miR-1/miR-133b在泡型包虫病患者肝纤维化中的作用及其临床意义

Xinjiang is the alveolar hydatid disease (AE) in high incidence area. Hepatic fibrosis is a common pathological outcomes of various kinds of chronic hepatic injury including alveolar echinococcosis (AE). Hepatic stellate cells (HSC) activation is a key link in the pathogenesis and development of liver fibrosis, but the mechanism is unknown. In our previous study, we found that TGF-β1 indicated an increased expression during the various stages of infection, whereas miR-1/miR-133 family indicated a decreased expression. The inverse correlation between TGF-β and miR-1/miR-133 expressions, suggest that they could be involved in the progression of HSC activation, of which mechanism, very little is known to date. The aim of this project is to identify TGF-β1 and miR-1/miR-133b how to regulate the mechanism of HSC activation in vitro; Secondly, based on the Em infected mice model and intervention, we would clarify the HSC activation rule, by which TGF-β1 and miR-1/miR-133b are mediated in different infection period. We would then decide whether or not, exogenous miR-1/miR-133b is a therapeutic target for reversing or retarding liver fibrosis. The verification of clinical samples will prove the feasibility and effectiveness of miR-1/miR-133b in the diagnosis of AE as a new diagnostic biomarker. These results will present new idea and direction for AE treatment.

新疆是泡型包虫病（AE）高发区，肝纤维化是包括其在内的各种慢性肝脏损伤的主要病理表现和共同病理结局，肝星状细胞（HSC）活化是关键，但机制不明。我们发现泡球蚴感染所致肝脏微环境中TGF-β1高表达，miR-1/miR-133b低表达，HSC被活化，提出“抑制miR-1/miR-133b调控TGF-β/Smad信号通路活性功能，可促进TGF-β1激活HSC致肝纤维化”的科学假说。我们拟在细胞水平明确TGF-β1和miR-1/miR-133b在静息HSC→活化HSC→ECM沉积过程中的调控机制；在动物水平阐明Em感染不同时期TGF-β1和miR-1/miR-133b协同介导激活HSC分子机制，确定外源导入miR-1/miR-133b逆转或延缓肝纤维化的效用；在临床水平验证miR-1/miR-133b作为新型AE肝纤维化诊断分子标志物的价值，为AE治疗提供新思路和新靶点。

多房棘球蚴感染所致的肝泡型包虫病中肝脏损伤较为严重，进而导致多种病理损伤并影响患者预后。本课题在临床病人外周血和肝泡型包虫病病灶微环境中的miR-1和miR-133b水平，通过组织定位和观察肝纤维化相关指标水平，阐述了疾病状态下的miR-1和miR-133b水平与肝纤维化的相关性，并探索了miR-1和miR-133b作为肝纤维化指标的可行性；在动物模型层面利用携带miR-1和miR-133b上调和下调的AAV-8载体经尾静脉注射，除了研究临床样本中所发现的规律以外，研究了miR-1和miR-133b的上调和下调与肝纤维化程度的变化，以及TGF-b1/Smad信号通路在此过程中的作用，进一步验证了miR-1和miR-133b导致泡型包虫病肝纤维化的机制。本项目可提供肝泡型包虫病肝纤维化的诊断新靶标、揭示miR-1和miR-133b导致肝纤维化的机制、提供干预miR-1和miR-133b来治疗肝泡型包虫病的新靶点。