The aim of this project is to identify the mechanism of action of factor VII activating protease (FSAP) in vascular diseases and to further develop its diagnostic and therapeutic potential

因子7激活蛋白酶（FSAP）是一种新型血浆蛋白酶，已被证明与人类血管疾病有关，因为马尔堡I型（MI, G534E）多态性是动脉粥样硬化、中风和静脉血栓栓塞的重要危险因素。我们已经开展了许多研究来研究这种蛋白酶在血管重构事件中的作用，如再狭窄、动脉粥样硬化和肺动脉高压。这些已经补充了a) FSAP的结构功能分析和b) FSAP抑制剂的开发。在应用项目中，我们将通过开发遗传模型来扩展这些先前的概念，以研究FSAP在体内的作用。这包括使用FSAP-/-小鼠，以及通过使用腺病毒表达系统表达FSAP- shrna或过表达野生型（WT）和MI-FSAP来调节内源性FSAP表达。这些fsap操纵的小鼠将在血管疾病模型中进行研究。此外，WT-和MI-FSAP将在细菌和酵母中过度表达，达到治疗量。这些蛋白质也将在上述动物模型中进行测试。此外，重组FSAP蛋白也将用于结构功能研究，底物特异性的确定和特异性抑制剂的开发。这些研究将是确定FSAP和MI-SNP在血管疾病中的作用的基础，并将有助于实现其治疗和诊断潜力。

Factor VII activating protease (FSAP), a novel plasma protease, has been shown to be linked to vascular diseases in humans since the Marburg I (MI, G534E) polymorphism is a prominent risk factor for atherosclerosis, stroke and venous thromboembolism. We have initiated many studies to investigate the role of this protease in vascular remodelling events such as restenosis, atherosclerosis and pulmonary hypertension. These have been complemented with a) structure function analysis of FSAP and b) the development of FSAP inhibitors. In the applied project we will extend these previous concepts by developing genetic models to investigate the role of FSAP in vivo. These will involve using the FSAP-/- mice and also the modulation of endogenous FSAP expression by using adenoviral expression systems to express FSAP-shRNA or to over-express wild type (WT)- and MI-FSAP. These FSAP-manipulated mice will then be investigated in models of vascular diseases. Furthermore, WT- and MI-FSAP will be over-expressed in bacteria and yeast in therapeutic quantities. These proteins will also be tested in the above described animal models. Moreover, recombinant FSAP proteins will also be used for structure function studies, determination of the substrate specificity and development of specific inhibitors. These investigations will be the basis to define the role of FSAP and the MI-SNP in vascular diseases and will help to realise its therapeutic and diagnostic potential.