级联启动并驱动大脑洞腔形 (CCM) 的发展和进展.

科学领域:

神经科学是一个神经科学.
血管生物学血管生物学
细胞信号传递细胞信号传递

背景情况:

大脑洞腔形 (CCM) 会增加中风和发作的风险.
CCM的发展与血脑屏障 (BBB) 完整性损失有关.
发起CCM的大脑内皮细胞/原始细胞中的精确信号通路尚不清楚.

研究的目的:

研究CCM3在大脑内皮细胞 (ECs) 和内皮原生细胞 (EPCs) 中的作用.
阐明 CCM 启动和进展背后的信号机制.
确定mTOR信号在CCM病变发生过程中的参与.

主要方法:

生成的大脑EC特异性CCM3缺陷 (Pdcd10BECKO) 的小鼠.
使用单细胞RNA测序来分析EC和EPC种群.
进行了体内成像,免疫光和生物化学测试,以研究mTOR信号和Cav1.

主要成果:

CCM3缺乏导致BBB相关EC减少,但增加了线粒体EC和具有高干细胞标记物的独特EPC集群.
在小鼠模型和人类样本中,mTOR信号在CCM病变中被上调.
抑制mTORC1 (但不抑制mTORC2) 信号,防止了CCM的形成;拉巴胺治疗改善了CCM的发病性.

结论:

CCM3对于维持血脑屏障的完整性至关重要.
失去CCM3会触发脑EPC中的mTORC1信号,从而启动和促进CCM的发病性.
准mTORC1信号代表了CCM的潜在治疗策略.

关键词:

在TOR氨酸-三氨酸激酶中,血脑屏障血脑屏障血脑屏障血脑屏障洞穴 (caveolae) 是一个洞穴.细胞内的形成细胞内的形成血管瘤,洞穴,中枢神经系统拉帕米辛复合物的机械性标1 1 单细胞基因表达分析分析

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