*4 Year WT PhD Programme* Interrogating and manipulating ligand-receptor signalling with structure and protein engineering

ells use an intricate network of intracellular signalling molecules to translate environmental changes, sensed via surface receptors, into cellular responses. Despite the prominent role that these networks play in life itself, we still lack a comprehensive understanding of how extracellular information is conveyed through them into specific bioactivities and fate decisions. In order to rationally manipulate cell fate, which could fundamentally change the way that we currently treat human diseases, first we need a systematic understanding of how signalling is initiated and propagated inside the cell. The focus of my laboratory is to understand the cellular and molecular mechanisms determining the specificity of signalling activated by cell surface receptors. The proposed project will aim to exploit new technologies for engineering surrogate ligands, developed recently in the lab, to unveil the mechanistic bases that allow a receptor to trigger different signal activation programs and bioactivities by recruiting different ligands. By quantitatively characterizing the signalling programs activated by these altered cytokine-receptor complexes, using biochemical, genetic and fluorescence imaging techniques, we plan to identify events critical for cellular decisions. We will then use the insights generated from these studies to engineer synthetic agonists with tailored functional properties for potential pharmaceutical applications.