Structural and molecular basis of proinflammatory assemblies mediated by thymic stromal lymphopoietin (TSLP).

Mammalian cellular development crucially depends on the ability of protein growth factors, also known as cytokines, to activate their cognate receptors at the cell-surface with high specificity. The downside of such a key physiological activity is that native and mutant forms of cytokines and their receptors have been implicated in inflammatory disorders, diverse cellular malignancies and cancer. Thymic stromal lymphopoietin (TSLP) is a key pro-allergic cytokine that has recently been linked to chronic airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD). TSLP-mediated signaling is initiated by the capacity of TSLP to recruit its cognate receptor, TSLPR, and the shared receptor IL7-Rα to an extracellular signaling complex. This interaction leads to a diversity of cellular effects including proliferation of pro-B cells, stimulation of myeloid and lymphoid cells, eliciting the proliferation of naive T cells, pro- and pre-B cells. TSLP has been critically linked to wound repair, cell proliferation and migration of airway epithelial cells in allergic asthma. Recent studies of TSLP have drawn a direct link to dendritic cell (DC) activation thereby linking at a molecular level that epithelial cells/tissue microenvironments directly communicate with DCs. The objective of the proposed research program in molecular structural biology is to elucidate the structural and molecular basis of the TSLP signalling complex, at a time when TSLP signalling is increasingly shown to play a central role in pro-inflammatory physiology. Our research initiative builds upon recent exciting developments in our research group and unites structural studies (X-ray crystallography, SAXS, NMR and EM) with interaction studies and cellular assays. The proposed program is timely given the recent maturation of the methods needed to tackle such complex research problems, and the worldwide thematic priority of studying protein complexes of biomedical significance in the post-genomic era. We therefore expect that our program will impact a wide scientific audience ranging from the molecular biosciences all the way to the applied biomedical and clinical sciences.