项目来源

台湾省政府科研基金(GRB)

项目主持人

张明熙

项目受资助机构

台湾省成功大学生物化学科暨生物化学暨分子生物学研究所

财政年度

2015,2014,2013

立项时间

未公开

项目编号

NSC102-2320-B006-041-MY3

项目级别

省级

研究期限

未知 / 未知

受资助金额

4920.00千元台币

学科

肝炎防治；生物技术(医)

学科代码

未公开

基金类别

基础研究/学术补助

关键词

未公开

参与者

未公开

参与机构

未公开

项目标书摘要：肝脏纤维化是肝脏处於持续受损与慢性发炎状态下所导致的结果，主要形成过程包括损害因子、细胞死亡、发炎激素等活化肝星状细胞、纤维母细胞(fibroblasts)或肌纤维母细胞(myofibroblast)使其增生与大量聚集，再经由大量生长因子、蛋白分解酵素及促纤维形成激素的产生，而造成细胞外基质蛋白的大量合成并沉积且抑制其分解，致使肝脏纤维化，最终发展成肝硬化。多种发炎激素参与纤维化，包括TNF-a与IL-6等；而具免疫调节功能的IL-10则可提供逆向的保护作用。与IL-10同属一家族的IL-20近来已证实参与多种组织的发炎作用，截至目前为止，只有研究指出IL-10与肝脏纤维化的关联，同属这一家族的其他细胞激素对肝纤维化有何作用尚未知。目前本实验初步的证据显示在纤维化的肝脏中会大量表现IL-20,因此，我们想要探讨IL-20是否在肝纤维化过程扮演重要的角色，并测试我们所研发的IL-20抗体是否在肝硬化的动物模式具有保护作用。首先从临床病人的肝脏硬化切片，侦测IL-20的高量表现，确定其与纤维化具有关联性。与纤维化形成相关的细胞包括：肝星状细胞(Stella cells)、纤维母细胞(fibroblast)及发炎细胞—Kupffer cells 等，因此确认肝脏中IL-20的来源细胞(source cells)及目标细胞_(target cells)後，便可以IL-20 作用於初代细胞(primary cell)或细胞株(cell line),侦测各种促纤维形成因子的变化、ROS 的侦测、细胞增生、趋化移动实验，以探讨IL-20对这些目标细胞的影响，同时探讨各种可能的致病因子对来源细胞的IL-20表现量有何影响。再经由建立的肝脏纤维化动物模式(liver cirrhosis disease model),印证IL-20在体内(in vivo)纤维化的的影响，同时也以IL-20 抗体处理，检测是否减少肝脏纤维化。我们已建立了IL-20接受器(IL-20 R1)剔除鼠，我们将此剔除鼠用CCL4处理以促进肝脏纤维化，测试此剔除鼠对於肝脏纤维化是否具有保护作用。期待未来在减缓肝脏纤维化的临床上，有些新药选择

Application Abstract: After liver injury,cytokines involved in the persistent inflammation can activate hepatic stellate cells and fibroblasts to secret several fibrogenic cytokines.These cells consequently synthesize large amount of extracellular matrix proteins and inhibit their degradation.Liver fibrosis is the excessive accumulation of extracellular matrix proteins in most types of chronic liver diseases.Advanced liver fibrosis results in cirrhosis.Several proinflammatory cytokines such as TNF- and IL-6 are involved in the the process of liver fibrosis.On the other hand,the anti-inflammatiry cytokine,IL-10,provides protective effects on liver fibrosis.IL-20 belongs to the IL-10 family and is involved in inflammation.Our previous studies have shown that IL-20 is involved in rheumatoid arthritis,renal failure,osteoporosis,psoriasis,stroke,atherosclerosis etc.Little is known about the role of IL-20 on liver diseases.Therefore,we are aimed to explore whether IL-20 is involved in the liver fibrosis.Our preliminary study has shown that IL-20 may be associated with liver fibrosis.Using immunohistochemical staining,we found IL-20 was upregulated in the liver section of liver cirrhosis patients.Cell sources and target cells of IL-20 have been identified.The effects of IL-20 in primary cells or cell lines involved in liver fibrosis will be determined by real-time PCR,ELISA assay,ROS detection,cell proliferation and migration assays.The signal transduction pathways regulating these effects of IL-20 wil be investigated.Liver fibrosis animal models can be established to confirm the in vivo functions of IL-20.We have generated the IL-20 monoclonal antibody and confirmed its specificity.We will treat the disease animal model with IL-20 antibody to monitor the efficacy of antibody to reduce fibrosis.In addition,we have successfully established an IL-20 receptor knock-out mice.We will generate the fibrosis animal model on the IL-20 R1 knock-out mice to study if the knock-out mice were protected from liver fibrosis.If the IL-20 receptor knock-out mice can be protected from liver fibrosis or our IL-20 antibody can alleviate liver fibrosis in the disease mice,our IL-20 antibody or IL-20 R1 antibody may be a potential therapeutic in clinics for treating liver fibrosis or cirrhosis.

项目受资助省

台湾省