Molecular pathobiological studies on anti-coagulant protein C pathway which is essential for the vital functions

在本研究项目中，我们对生命功能所必需的抗凝蛋白C通路相关因子进行了分子病理生物学研究。我们得到了几个新的发现，描述如下：首先，我们发现凝血酶激活纤维蛋白溶解抑制剂（TAFI）和纤溶酶原激活物抑制剂-1 （PAI-1）在非肥胖的2型糖尿病患者中存在不同的代谢相关性。其次，我们证明了脂多糖诱导的肝细胞中蛋白S表达下降是由MEK/ERK信号传导和NFkappaB激活介导的：这种现象与膜结合的CD14和toll样受体-4有关。然后，我们发现蛋白C抑制剂（PCI）在单芥蓝碱诱导的肺动脉高压中起保护作用。此外，我们通过使用tenascin C缺陷小鼠，证明了tenascin C缺乏可以减轻过敏原诱导的小鼠支气管哮喘。随后，我们通过体外和体内研究证明了组织因子途径抑制剂（TFPI）的气管内基因转移可减轻肺纤维化。此外，我们通过使用TAFI敲除小鼠发现TAFI缺乏可减轻博莱霉素诱导的肺纤维化。此外，我们证明肝硬化大鼠肝细胞和窦内皮细胞中蛋白S的表达存在差异调节。此外，我们在精浆凝血系统的一系列综述中描述了PCI、前列腺特异性抗原（PSA）和精浆胶质系统之间的相互作用。我们先后发现PCI对乳腺癌细胞生长、转移和血管生成的抑制作用独立于其蛋白酶抑制活性。最后，我们证明了人PCI在肝脏再生中也发挥了活化肝细胞生长因子激活因子抑制剂的作用。

In this research project, we performed molecular pathobiological studies on the factors involved in the anti-coagulant protein C pathway which is essential for the vital functions. We obtained several new findings, described as follows:First we found that there are different metabolic correlations of thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) in non-obese type 2 diabetic patients. Secondly we demonstrated that lipopolysaccharide-induced decreased protein S expression in liver cells is mediated by MEK/ERK signaling and NFkappaB activation: This phenomenon is involvement of membrane-bound CD14 and toll-like receptor-4. Then, we showed that protein C inhibitor (PCI) plays a protective role in monocrotaline-induced pulmonary hypertension. Further, we demonstrated that deficiency of tenascin C attenuates allergen-induced bronchial asthma in the mouse by using tenascin C deficient mice. Successively we demonstrated that intratracheal gene transfer of tissue factor pathway inhibitor (TFPI) attenuates pulmonary fibrosis by in vitro and in vivo studies. Further, we showed that TAFI deficiency attenuates bleomycin-induced lung fibrosis by using TAFI knockout mice. Furthermore, we demonstrated that there is a differential regulation of protein S expression in hepatocytes and sinusoidal endothelial cells in rats with cirrhosis. Moreover, we described a review in a series of reviews on seminal plasma clotting system that the interaction among PCI, prostate-specific antigen (PSA), and the semenogelin system. Successively, we found that human PCI inhibits breast cancer cell growth, metastasis and angiogenesis independently of its protease inhibitory activity. Lastly, we demonstrated that human PCI also plays a role as an inhibitor of activated hepatocyte growth factor activator in the liver regeneration.