SUMMARY

In hemostasis and thrombosis, platelet adhesion and signaling play key roles. Two platelet receptors, glycoprotein Ibα (GPIbα) and integrin αIIbβ3, mediate the early and mid-stages of platelet adhesion in arterial environments. GPIbα is part of the GPIbα-V-IX complex that constitutes the receptor for von Willebrand factor (VWF). Its binding to VWF A1 domain enables rolling of platelets on the sites of vascular injury. αIIbβ3, upon activation, allows for platelet stable adhesion to the sub-endothelial surface and facilitates the platelets aggregation by cross-linking via soluble fibrinogen, fibronectin and VWF. GPIbα and αIIbβ3 has been reported to trigger outside-in mechano-activating signals upon ligand engagement in a sequential fashion, but exactly how the extracellular mechano-signals are transduced and translated to intracellular chemical signals remains unknown. In my PhD thesis research, I study GPIbα and αIIbβ3 in the context of platelet adhesion and signal initiation. I conduct single-molecule and single-cell level experiments to investigate 1) the conformational and functional dynamics of integrin molecules under mechanical forces; and 2) the relation between mechanical signals received by GPIbα and αIIbβ3 and platelet activation readouts, including intraplatelet Ca2+ signals, β3 integrins up-regulation, P-selectin expression and more, and decode the signaling transduction process step-by-step.