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

该项目的目的是确定第七因子激活蛋白酶（FSAP）在血管疾病中的作用机制，并进一步开发其诊断和治疗潜力

• 批准号: 147662156
• 负责人: Professor Dr. Sandip M. Kanse, Ph.D.
• 金额: --
• 依托单位: Avdeling for biokjemi
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/147662156?language=en
• 关键词: aim; project; identify; mechanism; action

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.

因子VII活化蛋白酶（FSAP）是一种新型血浆蛋白酶，已显示与人类血管疾病相关，因为马尔堡I（MI，G534 E）多态性是动脉粥样硬化、中风和静脉血栓栓塞的突出危险因素。我们已经启动了许多研究，以探讨这种蛋白酶在血管重塑事件，如再狭窄，动脉粥样硬化和肺动脉高压的作用。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。这些将涉及使用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。然后将在血管疾病模型中研究这些FSAP操作的小鼠。此外，WT-和MI-FSAP将以治疗量在细菌和酵母中过表达。这些蛋白质也将在上述动物模型中进行测试。此外，重组FSAP蛋白还将用于结构功能研究、底物特异性测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。

项目成果

Factor VII-Activating Protease Is Activated in Multiple Trauma Patients and Generates Anaphylatoxin C5a

• DOI: 10.4049/jimmunol.1103029
• 发表时间: 2012-03-15
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Kanse, Sandip M.;Gallenmueller, Andrea;Huber-Lang, Markus
• 通讯作者: Huber-Lang, Markus

The Factor VII-activating Protease (FSAP) Enhances the Activity of Bone Morphogenetic Protein-2 (BMP-2)*

因子 VII 激活蛋白酶 (FSAP) 增强骨形态发生蛋白 2 (BMP-2) 的活性*

• DOI: 10.1074/jbc.m112.433029
• 发表时间: 2013
• 期刊: The Journal of Biological Chemistry
• 作者: Roedel EK;Schwarz E;Kanse SM
• 通讯作者: Kanse SM

Defective thrombus formation in mice lacking endogenous factor VII activating protease (FSAP)

缺乏内源性VII因子激活蛋白酶（FSAP）的小鼠中的缺陷性血栓形成

• DOI: 10.1160/th14-06-0519
• 发表时间: 2015
• 期刊: Thrombosis and Haemostasis
• 影响因子: 6.7
• 作者: Subramaniam S;Thielmann I;Morowski M;Pragst I;Sanset PM;Nieswandt B;Etscheid M;Kanse SM
• 通讯作者: Kanse SM