保存的长非编码RNATILAM通过与肝星细胞中PML的相互作用促进肝纤维化
bioRxiv : the preprint server for biology
|August 7, 2023
概括
长非编码RNATILAM通过激活肝星细胞驱动肝纤维化. 在小鼠中抑制TILAM可减少肝脏痕,这表明TILAM是肝脏疾病的治疗标.
科学领域:
- 分子生物学分子生物学
- 肝病学 肝病学是一种肝病学.
- RNA生物学的RNA生物学
背景情况:
- 纤维化是慢性肝损伤的常见结果,导致末期肝病.
- 肝星细胞 (HSC) 的激活和分化成肌纤维细胞驱动细胞外基质的积累和痕形成.
- 长非编码RNAs (lncRNAs) 调节HSC活动,是纤维化的潜在治疗点.
研究的目的:
- 确定和描述IncRNATILAM在肝纤维化中的作用.
- 调查TILAM如何影响HSC活动和ECM生产的机制.
- 评估TILAM作为肝纤维化的潜在治疗点.
主要方法:
- 鉴定了人类的 lncRNA TILAM 和它的小鼠正义基因.
- 在人类肝脏细胞和肝脏有机体中进行了功能丧失研究.
- 产生了蒂拉姆缺乏的小鼠,并评估了对CCl4和CDA-HFD的纤维化反应.
- 利用共同沉,质谱和基因表达分析来识别TILAM蛋白合作伙伴.
主要成果:
- 蒂拉姆在人类和小鼠中保持稳定,并调节ECM蛋白质表达,包括原蛋白.
- 在肝纤维化发育过程中,TILAM在肝纤维细胞中被选择性诱导.
- 在损伤的小鼠模型中,TILAM的损失减少了肝纤维化.
- 提拉姆与前列细胞白血病蛋白 (PML) 相互作用,使其稳定并增强HSC纤维化活性.
结论:
- 蒂拉姆在HSC中被激活,并通过PML相互作用驱动肝纤维化.
- 提拉姆的耗尽代表了对肝纤维化和末期肝病的潜在治疗策略.
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