当机体受到创伤感染时，革兰氏阴性菌侵入血循环并生长繁殖，产生的内毒素造成肝损伤，进而危害生命。其高发病率和高死亡率的主要原因是当前对其发病机制仍然认识不清，因此缺乏有效的靶向治疗药物。进一步深入阐明内毒素血症的发病机制，创立新的靶向干预措施具有极为重要的临床意义。最近的研究表明血小板膜蛋白C型凝集素样受体-2(CLEC-2)在炎症反应中参与维持血管壁完整性，但是其机制并不清楚。本课题的前期研究发现血小板CLEC-2缺乏的小鼠表现出更为严重的肝损伤。我们还发现CLEC-2与其配体平足蛋白作用保护肝组织的完整性和稳定性。本课题将利用组织特异性基因敲除小鼠，体内炎症模型和体外细胞分子生物学方法阐明内毒素血症过程中血小板CLEC-2与平足蛋白发生作用的途径及缓解肝损伤的机制，并为开发针对新靶点的抗炎药物提供理论依据。

Endotoxemia is the key pathophysiological process to many diseases including bacterial infections and autoimmune reactions. The main reason for its high morbidity and mortality is that its pathogenesis is still unclear, so there is a lack of effective targeted therapies. It is of great clinical significance to further clarify the pathogenesis of endotoxemia, and to establish a new targeted intervention. Platelets play an essential role in maintaining vascular integrity during inflammation. The platelet receptor C-type lectin-like receptor 2(CLEC-2) prevents inflammation-induced vascular leakage and hemorrhage. However, the mechanism by which CLEC-2 protects liver injury during endotoxemia is unknown. Our preliminary study suggests that the liver of mice lacking platelets CLEC-2 don’t have hepatic lobule structure and liver blood sinus form. The liver cells become swelling and degeneration as compared to that of wild type mice during endotoxemia. Podoplanin is the only known physiological ligand for CLEC-2. Our preliminary study shows that bacterial lipopolysaccharide (LPS) stimulation induces podoplanin expression on liver cells. It would be significant to examine whether CLEC-2 on platelets associates with podoplanin on perivascular macrophages during endotoxemia. In this proposal, we will investigate the mechanism which platelet CLEC-2 regulates liver injury by interacting with podoplanin. We will use transgenic mice and the in vitro methods to study this research. We will examine how platelet CLEC-2 ameliorates liver injury to interact with perivascular cells that express podoplanin. We will also examine the mechanism for platelet CLEC-2 to prevent vascular leakage during endotoxemia. Our study will provide novel insights into regulation of liver injury during inflammation and may lead to new therapies for inflammatory diseases.