Role of cyclophilins and other EMMPRIN-ligands for platelet function and platelet-monocyte interaction

血小板是炎症性心血管过程的中枢调节因子。活化后的血小板释放各种促炎物质，包括亲环蛋白。细胞外亲环蛋白A和B可以通过细胞外基质金属蛋白酶诱导剂EMMPRIN诱导单核细胞的促炎途径。在目前的资助期内，我们可以证明细胞内CyPA是血小板Ca2+稳态的关键调节因子。因此，缺乏CyPA的小鼠几乎不受动脉血栓形成的影响。除了在血小板中发挥重要的细胞内作用外，我们还可以描述细胞外CyPA对血小板活化的重要影响。我们目前的初步数据显示，除了EMMPRIN外，可能还有其他受体参与cypa激活过程。此外，其他DAMPs（与危险相关的分子模式）可以与EMMPRIN结合，反之亦然。在接下来的资助期内，我们将描述这些新的相互作用，并阐明它们对血小板-单核细胞相互作用的影响。最后，我们打算在患者队列中评估我们的实验数据。基于这些发现，可以开发新的抗血栓物质。

Platelets are central regulators of inflammatory cardiovascular processes. Upon activation platelets release a variety of pro-inflammatory substances including cyclophilins. Extracellular Cyclophilin A and B can induce proinflammatory pathways in monocytes via the Extracellular Matrix Metallo proteinase Inducer EMMPRIN. In the current funding period we could show that intracellular CyPA is a crucial regulator of platelets Ca2+ homeostasis. Thus, mice lacking CyPA are nearly protected from arterial thrombosis. In addition to its important intracellular role in platelets we could also describe the important influence of extracellular CyPA on platelet activation. Our current preliminary data show that may other receptors than EMMPRIN could be involved in CyPAactivation processes. Furthermore other DAMPs (¿danger associated molecular patterns¿) can bind to EMMPRIN vice versa. In the following funding period they we will characterize these novel interactions and clarify their influence in platelet-monocyte interaction. Finally we intend to evaluate our experimental data in patient cohorts. Based on these findings novel antithrombotic substances could be developed.