Project

Structural and molecular basis for the cooperative assembly of the pro-inflammatory TSLP:TSLPR:IL- 7Ralpha signaling complex.

Duration
01 October 2013 → 30 September 2019
Funding
Regional and community funding: Special Research Fund, Research Foundation - Flanders (FWO)
Research disciplines
  • Natural sciences
    • Other biological sciences
Keywords
pro-inflammatory TSLP:TSLPR:IL- 7Ralpha
 
Project description

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 into a ternary signaling complex. This interaction leads to a diversity of cellular effects including proliferation of pro-B cells, stimulation of myeloid and lymphoid cells, activation of dendritic cells and eliciting the proliferation of naive T cells. TSLP has been critically linked to wound repair, cell proliferation and migration of airway epithelial cells in allergic asthma. The objective of the proposed research program in molecular structural biology is to elucidate the structural and molecular basis of the TSLP signaling complex. My research proposal builds upon diverse molecular tools I developed over the last few months as well as recent exciting preliminary results, and unites structural studies (X-ray crystallography, NMR and SAXS) 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. I therefore expect that our research venture will impact a wide scientific audience ranging from the molecular biosciences all the way to the applied biomedical and clinical sciences.