Epimorphin对HIV/HCV共感染肝纤维化进展的作用及机制研究

HIV/HCV coinfection leads to accelerated hepatic fibrosis progression, with higher rates of cirrhosis, liver failure, and liver death than does HCV mono-infection. However, the pro-fibrogenic role of HIV on hepatic stellate cells (HSC) has not been fully clarified. Hepatic stellate cell(HSC) is remarkably versatile mesenchymal cells which is vital to hepatocellular function and the liver's response to injury. Epimorphin(EPM), also called syntaxin-2, a mesenchymal morphogenic protein expressed by hepatic stellate cells, is considered important to liver morphogenesis in both healthy and pathologic conditions. EPM binds to αv-integrin-containing receptors, leading to activation of the FAK-ERK-signaling pathway. EPM is overexpression on activated HSCs. Here, for the first time, we hypothesized that HIV, HCV induce liver fibrosis through altered regulation of the expression of EPM. Effects of EPM-overexpression on HSC proliferation、migration and apoptosis will be detected. The fibrogenesis- and fibrolysis-related gene activity in HSC in the presence of HIV will be examined. The role of EPM upon fibrosis gene expression was assessed using EPM shRNA and EPM-overexpressing cells. Whether EPM binds to αv-integrin-containing receptors, leading to activation of the FAK-ERK signaling pathway induces liver fibrosis will also be examined. To determine whether HIV/HCV co-infected and HCV infected have effects on liver fibrosis in vivo, we will measure mRNA levels in liver biopsy from non-infected, HCV infected, and HIV/HCV co-infected patients. Taken together, our project will provide the first reported mechanistic data on effect of EPM on hepatic fibrosis in HIV/HCV con-infected patients and appear a strategy to slow or block hepatic fibrosis.

HIV/HCV共感染后可加重感染者肝损伤，机制尚未阐明。肝星状细胞（HSC）生物学行为的改变是肝纤维化过程的中心环节，细胞膜表面受体整合素家族参与此过程。HIV可感染HSC改变其基因表达促进肝纤维化进展。表皮形态发生素（Epimorphin，EPM）特异性表达于HSC表面，脏脏损伤时表达增高，EPM由整合素介导激活FAK-ERK途径发挥作用。本课题拟考察HIV感染、HCV感染以及HIV/HCV共感染的HSC表达EPM的水平，并考察引起EPM表达变化的机制。并研究EPM表达变化对HSC增殖、迁移、凋亡的作用，并考察对肝纤维化相关基因表达的影响，进而研究其信号转导通路阐明EPM的作用机制。同时，对不同感染状态患者的肝组织中相关基因表达进行检测，进一步验证得出的结论。本项目旨在阐明EPM在HIV/HCV共感染肝损伤的快速进展中的作用及制，为预防和控制HIV/HCV共感染患者肝损伤提供有效靶点。

背景: HIV/HCV 共感染后可加重感染者肝损伤，机制尚未阐明。肝星状细胞（HSC）生物学行为的改变是肝纤维化过程的中心环节， 细胞膜表面受体整合素家族参与此过程。 HIV可感染 HSC 改变其基因表达促进肝纤维化进展。表皮形态发生素（Epimorphin，EPM）特异性表达于 HSC 表面，脏脏损伤时表达增高。.主要研究内容：本研究主要考察了 HIV 感染、HCV 感染以及 HIV/HCV 共感染的 HSC 表达 EPM 的水平，并考察引起EPM 表达变化的机制，研究了EPM 表达变化对 HSC 增殖、迁移的作用，研究其信号转导通路阐明 EPM 的作用机制。.重要结果及关键数据：1.HIV/HCV共感染促进肝星状细胞增殖与迁移；2.共感染促进HSC高表达EPM；3.EPM可以通过其启动子区的甲基化程度而调控；4.EPM可以促进HSC增殖与迁移；5.EPM能够调控TIMP-1的表达，此过程通过FAK-ERK途径介导。.科学意义:本研究阐明了HIV/HCV共感染过程中EPM表达变化情况及相关机制，证明EPM促进共感染后肝纤维化的进展，这为预防和控制 HIV/HCV 共感染患者肝损伤提供了潜在有效靶点。