Dokument-ID Dokumenttyp Verfasser/Autoren Herausgeber Haupttitel Abstract Auflage Verlagsort Verlag Erscheinungsjahr Seitenzahl Schriftenreihe Titel Schriftenreihe Bandzahl ISBN Quelle der Hochschulschrift Konferenzname Quelle:Titel Quelle:Jahrgang Quelle:Heftnummer Quelle:Erste Seite Quelle:Letzte Seite URN DOI Abteilungen OPUS4-25956 Wissenschaftlicher Artikel Beck, Sarah; Stegner, David; Loroch, Stefan; Baig, Ayesha A.; Göb, Vanessa; Schumbutzki, Cornelia; Eilers, Eva; Sickmann, Albert; May, Frauke; Nolte, Marc W.; Panousis, Con; Nieswandt, Bernhard Generation of a humanized FXII knock-in mouse-A powerful model system to test novel anti-thrombotic agents Background Effective inhibition of thrombosis without generating bleeding risks is a major challenge in medicine. Accumulating evidence suggests that this can be achieved by inhibition of coagulation factor XII (FXII), as either its knock-out or inhibition in animal models efficiently reduced thrombosis without affecting normal hemostasis. Based on these findings, highly specific inhibitors for human FXII(a) are under development. However, currently, in vivo studies on their efficacy and safety are impeded by the lack of an optimized animal model expressing the specific target, that is, human FXII. Objective The primary objective of this study is to develop and functionally characterize a humanized FXII mouse model. Methods A humanized FXII mouse model was generated by replacing the murine with the human F12 gene (genetic knock-in) and tested it in in vitro coagulation assays and in in vivo thrombosis models. Results These hF12\(^{KI}\) mice were indistinguishable from wild-type mice in all tested assays of coagulation and platelet function in vitro and in vivo, except for reduced expression levels of hFXII compared to human plasma. Targeting FXII by the anti-human FXIIa antibody 3F7 increased activated partial thromboplastin time dose-dependently and protected hF12\(^{KI}\) mice in an arterial thrombosis model without affecting bleeding times. Conclusion These data establish the newly generated hF12\(^{KI}\) mouse as a powerful and unique model system for in vivo studies on anti-FXII(a) biologics, supporting the development of efficient and safe human FXII(a) inhibitors. 2021 2835–2840 Journal of Thrombosis and Haemostasis 19 11 urn:nbn:de:bvb:20-opus-259567 10.1111/jth.15488 Rudolf-Virchow-Zentrum OPUS4-30405 Wissenschaftlicher Artikel Goeritzer, Madeleine; Kuentzel, Katharina B.; Beck, Sarah; Korbelius, Melanie; Rainer, Silvia; Bradić, Ivan; Kolb, Dagmar; Mussbacher, Marion; Schrottmaier, Waltraud C.; Assinger, Alice; Schlagenhauf, Axel; Rost, René; Gottschalk, Benjamin; Eichmann, Thomas O.; Züllig, Thomas; Graier, Wolfgang F.; Vujić, Nemanja; Kratky, Dagmar Monoglyceride lipase deficiency is associated with altered thrombogenesis in mice Monoglyceride lipase (MGL) hydrolyzes monoacylglycerols (MG) to glycerol and one fatty acid. Among the various MG species, MGL also degrades 2-arachidonoylglycerol, the most abundant endocannabinoid and potent activator of the cannabinoid receptors 1 and 2. We investigated the consequences of MGL deficiency on platelet function using systemic (Mgl\(^{−/−}\)) and platelet-specific Mgl-deficient (platMgl\(^{−/−}\)) mice. Despite comparable platelet morphology, loss of MGL was associated with decreased platelet aggregation and reduced response to collagen activation. This was reflected by reduced thrombus formation in vitro, accompanied by a longer bleeding time and a higher blood volume loss. Occlusion time after FeCl\(_3\)-induced injury was markedly reduced in Mgl\(^{−/−}\) mice, which is consistent with contraction of large aggregates and fewer small aggregates in vitro. The absence of any functional changes in platelets from platMgl\(^{−/−}\) mice is in accordance with lipid degradation products or other molecules in the circulation, rather than platelet-specific effects, being responsible for the observed alterations in Mgl\(^{−/−}\) mice. We conclude that genetic deletion of MGL is associated with altered thrombogenesis. 2023 International Journal of Molecular Sciences 24 4 urn:nbn:de:bvb:20-opus-304052 10.3390/ijms24043116 Rudolf-Virchow-Zentrum