Grant: CIHR Fellowship

The immune system is of vital importance to maintenance of human health. There are two main branches of the immune system - the innate and adaptive immune systems. While both of these systems are required for proper defence against pathogens and other foreign challenges, it is truly the combined efforts of the two systems that provides the protection seen. At the intersection between the two systems, there are cytokines and cytokine receptors, which allow for intricate crosstalk between these systems. Many cytokine receptors are seen to have one transmembrane helix in their architecture and are thought to function by dimerizing or rearranging upon cytokine binding, resulting in signalling within the cell. Despite the vast efforts applied to the study of these receptors, the nature of how the signal is able to cross from outside the cell, with binding of the receptor, to inside the cell, where proteins will bind and downstream genes will be regulated, is poorly understood. One area of confusion is the notion that these receptors can have varied cellular responses to differential stimulus, which goes against the dogma that simple dimerization is a driving factor in these systems. I aim to fill this gap in knowledge by pursuing the structures of various full-length cytokine receptors with varying stimuli and resultant internal factors. In addition, I will use an existing toolkit of engineered ligands for a specific non-immunological cytokine receptor, EpoR, to modulate the receptor in a tunable way. In addition, we will expand this toolkit to immune cytokine receptors to decipher the differences between various receptor subtypes. Through this structural and protein engineering, we will provide vast insight into the mechanisms for cytokine signals being transduced across the membrane and provide a framework for the development of novel cytokine receptor targeted therapeutics.