Structural and cell biology studies of the galectin-3-fibrosome

Fibrosis, the deposition of collagen in a scar when regeneration is not possible, is a wound healing response that preserves tissue integrity but not function. Abnormal activation of fibrosis pathways therefore leads to chronic loss of organ function. Such disorders (e.g. IPF, a lung scarring condition with a median survival of 3 years) increase in incidence as life expectancy increases, and there are few effective treatment options.

We have identified a macromolecular assembly on the surface of epithelial and mesenchymal cells that clusters pro-fibrotic factors (for Figure see equivalent description (scroll to 2nd project listed at https://www2.le.ac.uk/colleges/medbiopsych/research/pg-research/college-studentships-2017/department-of-infection-immunity-and-inflammation-studentships-2017/infection-immunity-and-inflammation-studentships). Perturbation of this assembly protects organs from fibrotic responses to injury. It is nucleated by oligomerisation of the protein galectin-3, and so we have termed it the gal-3-fibrosome. The gal-3-fibrosome is a promising target for new anti-fibrotic therapies; the first of these is currently in clinical trials for IPF.

Galectin-3 oligomerises via its N-terminal domain, and also binds modified glycan chains on glycoproteins. Such interactions stabilise two complexes that mediate inflammatory and fibrotic cellular responses to extracellular stimuli. TGF-βRII is a key receptor for the profibrotic cytokine TGF-β1. The CD98 heavy chain (CD98hc):β1-integrin complex mediates inflammatory cytokine responses to extracellular factors including mechanical strain, via activation of a calcium channel. The plan for the studentship is to characterise galectin-3 oligomerisation, TGF-βRII structure/function and CD98hc:β1-integrin interactions in detail. To these ends the student will integrate complementary structural (X-ray crystallography, single particle EM), biophysical and cell biological (functional assays, Ca2+ influx, confocal and super resolution fluorescence microscopy) methods. The work will define novel gal-3-fibrosome targets for the treatment of IPF and other fibrotic diseases. The project will involve work with collaborators and will be based in the Leicester Institute of Structural and Chemical Biology, and will benefit from its world-class facilities, expertise and training opportunities.

For further information and to discuss the planned project further please contact Prof. Bibek Gooptu ([Email Address Removed]).