Transcytosis in the blood-cerebrospinal fluid barrier of the mouse brain with an engineered receptor/ligand system.
Transcytosis in the blood-cerebrospinal fluid barrier of the mouse brain with an engineered receptor/ligand system.
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DOI：
10.1038/mtm.2015.37
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Muzyczka N
中科院分区：
文献类型：
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作者：
Méndez-Gómez HR;Galera-Prat A;Meyers C;Chen W;Singh J;Carrión-Vázquez M;Muzyczka N
跨越血脑屏障和血脑脊液屏障（BCSFB）是开发脑部疾病新治疗分子的基本挑战之一，因为这些屏障阻止大多数药物从血液进入大脑。然而，一些大分子，如转铁蛋白，可以通过特定的受体跨越这些屏障，将它们转运到大脑中。基于这种机制，我们通过将人转铁蛋白受体与来自热纤梭菌的粘连蛋白结构域相结合，设计了一种受体/配体系统来克服脑屏障，并用dockerin配体在小鼠大脑脉络丛中测试了这种混合受体。通过在脉络膜室管膜细胞（BCSFB 的一部分）中表达我们的受体，我们发现我们全身施用的配体能够与受体结合并在室管膜细胞中积累，其中一些配体从血液侧转运到大脑侧。
Crossing the blood–brain and the blood–cerebrospinal fluid barriers (BCSFB) is one of the fundamental challenges in the development of new therapeutic molecules for brain disorders because these barriers prevent entry of most drugs from the blood into the brain. However, some large molecules, like the protein transferrin, cross these barriers using a specific receptor that transports them into the brain. Based on this mechanism, we engineered a receptor/ligand system to overcome the brain barriers by combining the human transferrin receptor with the cohesin domain from Clostridium thermocellum, and we tested the hybrid receptor in the choroid plexus of the mouse brain with a dockerin ligand. By expressing our receptor in choroidal ependymocytes, which are part of the BCSFB, we found that our systemically administrated ligand was able to bind to the receptor and accumulate in ependymocytes, where some of the ligand was transported from the blood side to the brain side.