在小鼠和人类巨细胞中通过葡萄皮质激活分离转录
Alasdair Jubb1, Robert Young2, Wendy Bickmore2
1Roslin Institute, University of Edinburgh, Edinburgh, UK; MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Lancet (London, England)
|August 28, 2015
概括
由于基因调节的进化变化,葡萄糖皮质剂对免疫细胞的影响在人类和小鼠之间有所不同. 这突出了对抗炎症疗法的特定物种反应.
科学领域:
- 免疫学
- 基因组学
- 药理学
背景情况:
- 天生的免疫细胞是抗炎药物治疗的关键点.
- 葡萄皮质类药物调节免疫功能,但具有剂量限制的副作用.
- 鼠标模型被广泛使用,但它们与人类巨生物学的相关性是不确定的.
研究的目的:
- 研究巨细胞对葡萄皮质激素的转录反应的特定物种差异.
- 阐明人类与小鼠巨细胞中糖皮质激素调节的基因表达的潜在机制.
主要方法:
- 用葡萄糖皮质剂治疗的小鼠和人类巨细胞的全球基因表达概况.
- 染色体免疫沉,然后进行测序 (ChIP-seq) 来映射葡萄皮质体受体 (GR) 的结合部位.
主要成果:
- 在人类和小鼠的巨细胞中,葡萄糖皮质类药物诱导了不同的基因表达模式,并且几乎没有重叠.
- 与炎症性疾病相关的单核酸多态 (SNPs) 在人类葡萄皮质激素调节基因附近得到丰富.
- 特别是在诱导基因附近的增强剂中,GR结合部位和相关动机在物种之间显示出显著的差异.
结论:
- 葡萄皮质类药物对先天性免疫细胞的抗炎作用在人类和小鼠之间有显著差异.
- 特定物种的差异归因于葡萄皮质激素反应增强剂的增加或减少.
- 了解这些差异对于将动物模型的发现转化为人体疗法至关重要.
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