肝缺血再灌注损伤（IRI）是导致术后肝功能衰竭的重要原因。大量研究报道肝IRI存在明显的性别差异，表现为男性较女性损伤更为显著，但具体机制尚不清楚。项目组前期研究发现Y染色体性别决定区域基因SRY是介导男性肝癌发生的重要原因，由此进一步推测：SRY可能是介导男性肝IRI的重要因子。我们的前期结果显示：SRY蛋白在雄鼠肝I/R后的肝组织及外周血中显著上调，而在雌鼠中不表达，肝脏特异性过表达SRY可加重小鼠肝IRI，体外实验表明SRY蛋白可激活库否细胞并上调TLR4的表达。基于此，本项目拟应用已有肝脏特异性SRY转基因小鼠，结合体外实验及临床研究，深入探讨肝I/R后激活的SRY蛋白在肝IRI中的作用及其具体分子机制：SRY蛋白在肝细胞低氧刺激下高表达并分泌至胞外，作为一种雄性特有的内源性危险信号，通过识别库否细胞表面TLR4，促发下游系列炎症反应，从而介导性别特异性肝IRI的发生。

Hepatic ischemia reperfusion injury (IRI) is an important cause of hepatic failure after operation. Considerable researches show that there is a significant gender differences in the liver ischemia/reperfusion injury, which manifests that the female are more tolerant to liver ischemia reperfusion injury than the male. Previously, we conformed that Sex-determination region on Y chromosome (SRY) is a potential oncogene accounting for gender disparity of HCC. Thus, we speculated that SRY plays an important role in the development of male liver ischemia/reperfusion injury, which might account for gender differences of the liver ischemia/reperfusion injury. The prelimary data showed that SRY expression was up-regulated in male mice liver and serum after liver ischemia/reperfusion injury and it does not express in female liver. In addition, transgenic animal model revealed that liver-specific overexpression of SRY exacerbated liver ischemia/reperfusion injury. Experiment in vitro showed that recombinant protein SRY could active Kupffer cells and up-regulate the expression of Toll like receptor 4 (TLR4). In this project, we would apply transgenic animal model together with in vitro study and clinical research, to further investigate the SRY which expressed and secreted by hepatocytes under the condition of ischemia/reperfusion via TLR4 triggering pro-inflammatory signaling pathways, and enhancing the production of inflammatory cytokine, all of which lead to sex-specific hepatocyte ischemia/reperfusion injury.