CHOP 调控ERO1α在急性肝损伤中的作用及其机制研究

各种肝损伤因素均可引起急性肝细胞损伤和不同程度的肝功能障碍。严重的肝细胞损伤可导致肝功能不全，甚至急性肝功能衰竭。近年来研究发现ERS(内质网应激)介导的细胞凋亡参与了缺血再灌注损伤、病毒性肝炎等肝损伤。ERS信号分子CHOP已被证实参与调节多条凋亡信号通路。本组研究证实抑制CHOP表达能明显减轻肝脏缺血再灌注损伤。ERO1α(内质网氧化酶1α)是新近发现的CHOP靶分子，在急性肝损伤中作用尚不明确。预实验发现CHOP和ERO1α在急性肝损伤肝组织中表达明显升高。本项目拟采用GaIN/LPS诱导急性肝损伤模型、CHOP基因敲除小鼠和ERO1α腺病毒，研究CHOP对ERO1α调控作用，及其在急性肝损伤的作用，探讨其对肝脏局部炎症及对肝细胞凋亡、坏死的影响。体外建立肝细胞损伤模型，探讨CHOP调控ERO1α在肝细胞凋亡中的作用及其机制。本项目的实现将为急性肝损伤的分子治疗提供新的靶点。

All kinds of liver harmful factor could cause hepatocellular damage and liver dysfunction. Severe hepatocellular damage leads to liver dysfunction, and further develops acute liver failure. Recent studies have demonstrated that ERS (Endoplasmic reticulum stress) plays key role in liver injury induced by virus hepatitis, Non-alcoholic fatty liver disease, etc. CHOP, a key ER stress molecule, which regulates many apoptosis pathways during procedure of diseases. We have demonstrated that inhibition expression of CHOP attenuated liver ischemia reperfusion injury (IRI). ERO1α (Endoplasmic reticulum oxidoreductin 1α), as a new target of CHOP, did not be investigated during acute liver injury. Our pre-experiments have shown that ERO1α was significantly increased in acute liver injury. CHOP deficiency mice, ERO1α adenovirus and GaIN/LPS induced acute liver injury model will be used to analyze relation between CHOP mediated ERO1α and acute liver injury, and investigate effects of ERO1α on inflammation and apoptosis/necrosis in liver. To further analyze effects and mechanisms of CHOP mediated ERO1α in hepatocellular apoptosis, we set up models of hepatocellular damange in vitro. The success of the project will provide a new target for molecular therapy of acute liver injury.