Structure and function of the platelet receptor Ib receptor. Opening doors to novel treatments for stroke.
Ischemic stroke is a devastating disease that represents the primary reason for sustained disability and the second leading cause of death worldwide. A better understanding of underlying molecular mechanisms of the disease are required to develop new treatment strategies. The interaction between platelet glycoprotein Iba (GpIbα) and von Willebrand factor (vWF) bound to damaged sub-endothelium represents the first step in platelet adhesion and is essential for normal hemostasis and vascular repair. The interaction is mediated between the N-terminal ligand-binding domain of GpIbα and the vWF-A1 domain and is markedly enhanced as hydrodynamic shear increases, due to conformational activation of vWF or GpIbα or both. In pathological situations, such as stroke or myocardial infarction, vascular damage and enhanced shear rates occurring in stenosised arteries can cause inappropriate activation, GpIbα-vWF binding contributing to thrombus formation. This project involves studying the molecular structure of the three proteins which form the GPIb complex (GPIba,GPIbb,GPIX) in complex with a key co-factor to coagulation enzyme and cell receptor function high molecular weight kininogen.
The Emsley group solved the first crystal structure of the GPIb N-terminal domain and an inhibitor complex (Blood.2009;114(23):4883-5). JE group subsequently described the structural organisation of the receptor and the molecular basis of the rare platelet disorder BSS (Blood.2011;118(19):5292-301). More recently through collaboration a peptide anti-GPIb approach was demonstrated in a mouse model of thrombosis (Blood.2014;124(25):3799-807). Experimental evidence suggests that GPIb is a critical pathogenic factor in innate immune inflammation in the brain. Ultimately the holy grail of my research is a greater overall understanding of GPIb assembly, regulation, and a more complete description of GPIb ligand and inhibitor interactions. This will provide a toolkit to open doors in establishing structure-function relationships and probe mechanism of brain disease (JournalofCerebralBloodFlow&Metabolism (2012)32,1831–1840)
This project is open to UK, EU students and international students who are self funded.
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FTE Category A staff submitted: 44.10
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