近期研究发现靶向“肠肝轴”治疗非酒精性脂肪肝炎（NASH）有望成为肝病外治的新策略。并且我们前期研究证实肠源性5-HT可通过肝HTR2A通路调控NASH的进展。进一步探究发现肠嗜铬细胞中Adora2b基因表达随着NASH的进展而上调，且与肠源性5-HT-肝HTR2A轴相关基因呈正相关。基于此，本项目旨在探究肠源性ADORA2B受体通过肠源性5-HT-肝HTR2A轴调控NASH的作用及其分子机制。本课题拟应用条件性敲除小鼠（Adora2bgut-/-）、基因过表达和沉默等技术探究：①肠源性ADORA2B受体调控NASH中肠嗜铬细胞产生5-HT；②特异性阻断肠源性ADORA2B受体可通过抑制肠源性5-HT-肝HTR2A轴改善NASH；③ADORA2B受体通过激活肠嗜铬细胞中CREB和ERK1/2通路促进5-HT的产生，进而调控NASH。本项目可为NASH的治疗寻找新的思路和药物靶点。

Recent studies have found that targeting "gut-liver axis" is expected to become a new strategy for nonalcoholic steatohepatitis (NASH). And our previous studies have confirmed that gut-derived serotonin controls the progression of NASH through hepatic HTR2A signals. Further investigation revealed that the mRNA expression of Adora2b in Enterochromaffin cells was up-regulated with the progression of NASH, and was positively correlated with the gene related with gut-derived 5-HT-liver HTR2A axis of NASH. Therefore, this study is proposed to explore the molecular mechanism of intestinal ADORA2B receptor regulating the progression of NASH based on gut-derived serotonin-liver HTR2A axis. This subject is intended to use conditional knockout mice (Adora2bgut-/-) , gene overexpression and silencing, and other techniques to explore: ①Intestinal ADORA2B receptor regulates the synthesis and secretion of serotonin in enterochromaffin cells of NASH; ②Intestine-specific ADORA2B disruption ameliorates NASH through inhibiting gut-derived serotonin-liver HTR2A signals. ③ADORA2B receptor regulates serotonin production through CREB and ERK1/2 pathway in enterochromaffin cells of NASH. This project aims to find new idea and drug target for the treatment of NASH.