原发性胆汁性肝硬化（PBC）是一种肝脏特异的自身免疫性疾病。多种免疫细胞在汇管区浸润导致肝内中小胆管损伤，胆汁淤积，导致肝脏纤维化，肝硬化，甚至肝衰竭。目前，在PBC疾病发生早期发挥重要作用的天然免疫调控机制的研究相对受到忽视。肝窦内大量存在的巨噬细胞能够广泛调控肝脏内的代谢平衡和免疫应答。而在PBC中，巨噬细胞发挥的作用及分子机制尚不明确。本项目以肝脏免疫中发挥重要功能的巨噬细胞为研究对象，在细胞免疫层次对巨噬细胞进行功能亚群的拆分；并采用分子免疫学的研究方法，致力于明确肝脏中巨噬细胞在自身免疫病理微环境中的不同功能状态，揭示巨噬细胞所发挥的免疫调控机制。在巨噬细胞组学研究的基础上，进一步筛选能够干预巨噬细胞免疫功能的特异分子，利用稳定性好、细胞靶向性高的纳米分子包被这些调控性分子，向体内的巨噬细胞输送，从而达到以巨噬细胞为靶点调控肝脏免疫微环境，恢复免疫平衡的目的。

Primary biliary cirrhosis (PBC) is a liver-specific autoimmune disease. Increased portal infiltration of various immune cells result in bile duct damage and cholestasis, which translate into fibrosis, cirrhosis and even liver failure. To date, researches regarding the innate immune regulation, which plays an important role during the early stage of PBC,were negleted. The metabolic adaptation and hepatic immune responses are extensively regulated by liver macrophages that abundantly reside in liver sinusoids. However, the exact role of liver macrophages in PBC and the molecular mechanisms undertaken are largely uncertain. The project will focus on liver macrophages that exert crucial roles in liver regional immunity. At the level of cellular immunity, liver macrophages with different phenotypes will be separately analyzed with respect to origin and function; at the level of molecular immunity, we strive to clarify the different functional status of liver macrophages under pathological microenvironment, and to illustrate their critical immunregulatory roles in autoimmune liver disease. Further, based on omics studies in macrophages, our group will screen for specific agents that may intervene in the immune function of liver macrophages. Then we seek to target liver macrophages by transferring these agents coated with stable nanomaterials for cell-specific uptake, thus modulating immune microenvironment and finally to restore the immune balance in liver.