This multidisciplinary PhD project will determine how changes in apical/basal spatial positioning of primary cilia regulate fundamental epithelial mechanosensitivity and kidney health.

Primary cilia are slender hair-like organelles, found in most eukaryotic cells where they function as a nexus for a variety of cell signalling pathways important in tissue development, health, and disease. These ciliary signalling pathways include mechanosignalling through which cells sense and respond to mechanical forces. In particular, fluid flow over the apical surface of a cell is thought to trigger changes in cell function associated with bending of the primary cilia. However, the underpinning mechanisms and factors which regulate this behaviour remain to be discovered.

This study will utilise kidney epithelial cells from the proximal tubule for which physiological fluid flow and cellular mechanosensing are critical to kidney health.

Initial studies will initially identify compounds that alter the expression and spatial localisation of primary cilia on either the basal or apical surfaces. This work will utilise our existing high throughput confocal microscopy screening data of 1700 FDA-approved small molecules. The student will validate the hit compounds using confocal and super resolution microscopy in the kidney epithelial cells. Studies will also determine whether cilia localisation is modulated by changes in the stiffness of the cellular microenvionment, such as might occur during fibrosis and disease.

Studies will examine the mechanisms regulating spatial control of cilia expression and then test whether this is associated with modulation of cellular mechanosensitivity. This will involve live intracellular calcium imaging and analysis of gene and protein expression in response to fluid flow.

Finally, the project will utilise a microfluidic organ-on-a-chip model of the kidney to determine the impact of basal/apical manipulation of cilia expression on kidney health. This aspect of the work will be supported by the Queen Mary Centre for Predictive in vitro Models with extensive industry.

The student will integrate with the rest of the SurfEx doctoral training network and be part of a multidisciplinary research team at Queen Mary University of London investigating primary cilia mechanosignalling and developing and using organ-on-a-chip models.

The primary supervisor, Prof Martin Knight is the Director of the Queen Mary Centre for Predictive in vitro Models, the chair of Council for the BioMedical Engineering Association and on the leadership team for the UK Cilia Network.

  • WP: WP3