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

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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.