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Regulation of the tight junction barrier by synthetic peptides: Towards the development of a new drug delivery method

合成肽调节紧密连接屏障：开发新的药物递送方法

基本信息

批准号：
13557013
负责人：
FURUSE Mikio
金额：
$ 8.58万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557013/
关键词：
claudin occludin tight junction barrier peptide drug delivery blood-brain barrier ZO-1 クローディアンノックアウトマウス脳腫瘍 CNS 血管皮膚

项目摘要

The blood-brain barrier (BBB) is thought to protect the brain from various harmful materials circulating in the blood. On the other hand, BBB prevents many potential drugs from entering the central nervous system (CNS). Many researchers have therefore tried to loosen the BBB for therapeutic purposes in various CNS disorders, but limited information on the molecular basis for BBB has hampered these trials. To establishment of the BBB, well-developed tight junctions (TJs) between adjacent endothelial cells are indispensable, in addition to various transporters in their plasma membranes. Recently, claudin-5 was identified as a major TJ cell adhesion molecule in brain endothelial cells. Here we show that in claudin-5-deficient mice, BBB is loosened in a size-selective manner. In the brain of these mice, the morphology/development of blood vessels was not altered, and TJs consisting of claudin-12 remained in the endothelial cells. Tracer experiments and magnetic resonance imaging revealed that in the claudin-5-deficient brain, the BBB against small molecules (<800 Da), but not larger molecules, was selectively affected. These findings not only provide new insight into the basic molecular physiology of BBB but also improve drug delivery methods.

血脑屏障（BBB）被认为可以保护大脑免受血液中循环的各种有害物质的影响。另一方面，血脑屏障阻止许多潜在的药物进入中枢神经系统（CNS）。因此，许多研究人员试图放松血脑屏障，以治疗各种中枢神经系统疾病，但有限的信息，血脑屏障的分子基础上阻碍了这些试验。对于血脑屏障的建立，除了细胞膜上的各种转运蛋白外，相邻内皮细胞之间发达的紧密连接（TJ）也是必不可少的。最近，claudin-5被鉴定为脑内皮细胞中主要的TJ细胞粘附分子。在这里，我们表明，在claudin-5缺陷的小鼠，血脑屏障松动的大小选择性的方式。在这些小鼠的脑中，血管的形态/发育没有改变，并且由claudin-12组成的TJ保留在内皮细胞中。示踪剂实验和磁共振成像显示，在claudin-5缺陷的大脑中，针对小分子（<800 Da）而不是较大分子的BBB被选择性地影响。这些发现不仅为BBB的基本分子生理学提供了新的见解，而且还改进了药物递送方法。