lncRNA HART-miRNA-TGFβ/SMAD“恶性反馈回路”：肝内型门脉高压干预新靶点

Hepatic stellate cells (hepatic stellate cell, HSC) activation to the myofibroblast transformation is the key player in the pathogenesis of portal hypertension,which is mainly regulated by TGF-beta signal transduction pathways. We previously analyzed the lncRNA expression profile in quiescent and culture- activated primary rat HSCs and identified lncRNA HART to be the most enriched upregulated during the activation of HSCs. Using bioinformatic tools, We speculate that there exists a lncRNA HART-TGF-β/SMAD signaling pathway crosstalk pipeline in the process of HSC activation, that is a malignant feedback loop (upregulated HART→microRNA19b/29b/101 downregulated→TGF-β/SMAD signaling pathway activation→ amplified HART ). Based on previous work, we intend to block the feedback loop and reverse the activation of HSC by lenti-virus-mediated HART expression knockdown, This may lead to blocking of the HART-microRNA-TGF-β/SMAD mediated feedback loop and reduces HSC proliferation, contractility, thereby improving the sinusoidal microcirculation, preventing and even reversing the progress of intrahepatic portal hypertension and its complications.

肝星状细胞（hepatic stellate cell, HSC）激活并向肌成纤维细胞转化是肝内型门脉高压形成的关键，而TGF-β/SMAD信号通路是介导 HSC 表型转化的重要信号通路。我们基因芯片的研究发现lncRNAHART在HSC表型转化过程中表达差异明显，进一步生物信息学预测提示在HSC活化过程中可能存在一lncRNAHART-TGF-β/SMAD信号通路对话机制，即HART表达上调→miRNA-19b/29b/101下调→TGF-β/SMAD激活→SMAD3转录上调HART表达这一恶性正反馈回路。本研究拟在前期工作基础上，期望通过尝试沉默HART 表达，阻断HART与TGF-β/SMAD通路“对话”形成的恶性回路，从而抑制HSC的激活、增殖过程，解除肝窦及其流出道受阻状态，改善肝内微循环，发挥延缓、防止乃至逆转肝内型门脉高压进展及其并发症的作用。

肝星状细胞激活并向为肌成纤维细胞转化是肝内型门脉高压形成的关键，而非编码RNA(ncRNA)是介导HSC表型转化的小分子。我们基因测序发现lncRNA-NONRATT013819.2在HSC表型转化过程中表达差异明显，本研究在前期工作基础上，将Lv-shRNA-NONRATT013819.2重组慢病毒导入HSC，通过沉默NONRATT013819.2表达，阻断NONRATT013819.2与miR24-3p/Lox对话通路，从而抑制HSC的激活、增殖过程，解除肝窦及其流出道受阻状态，改善肝内微循环，发挥延缓、防止乃至逆转肝内型门脉高压进展及其并发症的作用。