肝巨噬细胞在肝纤维化进展和消退中发挥重要调控作用，是极具潜力的治疗靶点。近来巨噬细胞亚群来源和活化模式的异质性研究获突破性进展，但不同亚群和活化模式的巨噬细胞在肝纤维化中的作用及机制仍不清楚。我们利用巨噬细胞特异性RBP-J剔除小鼠发现： Notch-CYLD信号通过抑制NF-κB减轻肝纤维化；给肝纤维化小鼠回输培养的M1型巨噬细胞或Kupffer细胞可有效减轻肝纤维化。提示：Notch信号可能调控不同来源或活化模式的肝巨噬细胞参与肝纤维化的进展和消退。本课题拟以Notch信号为切入点，利用细胞命运示踪和基因修饰小鼠，结合肝纤维化模型，从分子、细胞、动物和临床标本水平回答不同亚群和活化模式的肝巨噬细胞在肝纤维化中的作用及其调控的分子机制，并建立基于巨噬细胞的肝纤维化干预方案。本研究有望揭示巨噬细胞亚群和功能异质性在肝纤维化中的作用和机制，为肝纤维化治疗提供新策略，具有重要的理论和实践意义。

Hepatic macrophages can exert dual function in the progression and regression of liver fibrosis by either promoting or abrogating the excessive deposition of extracellular matrix, which have been proposed as potential targets in combating fibrosis. Recent experimental studies reveal the breakthrough progression on macrophages heterogeneity that have been presented by the origin of macrophages subsets and macrophages function. However, the detailed molecular mechanisms of regulation on macrophages heterogeneity during liver fibrosis are not well understood. Using macrophage-specific RBP-J deficient mice, our previous studies have shown that Notch signaling blockade is required for macrophages to ameliorate hepatic fibrosis by inhibiting NF-κB activation through cylindromatosis (CYLD). Moreover, the transplantation of cultured macrophages, either bone marrow derived macrophages or Kupffer cells, into mice suffering from liver fibrosis can obviously impede the progression of liver fibrosis, suggesting that Notch signaling could regulate different origin of macrophage subsets and distinctive activation of macrophages involved in liver fibrosis. In the current project, based on Notch, we intend to clarify the molecular and cellular role of heterogeneity of hepatic macrophages subsets and macrophages activation in liver fibrosis by using several fate mapping mice and genetic modified mice. Furthermore, we will verify the role of macrophages heterogeneity in patients with liver fibrosis by using clinical tissue samples, and try to develop some possible macrophages-based interventional strategies for liver fibrosis therapy in near future These studies are expected to uncover the new molecule mechanisms on regulation of macrophages heterogeneity in liver fibrosis, and provide new strategies and targets for the treatment of liver fibrosis. Therefore, our studies are of important theoretical significance and potential application value.