Arthritis is defined by the uncompensated catabolism of matrix by extracellular proteases, but we have a very limited understanding of how the levels of these proteases in the extracellular matrix are kept in check or how this process is disrupted in disease.
Our recent data has unveiled a putative regulatory axis between the primary cilium, a nanoscale microtubule-based organelle and the endocytotic clearance of proteases in mouse chondrocytes. We are now exploring the hypothesis that the peri-ciliary membrane is a unique site for rapid endocytosis, conserved in evolution, particularly focusing on the narrow pit or ciliary pocket around the ciliary axoneme.
As we have no specific means to label this pocket we have combined super resolution fluorescent microscopy (using endogenous labelling of centrioles and cilium) with soft-X-ray tomography which uses natural carbon contrast to decipher the peri-ciliary membrane topography. We have high resolution 3D imaging data that clearly delineates cellular ultrastructure of primary chondrocytes and accumulated evidence using gold-and fluorophore-tagged recombinant proteases to cells that is indicative of endocytosis. This data now needs to be analysed and segmented to allow us to understand the processes that govern chondrocyte biology.
The successful candidate will work with existing data to segment and analyse cellular ultrastructure surrounding the ciliary pocket and will collect new data using the available microscopy infrastructure at beamline B24 to further understand ciliary function in primary cells.
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