Dr. Cheng Zhu (BioE, Gatech)

Committee:

Dr. Larry McIntire (BioE, Gatech)
Dr. Wilbur Lam (BioE, Gatech)
Dr. Xiaoping Du (University of Illinois at Chicago)
Dr. Renhao Li (Emory University)

“Platelet Mechanosensing via Surface Receptors GPIbα and Integrin α_IIbβ₃”

In hemostasis and thrombosis, platelet adhesion and signaling play key roles. Two platelet receptors, glycoprotein Ibα (GPIbα) and integrin α_IIbβ₃, 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. α_IIbβ₃, 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 α_IIbβ₃ 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 α_IIbβ₃ 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 α_IIbβ₃ 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.