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最前沿，并在血管系统中巡逻以寻找损伤和炎症的迹象。当血管发生泄漏时，血小板立即被激活并通过形成栓塞来密封病变-这一过程称为止血。虽然生理止血对于维持血管完整性和生命至关重要，但血小板活化的失调会导致有害的血栓性血管闭塞。病理性血栓形成与炎性疾病如动脉粥样硬化和深静脉血栓形成有关，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。迁移的血小板机械探测它们的环境并定向地向更高浓度的细胞外基质迁移。这将血小板引导到血管损伤部位，对于精确堵塞发炎血管中的微小病变至关重要。然而，血小板迁移的作用超出了止血。血小板迁移以扫描其环境中的致病性入侵者，并堆积细菌以防止它们在生物体内传播并激发宿主免疫反应。因此，血小板迁移的分子基础的机制的理解可能会提供独特的机会，开发新的治疗策略，在治疗或预防血栓性和感染性疾病。然而，启动和控制血小板迁移的机械感应和信号转导事件仍然未知。钙信号在迁移细胞的机械转导中起着至关重要的作用，细胞外钙内流是血小板迁移所必需的。血小板在质膜中表达过多的钙通道，包括机械敏感性钙通道，其是已知调节细胞迁移的进化保守的整合膜蛋白。Piezo 1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，但它与几种人类病理学有关。Piezo 1在血小板中表达，并显示在血小板活化中起作用。基于我们的初步数据，我们假设Piezo 1激活对迁移血小板的机械致敏起着至关重要的作用。我们的目的是剖析（1）Piezo 1介导的机械传感在血小板迁移中的机制，（2）Piezo 1介导的血小板钙内流的分子下游靶点，以及（3）Piezo 1激活在止血，血栓形成和感染小鼠模型中的作用。

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.