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染色体重塑蛋白BRG1通过调节NOXA表达来促进肝脏缺血-再输液损伤
Nan Li1, Hong Liu1, Yujia Xue1
1Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Departments of Human Anatomy and Pathophysiology, Nanjing Medial University, Nanjing, China.
Life sciences
|November 5, 2023
概括
BRG1 (Smarca4) 通过促进肝细胞亡,在肝脏缺血-再损伤 (IRI) 中发挥关键作用. 抑制BRG1可以防止肝脏的IRI,提供一种潜在的治疗策略.
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
- 免疫学 免疫学 免疫学
背景情况:
- 肝缺血-再输损伤 (IRI) 是移植后肝损伤的主要原因之一.
- 肝细胞亡是IRI病理的一个重要因素.
- 染色体重塑蛋白在IRI中的作用尚未完全理解.
研究的目的:
- 调查BRG1 (Smarca4) 在肝脏IRI病变发生过程中的作用.
- 阐明BRG1参与肝脏IRI的背后的转录机制.
- 探索针对治疗干预的BRG1的转化潜力.
主要方法:
- 使用Smarca4 ((f/f) 和Alb-Cre模型生成肝细胞特异性BRG1淘汰赛小鼠 (CKO).
- 在IRI后评估肝损伤标志物 (ALT/AST) 和肝细胞亡.
- RNA测序 (RNA-seq) 用于分析转录基因的变化.
- 在体内对小分子BRG1抑制剂 (PFI-3) 的评估.
主要成果:
- 在对缺血-再输液 (I/R) 和缺氧-再氧化 (H/R) 的反应中,BRG1表达被上调.
- 与野生型 littermates 相比,BRG1 CKO小鼠在I / R后显著减少肝损伤和亡.
- BRG1调节了博-12-米里-13-乙酸盐诱导蛋白1 (PMAIP1,NOXA) 的表达,这是一个亲亡的因素.
- 用PFI-3对BRG1进行药理性抑制,可以防止肝脏IRI.
结论:
- 通过促进肝细胞亡,BRG1是肝脏IRI的关键调解者.
- 针对BRG1,特别是小分子抑制剂,是缓解肝脏IRI的有前途的治疗策略.
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