Kupffer细胞（KC）介导的细胞凋亡及有效清除与免疫耐受微环境形成密切相关；当KC吞噬大量凋亡细胞超出其自身降解能力，则会诱导炎性反应。如何增强KC降解凋亡细胞能力进而诱导免疫耐受是亟待解决的重要问题。新近研究发现非经典自噬途径—LAP是吞噬细胞有效降解凋亡细胞的关键途径，Rubicon是启动LAP的核心蛋白，调控Rubicon蛋白活性可直接影响LAP功能。课题组预实验证实Rubicon参与肝移植术后免疫调控，改变其活性可以影响凋亡细胞降解及促炎/抗炎免疫平衡。因此，增强Rubicon的表达可能有利于形成免疫耐受微环境。本项目选择肝脏KC为靶细胞，以Rubicon为切入点，采用基因敲除、敲入及纳米技术，沉默或增强Rubicon表达，通过KC体外培养和大鼠肝移植体内实验，探讨Rubicon调控LAP在KC降解凋亡细胞中的作用及机制，阐明该途径在调节免疫微环境及诱导免疫耐受中的作用。

Previous studies demonstrated that the induction and effective clearance of apoptotic cell by Kupffer cell (KC) are closely related to the formation of immune tolerance. When phagocytizing apoptotic cells are more than KC degradation ability, it will induce inflammatory response. How to enhance the ability of KC to degrade apoptotic cells and induce immune tolerance in liver transplantation is an important problem to be solved. Recent study described that the pathway of LC3 (microtubule-associated protein 1 light chain3)-associated phagocytosis (LAP) has shed some light on this issue, and the Rubicon (Run domain protein as Beclin-1-interactingand cysteine-rich-containing) is the key component for activating the LAP pathway. Our preliminary shows Rubicon involved in the immunoregulation after liver transplantation and regulation of Rubicon activity in KC has a significant effect on the degradation of the apoptotic cells and the balance of pro-inflammatory/anti-inflammatory. We hereby put forward a hypothesis that enhancement of the LAP by Rubicon may induce liver transplant tolerance. To clarify the role of the molecule in liver tolerance induction, we will separate KC and establish liver transplantation model in rat, using knock-out or knock-in of Rubicon to inhibit or enhance Rubicon expression both in vitro and in vivo. Once the hypothesis of up-regulation of LAP by Rubicon in KC mediating tolerance induction in liver transplantation is corroborated, this molecule can become a novel target for treatment of acute rejection.