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概念验证研究:APOE4脑内皮细胞作为一种表型化合物屏幕
Ana C Valencia-Olvera1, Felecia M Marottoli1, Kiira Ratia2
1Department of Anatomy and Cell Biology, University of Illinois, M/C 512, Rm 578, 808 S. Wood St, Chicago, IL, 60612, USA.
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概括
这项研究开发了一种新的选方法,以找到能保护APOE4大脑内皮细胞免受损伤的化合物. 确定了几种化合物,这些化合物在预防脑血管功能障碍方面表现有前途.
科学领域:
- 神经科学是一个神经科学.
- 药理学 药理学是指药理学的学科.
- 细胞生物学 细胞生物学
背景情况:
- APOE4基因型与增加的神经退行风险有关,可能是由于大脑血管透性更高.
- 大脑内皮细胞APOE基因型影响大脑血管功能,APOE4细胞更容易发生功能障碍.
- 这项研究通过识别保护APOE4大脑内皮细胞的化合物来探索治疗应用.
研究的目的:
- 建立和验证使用APOE4脑内皮细胞的表型查试验.
- 为了确定保护这些细胞免受脂聚糖 (LPS) 诱导的功能障碍的化合物.
主要方法:
- 将一个测量跨内皮细胞电阻 (TEER) 的体外测定适应到一个经过验证的表型屏幕中.
- 缩放细胞隔离协议和优化测试条件 (最小,中,最大信号).
- 从生物活性库中选了大约900种化合物,并在体内验证了匹配结果.
主要成果:
- 确定了33种保护性化合物,根据它们对信号通路 (生长因子受体,细胞内信号) 的影响进行分类.
- 出现了两个主要的化合物组:破坏细胞 (通常抑制mTOR) 和保护LPS诱导的TEER减少的化合物.
- 四种主要化合物 (塔达拉菲尔,沃里诺斯塔特,CCT196969,SGI-7079) 在APOE4小鼠中减轻了LPS诱导的大脑血管功能障碍.
结论:
- 开发的体外镜有效识别化合物,防止APOE4大脑内皮细胞中LPS诱导的功能障碍.
- 这种测试有可能发现针对APOE4相关的脑血管问题的新疗法.
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