Mapping cytokine signalling networks using engineered surrogate ligands

Cells sense their environment through surface molecules known as receptors. Engagement of these receptors by factors present in the cellular milieu triggers a series of molecular events inside the cells. This leads to activation of specific gene expression programs and modification of cellular responses. How environmental information is transmitted through these intracellular signalling wires remains one of the longest-standing questions in biology. Deregulation of this process often results in disease, making its molecular understanding very relevant for human health.

I propose to obtain a detailed characterisation of the components that form these intracellular wires and their dynamics in response to alterations in the environmental conditions. I plan to engineer soluble factors that are able to engage surface receptors with different binding topologies and alter the activation of intracellular signalling networks.

By combining these engineered factors with quantitative methodologies that allow the characterisation of the signalling state of a given cell in time, I will obtain a precise understanding of how the intracellular signalling networks are formed and shaped in response to cellular stress. I believe that this will translate into a better comprehension of the functional plasticity exhibited by cells and the development of more specific and less toxic therapies.