LncRNA-COX-2和CircRNA-Stag1通过环氧化物合酶2调节肝纤维化血管新生的机制研究

Liver fibrosis, which characterizes as excessive extracellular matrix deposition and disharmony of intrahepatic vascular homeostasis, is inevitable outcome triggered by consistent chronic inflammation. The poor prognosis and serious burden of liver fibrosis make it be one of the most widely concerned diseases by gastroenterologists and health organizations in the world. It has been focused on the formation of collagen in most previous studies, however, little attention have been paid on intrahepatic angiogenesis, which characterizes as abundant irregular and tortuous portal veins in the fibrotic liver. In the present program, cyclooxygenase 2 (COX-2) is identified as a potential molecular target, long non-coding RNA-COX-2 (LncRNA-COX-2) and circular RNA-Stag1 (CircRNA-Stag1) will be employed to explore the mechanism of COX-2 on regulation of intrahepatic angiogenesis. Secondly, we will provide an in-depth look at molecular mechanisms of interactions of LncRNA-COX-2 with heterogeneous nuclear ribonucleoprotein, bindings of CircRNA-Stag1 with miRNA-146 and miRNA-200a, and crosstalk between the two moleculars, which will establish a theoretical basis for the early multifaceted treatment of liver fibrosis and liver cirrhosis. Finally, the multifaceted therapy targeting COX-2 (LncRNA-COX-2, CircRNA-Stag1 and selective COX-2 inhibitor celecoxib) will be applied to the experimental treatment of liver fibrosis and liver cirrhosis, which might stimulate consideration of the multifaceted therapy as an effectively treatment for patients suffering from liver fibrosis.

肝纤维化是由多种原因引起的一种以胶原沉积和血管失稳态为特征的慢性、进行性、弥漫性炎症过程，其不良预后、严重的疾病负担使之成为全球消化学界及政府卫生部门关注的重要问题之一。以往对肝纤维化的研究多关注于胶原纤维是如何产生及沉积，我们近年研究发现肝纤维化过程中肝内出现大量紊乱、扭曲的新生血管，但目前对肝内血管新生缺乏系统研究。本项目将以环氧化物合酶-2（COX-2）为分子靶点，以长链非编码RNA-COX-2（LncRNA-COX-2）和环状RNA-Stag1（CircRNA-Stag1）为工具分子，深入探讨COX-2内源性调控肝内血管新生的机制。此外，我们将深入研究LncRNA-COX-2和CircRNA-Stag1调节COX-2表达的分子机制，为早期干预肝纤维化→肝硬化进程提出恰当的时机。最后通过外源性多层面干预COX-2，创新肝纤维化→肝硬化的防治策略。

肝纤维化的研究多关注于胶原纤维是如何产生及沉积的，我们研究发现肝纤维化过程中肝内出现大量紊乱、扭曲的新生血管，项目通COX-2敲除小鼠肝纤维化模型，以环氧化物合酶-2（COX-2）为分子靶点，以环状RNA-Stag1（CircRNA-Stag1），lncRNA-COX2为工具分子，研究COX-2内源性调控肝内血管新生机制，为早期干预肝纤维化→肝硬化进程提出恰当的时机，提供理论基础；外源性多层面干预COX-2（CircRNA-Stag1，lncRNA-COX2, COX-2抑制剂塞来昔布），创新肝纤维化→肝硬化的防治策略。项目按照计划完成，达成预期目标，已发表SCI论文10篇，其中IF≥10分3篇，参加国际会议并发表会议论文9篇。在站博士后3名，培养毕业博士研究生6名，硕士研究生4名。