Member for
2 years 8 months1) Mechanotransduction of platelet surface receptors GPIbα and integrin αIIbβ3 during haemostasis and thrombosis; 2) Platelet hyperreactivity in prothrombotic diseases including type 1 and type 2 diabetes and thrombotic thrombocytopenic purpura (TTP); 3) Integrin affinity and signaling and its molecular dynamics.
In hemostasis, platelet adhesion and signaling play key roles. Specifically, two platelet receptors: GPIbα and GPIIb/IIIa mediate the early and mid-stages of platelet adhesion. Platelet glycoprotein Ibα (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. GPIIb/IIIa is also known as integrin αIIbβ3 and is found exclusively on platelets; upon activation, it allows for platelet stable adhesion to VWF on the surface of sub-endothelium and promotes the expansion of the platelets plug by cross-linking via Arg-Gly-Asp (RGD) bearing ligands like soluble fibrinogen and VWF. Ligation of GPIbα and GPIIb/IIIa has been reported to trigger outside-in platelet-activating signals in a sequential fashion. In this project, I will study GPIbα and GPIIb/IIIa in the context of platelet adhesion and signal initiation. The goal is to address how ligand binding of GPIbα and GPIIb/IIIa initiates signaling in a mechanically dependent way and how GPIbα and GPIIb/IIIa trigger platelet activation. I conduct single-molecular level experiments with a fluorescence biomembrane force probe (fBFP) to systematically correlate mechanically dependent GPIbα and GPIIb/IIIa ligation with readouts of platelet activation including GPIIb/IIIa up-regulation and unbending conformational change, platelet intracellular Ca2+ signal and lipid scrambling on the plasma membrane.