Mammalian cellular development and regulation of the immune system crucially depend on appropriate signalling pathways initiated by dedicated cytokine-receptor assemblies at the cellsurface. The downside of such a key physiological activity is that native and mutant forms of cytokines and their receptors are often pivotal to the initiation and progression of inflammatory disorders, cellular malignancies and cancer. Interleukin-12 (IL-12) and Interleukin-23 (IL-23) are the prototypic members of the IL-12 family of cytokines and have emerged as key therapeutic targets as a result of their role in pro-inflammatory responses in psoriasis, arthritis, airway inflammation, atherosclerosis, and cancer. Such functional plurality is additionally fuelled by the sharing of common features by IL-12 and IL-23 in terms of molecular organization and utilization of receptor modules.
The objective of the proposed research program in molecular structural biology is to provide long awaited insights into the structural and molecular basis of signalling assemblies mediated by IL-12 and IL-23 and the principles of receptor sharing among cytokines of the IL-12 family. Our research initiative builds upon recent experimental work and molecular tools generated in our group. We envisage that our work will greatly impact mechanistic and therapeutic interrogation of IL-12 and IL-23 mediated signalling.