抗菌肽Hepcidin介导铁沉积在华支睾吸虫感染致肝纤维化中的作用及其机制研究

As a parasitic disease, Clonorchiasis significantly endangers people’s health. The disease mainly leads to hepatobiliary system disease, even liver fibrosis and cholangiocarcinoma. Research showed that the antimicrobial peptide Hepcidin induced iron deposition, promoted the activation of hepatic stellate cell and accelerated the development of hepatic fibrosis. Our previous study found that Clonorchis sinensis infection caused hepatocyte apoptosis and hepatic iron deposition. However, its mechanism had not been elucidated. Therefore, we will take hepcidin induced iron deposition caused by Clonorchis sinensis infection as the pointcut, urilize Clonorchis sinensis infection model established by gene deficient mouse and analysis the mechanism of Hepcidin mediated iron deposition in liver fibrosis by Western blot, Realtime-PCR, and flow cytometry. On this basis, using cell coculture model at the cellular level, we could further study on the mechanism of Hepcidin- iron deposition-ROS signal transduction pathway during the excretory secretory antigen of Clonorchis sinensis activated hepatic stellate cells. Through the above study, we expect to reveal that the mechanism of Hepcidin induces iron deposition and promotes liver fibrosis with Clonorchis sinensis infection, providing new targets for the prevention and treatment of liver fibrosis caused by Clonorchis sinensis.

华支睾吸虫病是严重危害人民健康的重大寄生虫病。该病主要表现为肝胆系统病变，甚至发生肝纤维化、肝胆管癌。研究表明抗菌肽Hepcidin诱导铁沉积能够活化肝星状细胞，促进肝纤维化的发生、发展。本课题前期研究发现华支睾吸虫感染致肝细胞凋亡、肝铁沉积，但其作用机制还未阐明。因此，本项目拟以华支睾吸虫感染引起Hepcidin介导铁沉积为切入点，利用相关基因缺陷型小鼠建立华支睾吸虫感染模型，采用Western blot、Realtime-PCR、流式细胞术等手段分析Hepcidin介导铁沉积在肝纤维化过程中的作用和机制。在此基础上，利用共培养细胞模型在细胞水平深入研究Hepcidin-铁沉积-ROS信号转导通路在华支睾吸虫分泌排泄抗原活化肝星状细胞过程中的作用机制。拟通过上述研究，揭示Hepcidin介导铁沉积促进华支睾吸虫感染致肝纤维化的分子机制，为防治华支睾吸虫感染致纤维化提供新的思路和靶点。

华支睾吸虫病是危害人类健康的重要食源性寄生虫疾病之一，且感染率呈上升趋势。长期慢性感染可导致肝纤维化和肝胆管癌，预后较差，但是该病经常被人们忽视，且致病机制尚未完全阐明。因此本项目研究其致病机制，从铁代谢的角度，为防治该病提供新思路和新靶点。本研究的主要内容包括：收集正常人、华支睾吸虫病患者尸检肝脏标本和华支睾吸虫患者血清标本；制备华支睾吸虫感染模型，华支睾吸虫感染诱导肝纤维化模型；检测华支睾吸虫感染后铁代谢变化；检测不同阶段华支睾吸虫病肝胆损伤情况（肝纤维化和肝细胞凋亡等）；最后分析肝铁沉积与肝胆损伤、肝细胞凋亡、肝脏纤维化的关系，与进一步阐明铁沉积的作用；同时利用芯片检测华支睾吸虫感染后肝脏组织的microRNA的表达变化，筛查有意义的microRNA，进一步阐明华支睾吸虫感染后宿主肝脏组织的病理变化，从基因的角度深入研究铁沉积的机制。研究成果发表文章两篇。通过上述研究，揭示了铁沉积参与华支睾吸虫感染致肝纤维化的分子机制，为防治华支睾吸虫感染致纤维化提供新的思路和靶点。