黄晓雯,朱亚东,尹美芳,马寅仲,畅君雷.Wnt 信号通路激活蛋白 R-spondin 对血脑屏障功能和卒中后脑损伤的调节作用和分子机制研究[J].集成技术,2019,8(6):39-47
Wnt 信号通路激活蛋白 R-spondin 对血脑屏障功能和卒中后脑损伤的调节作用和分子机制研究
Investigation of the Regulatory Effect and Molecular Mechanism ofa Wnt Signaling Agonistic Protein R-spondinon Blood-Brain BarrierFunction and Post-Stroke Brain Injury
  
DOI:
中文关键词:  缺血性脑卒中;血脑屏障;缺血再灌注损伤;信号转导;Wnt 通路
英文关键词:ischemic stroke; blood-brain barrier; ischemia/reperfusion injury; signal transduction; Wnt signaling
基金项目:国家自然科学基金项目(81771293);中国科学院“率先行动”百人计划;深圳市基础研究自由探索项目(JCYJ20170307170338498); 深圳市基础研究学科布局项目(JCYJ20170413165705083)
作者单位
黄晓雯 中国科学院深圳先进技术研究院 深圳 518055;中国科学院大学深圳先进技术学院 深圳 518055 
朱亚东 中国科学院深圳先进技术研究院 深圳 518055 
尹美芳 中国科学院深圳先进技术研究院 深圳 518055 
马寅仲 中国科学院深圳先进技术研究院 深圳 518055 
畅君雷 中国科学院深圳先进技术研究院 深圳 518055 
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中文摘要:
      缺血性脑卒中是一种急性脑血管病,目前主要的治疗手段是及时进行溶栓或取栓治疗以 实现血管再通,但这一过程会对脑血管造成严重的再灌注损伤,使血脑屏障的结构和功能受到破坏,增加脑出血的风险。有研究表明 Wnt/β-catenin 信号通路对血脑屏障的功能起重要调节作用,但Wnt/β-catenin 信号通路激活蛋白 R-spondin 对血脑屏障和脑损伤的调节作用尚不清楚。该文通过体外制备小鼠 R-spondin-1 重组蛋白,在小鼠原代脑血管内皮细胞中证实了 R-spondin-1 蛋白协同 Wnt3a蛋白对 Wnt/β-catenin 信号通路的激活作用,并发现 R-spondin-1 能够显著改变血脑屏障功能相关基因Cldn3 和 Plvap 的表达水平;在小鼠脑缺血再灌注模型中,静脉注射 R-spondin-1 重组蛋白具有降低 脑组织梗死和提高小鼠存活率的趋势,但与生理盐水对照组相比未达到显著性差异。另外,该文还报道了 R-spondin 蛋白对血脑屏障功能的分子作用机制,并初步鉴定了其对卒中后脑损伤的治疗效果和 临床应用潜力。
英文摘要:
      Ischemic stroke is an acute cerebrovascular disease. Currently, it is treated mainly by timely thrombolysis or mechanical thrombectomy to achieve vascular recanalization, but this process causes serious reperfusion injury to cerebrovasculature, damages the structure and function of the blood-brain barrier (BBB), and increases the risk of cerebral hemorrhage. Studies have shown that the Wnt/β-catenin signaling pathway plays a critical role in regulating the function of BBB, but whether the R-spondin, an agonistic protein of the Wnt/β-catenin signaling pathway, plays a role in regulation of BBB and cerebral injury is unclear. In this study, using mouse recombinant R-spondin-1 protein prepared in vitro, we determined the activation of Wnt/β-catenin signaling pathway induced by combined treatment of the R-spondin-1 protein and Wnt3a protein in mouse primary cerebrovascular endothelial cells, and found that R-spondin1 significantly changed the expression levels of BBB function related genes Cldn3 and Plvap. In a mouse cerebral ischemia/reperfusion model, intravenous injection of recombinant R-spondin-1 protein was inclined to reduce the cerebral infarction and increase mouse survival but did not reach statistical significance compared to phosphate buffer solution controls. Our study reported the molecular mechanisms of BBB function regulation by R-spondin protein, and preliminarily identified its therapeutic effect on cerebral injury following stroke and potential for clinical use.
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