肝脏是人体重要器官，具很强再生能力。但在长期的肝损伤条件下，肝脏会失去再生能力，造成肝功能丧失，甚至肝衰竭。因此，深入了解肝脏再生不仅对于组织稳态维持和再生非常重要，而且对于肝脏疾病治疗也能提供新策略。传统认为肝脏再生由肝细胞自身复制或者肝干细胞增殖分化完成，但最近的系列研究明确指出在肝脏损伤再生过程中，存在以肝细胞去分化为基础的再生。显然对这一现象的分子调控机制的解析，将为促进肝脏再生提供全新思路。本项目我们拟利用肝损伤再生小鼠模型和人类病理样品，研究肝脏再生过程中细胞属性转换及其分子调控机制。鉴于SWI/SNF等染色体重塑复合物在细胞属性转换过程的重要功能，我们将聚焦SWI/SNF核心调控蛋白Arid1a，阐明其对肝细胞属性转换调控及其对肝脏再生的作用；鉴定Arid1a在此过程中调控的重要信号通路；并揭示与人类肝脏再生的相关性，从而为利用肝细胞属性转换促进肝脏再生提供新的思路。

Liver is a pivotal organ possessing strong regenerative capability. The regenerative capability diminishes in the chronic liver diseases. A deep understanding of liver regeneration not only sheds new light on the regulation of tissue homeostasis and regeneration, but also provides new strategy to treat end-stage liver diseases. Classically, it is hold that liver regenerates by either direct duplication of hepatocytes or differentiation of liver progenitor cells (LPC). Notably, latest studies showed compelling evidence of a new paradigm that liver regenerates through hepatocyte dedifferentiation into LPCs. Apparently, it is compelling to delineate the underlying molecular regulation of hepatocyte dedifferentiation in vivo. In this study, we wish to characterize the change of hepatocyte identity during injury-induced liver regeneration using mouse models and clinical human samples. Given the importance of chromatin remodeling complex in cell reprogramming, we will focus on the chromatin remodeler protein Arid1a. Arid1a is a key component of the SWI/SNF complex and is highly mutated during tumorigenic transformation of human liver cells. We will delineate the role of Arid1a in regulating dedifferentiation of hepatocytes and consequently in liver regeneration by applying genetic modified mouse line. Next, we will identify by which molecular pathway Arid1a involves in the process of dedifferentiation. Finally, by characterization of human samples with chronic liver diseases, we wish to reveal whether Arid1a and chromatin remodeling has a role in human liver pathologies. By answering these questions, we hope to provide new knowledge about injury-induced reprogramming of hepatocytes and also, suggest likely strategies to promote regeneration in livers with chronic injury.