Ghrelin调节肝细胞外泌体-MALAT1途径抑制肝星状细胞活化的机制研究

Liver fibrosis is the basis of the progress of chronic liver disease. Exosomes and lncRNAs included in them play important roles in the occurrence and development of liver fibrosis. Through the preliminary study we found that: MALAT1 in exosomes secreted by damaged hepatocytes significantly contributed to the activation of hepatic stellate cells (HSCs). Ghrelin significantly attenuated hepatocellular inflammatory injury, decreased secretion of exosomes by damaged hepatocytes, reduced MALAT1 levels in exosomes and HSCs which were co-cultured with exosomes, and inhibited HSCs activation. However, whether ghrelin reduces the activation of HSCs by reducing the expression of MALAT1 in exosomes secreted by impaired hepatocyte and its specific mechanism remain unclear. This research intends to verify the hypothesis that ghrelin plays critical roles in anti-liver fibrosis by regulating damaged hepatocytes exosome-MALAT1 pathway through research methods such as gene chip, virus transfection, immunofluorescence and proteomics. The aim of this study is to establish new evidences for anti-liver fibrosis drug development, and help provide novel ideas for exosome targeted anti-liver fibrosis study.

肝纤维化是慢性肝病进展的基础，外泌体及其包含的lncRNA在肝纤维化的发生发展中具有重要作用。我们通过前期研究发现：受损肝细胞分泌的外泌体中的MALAT1显著促进肝星状细胞（HSCs）活化。Ghrelin明显减轻肝细胞炎症损伤，减少肝细胞分泌外泌体，降低外泌体中以及与外泌体共培养的HSCs中MALAT1的水平，抑制HSCs活化。但ghrelin是否通过减少受损肝细胞外泌体中MALAT1表达，抑制HSCs活化及其具体机制，目前还不明确。本课题拟通过基因芯片、病毒转染、免疫荧光和蛋白组学等方法验证ghrelin调节肝细胞外泌体-MALAT1途径抑制HSCs活化这一假说。本课题旨在为ghrelin成为抗肝纤维化新药物提供依据，为以外泌体途径为机制的抗肝纤维化研究提供新思路。

肝纤维化是慢性肝病进展的基础，外泌体及其包含的lncRNA在肝纤维化的发生发展中具有重要作用。我们通过前期研究发现：受损肝细胞分泌的外泌体中的MALAT1显著促进肝星状细胞（HSCs）活化。Ghrelin明显减轻肝细胞炎症损伤，减少肝细胞分泌外泌体，降低外泌体中以及与外泌体共培养的HSCs中MALAT1的水平，抑制HSCs活化。本课题进一步研究发现，ghrelin明显减少受损肝细胞外泌体的分泌，并通过外泌体转运MALAT1进而抑制HSCs活化改善肝纤维化进程。本课题通过基因芯片、病毒转染、免疫荧光和蛋白组学等方法验证了ghrelin调节肝细胞外泌体-MALAT1途径抑制HSCs活化这一假说。本课题旨在为ghrelin成为抗肝纤维化新药物提供依据，为以外泌体途径为机制的抗肝纤维化研究提供新思路。