The role of Piezo 1 in mechanosensing and mechanotransduction of migrating platelets

血小板处于哺乳动物免疫反应的前沿，在脉管系统中巡逻，寻找损伤和炎症的迹象。当血管出现渗漏时，血小板立即被激活，并通过形成堵塞来密封患处——这个过程被称为止血。虽然生理性止血对维持血管完整性和生命至关重要，但血小板活化失调会导致有害的血栓性血管闭塞。病理性血栓形成与动脉粥样硬化和深静脉血栓形成等炎症有关，但也发生在全身性病毒和细菌感染中。最近的研究表明，血小板具有迁移能力。迁移血小板机械地探测它们的环境，并定向地向浓度较高的细胞外基质迁移。这引导血小板到血管损伤的地方，是必要的精确堵塞微病变在发炎的血管。然而，血小板迁移的作用超出了止血。血小板会迁移，扫描周围环境，寻找致病入侵者，并聚集细菌，防止它们在机体内传播，并为宿主的免疫反应提供动力。因此，对血小板迁移分子基础的机制理解可能为开发治疗或预防血栓性疾病和感染性疾病的新治疗策略提供独特的机会。然而，启动和控制血小板迁移的机械传感和转导事件仍然未知。钙信号在迁移细胞的机械转导中起着至关重要的作用，细胞外钙的内流对血小板迁移至关重要。血小板在质膜上表达过多的钙通道，包括机械敏感钙通道，这是一种进化保守的整体膜蛋白，已知可调节细胞迁移。piezo1是一个新发现的机械敏感通道家族的成员，尽管最近才被发现，但它与几种人类疾病有关。piezo1在血小板中表达，并在血小板活化中发挥作用。根据我们的初步数据，我们假设压电1激活在血小板迁移的机械机制中起着至关重要的作用。我们的目的是分析(1)Piezo - 1介导的血小板迁移力学传感机制，(2)Piezo - 1介导的血小板钙内流的分子下游靶点，以及(3)Piezo - 1激活在小鼠止血、血栓形成和感染模型中的作用。

Platelets are at the forefront of the mammalian immune response and patrol the vasculature for signs of injury and inflammation. When a vessel springs a leak, platelets instantaneously get activated and seal the lesion by forming a plug – a process termed hemostasis. While physiological hemostasis is essential for maintaining vascular integrity and vital to life, dysregulation of platelet activation causes detrimental thrombotic vascular occlusions. Pathological thrombosis is associated with inflammatory conditions such as atherosclerosis and deep vein thrombosis, but also occurs in systemic viral and bacterial infections. Recent studies have shown that platelets have the ability to migrate. Migrating platelets mechanical probe their environment and directionally migrate towards higher concentrations of the extracellular matrix. This guides platelets to sites of vascular injury and is essential for precise plugging of microlesions in inflamed blood vessels. However, the role of platelet migration reaches beyond hemostasis. Platelets migrate to scan their environment for pathogenic invaders and pile up bacteria to prevent their dissemination within the organism and to fuel the host immune response. Consequently, a mechanistic understanding of the molecular basis of platelet migration may offer the unique opportunity to develop novel therapeutic strategies in the treatment or prevention of thrombotic and infectious diseases. The mechanosensing and -transduction events that initiate and control platelet migration however remain unknown. Calcium signaling plays a crucial role in mechanotransduction of migrating cells and influx of extracellular calcium is essential for platelet migration. Platelets express a plethora of calcium channels in the plasma membrane including mechanosensitive calcium channels which are evolutionary conserved integral membrane proteins known to regulate cell migration. Piezo 1 is a member of a newly discovered family of mechanosensitive channels and, despite only recently being identified, it has been linked to several human pathologies. Piezo 1 is expressed in platelets and was shown to play a role in platelet activation. Based on our preliminary data we hypothesize that Piezo 1 activation plays a crucial role for mechanosening of migrating platelets. Our aims are to dissect (1) the mechanisms of Piezo 1-mediated mechanosensing in migrating platelets, (2) the molecular downstream targets of Piezo 1-mediated calcium influx in platelets, and (3) the role of Piezo 1 activation in mouse models of hemostasis, thrombosis and infection.