Ball, GJ; (2013) Supporting cells and ERK signalling: determining their roles in hair cell death. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Hearing impairment is a growing problem in the human population with increased life expectancy meaning more people will be affected. Much impairment is sensorineural, arising from loss of receptor hair cells in the inner ear. Work in the neonatal cochlea and the avian inner ear has suggested that the supporting cells surrounding the hair cells may play a role in hair cell death. The cell signalling molecules ERK1/2 have been implicated in this, with their activation localised to supporting cells following hair cell damage. However, the roles of supporting cells and ERK1/2 signalling in hair cell death remain relatively uncharacterised and this thesis aims to advance characterisation. In this work, a new laser-damage paradigm has been developed to target damage to different cell types within the sensory epithelia of the inner ear. This technique has been used to demonstrate supporting cell ERK1/2 activation in both neonatal and adult epithelia following damage. Use of the protocol in MDCK monolayers revealed similar ERK1/2 activation surrounding a damage site, indicating a potentially conserved mechanism. The adult utricle preparation has been used to show that aminoglycoside-induced hair cell damage activates ERK1/2 in the nearest neighbouring supporting cells. Pharmacological inhibition of the upstream kinase MEK1/2 produced a small but significant protection of hair cells, suggesting ERK1/2 activation may play a role in hair cell death. Recent work has shown that adenoviral infection in the same utricle preparation can be used to manipulate gene activation, specifically in supporting cells (Brandon, Voelkel-Johnson et al. 2012). A constitutively-active MEK1 construct has been used to show that activating ERK1/2 exclusively in supporting cells results in hair cell phagocytosis and death. This finding supports the idea that supporting cells play a significant role in mediating hair cell death, and that activation of the ERK1/2 signalling pathway is sufficient for this.

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