Mapping mechanotransduction mediated by primary cilia at nanoscale

Mechanical stimulation is one of the key physiological stimuli. Abnormalities in mechanical load or in cellular mechano-sensitivity have been linked to diseases such as osteoporosis, osteoarthritis and polycystic kidney disease. No effective treatment exists for these conditions as our understanding of mechanotransduction is still incomplete. A unique membrane protrusion called primary cilium, and a number of membrane receptors sensitive to mechanical and chemical stimuli have been implicated in mechanotransduction, however the signalling pathways remain uncertain.

We hypothesise that the role of receptors involved in mechanosensing is affected by their precise location within the fine ultrastructure of the primary cilium. We will investigate this hypothesis using scanning nanopipette microscopy. We will establish recordings of channel activity in response to mechanical stimulation at precisely defined locations on primary cilium and develop a technique for mapping local sensitivity to chemical stimuli using highly localised dosing.

The established techniques will be used to gather preliminary data on the distribution of mechano-chemical receptors to support a research proposal aimed at understanding the reorganisation of mechanotransduction in ciliated cells during disease.