CD100-Plexin B信号通路促进病毒性肝炎肝纤维化的作用机制

病毒性肝炎肝纤维化是HBV/HCV等诱导的肝损伤修复异常。最新研究发现，CD100-PlexinB在损伤修复中发挥重要作用。本实验初步研究证实，肝脏炎症诱导CD100、PlexinB表达水平增加，激活肝细胞CD100-PlexinB信号转导。该信号的活化一方面可能通过干扰再生细胞的有丝分裂定位引起肝窦修复异常，另一方面可影响TGF-β1/DAN旁分泌诱导肝星状细胞活化，最终促进肝脏结节状再生和纤维化沉积等病理过程。依此提出本实验思路：在病毒介导的肝纤维化患者中检测CD100及相关因子的表达，分析CD100-PlexinB在肝细胞增殖定位、纤维化因子旁分泌过程中发挥的作用；构建CD100/PlexinB表达/干扰体系，在细胞及小鼠模型中探讨该信号诱导肝脏纤维沉积和结节状再生的分子机制；在小鼠模型中评价CD100信号阻断对肝纤维化的治疗作用及应用前景，为肝纤维化机制研究及药物研发提供实验依据。

Viral-hepatitis-induced liver fibrosis accompanied with extracellular fibrin deposition and liver nodular regeneration. Inflammation-specific hepatocyte signals plays an important role in this abnormal wound healing process. The role of CD100 in tissue repair has been discovered currently. Our experiment has confirmed that CD100-Plexin B signal was activated in inflammatory hepatocytes, which may influences hepatocyte proliferation, cellular localization and induces abnormal tissue regeneration. The activation of CD100-PlexinB signal would cause TGF-β1 / DAN expression change in hepatocyte, and affect the activation of hepatic stellate cells. For further confirm our hypothesis, we planed our experiment as: collecting blood and liver tessues from patients with viral hepatitis and liver fibrosis, analysis the fibrosis related cytokines; detecting the functions of CD100-Plexin B in hepatocyte relocalization of liver tissue; constructing CD100 and Plexin B gene-interference system and analysis the mechanism of CD100-PlexinB in fibrosis regulation; constructing mouse model to confirm the roles of CD100-Plexin B involved in hepatocyte relocalization, stellate cell activation and liver fibrosis. We hope the expected results could provide experimental evidences for studies of viral hepatitis induced liver fibrosis, as well as benefit the drug development for anti-fibrosis therapy.