一个维生素D受体/SMAD基因组电路门肝脏纤维化反应
Ning Ding1, Ruth T Yu, Nanthakumar Subramaniam
1Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Cell
|April 30, 2013
概括
维生素D受体 (VDR) 连接体通过阻断肝星细胞激活来抑制肝纤维化. VDR在调节肝脏伤口愈合方面发挥着至关重要的作用,并可能为肝纤维化提供一种新疗法.
科学领域:
- 肝病学 肝病学是一种肝病学.
- 分子生物学分子生物学
- 内分泌学 在内分泌学.
背景情况:
- 肝纤维化是一种病理性伤口愈合反应,其特征是细胞外矩阵沉积过多.
- 由TGFβ1/SMAD信号驱动的肝星细胞 (HSC) 激活,是肝纤维化的主要原因.
- 维生素D受体 (VDR) 在肝纤维生成中的作用尚未完全理解.
研究的目的:
- 调查VDR在HSC激活和肝纤维化中的作用.
- 阐明VDR影响高细胞TGFβ1/SMAD信号传递的分子机制.
- 探索VDR配体在治疗肝纤维化的治疗潜力.
主要方法:
- 在体外研究中,使用用TGFβ1和VDR配体治疗的HSC进行了研究.
- 在体内研究使用VDR淘汰赛小鼠和野生型小鼠.
- 染色体免疫沉测序 (ChIP-seq) 用于绘制VDR和SMAD3结合部位的地图.
- 对基因表达的分析,以评估profibrotic标记物.
主要成果:
- VDR配体抑制了TGFβ1诱导的HSC激活和废止的肝纤维化.
- Vdr淘汰赛小鼠表现出自发性肝纤维化.
- TGFβ1信号改变了VDR全基因组的结合部位,促进了VDR与益纤维素基因的相互作用.
- VDR配体治疗减少了这些基因的SMAD3占用率,从而抑制了纤维化.
结论:
- VDR充当内分泌检查点,调节肝脏的伤口愈合反应.
- 一个交叉的VDR/SMAD基因组电路调节肝脏纤维化.
- VDR配体代表了肝纤维化的一种有前途的治疗策略.
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