Sussex Neuroscience

Professor Corne Kros

CorneMechanisms and prevention of drug-induced ototoxicity

Our sense of hearing depends on the correct functioning of hair cells, the cells in the inner ear that convert sounds such as speech and music into electrical signals that the brain can interpret. The aminoglycoside antibiotics, of which gentamicin is the most widely used, combat serious infections but have the unfortunate side-effect of causing damage to these hair cells, so that some 20-50% of treated patients are left with measurable hearing loss. We discovered that these drugs enter hair cells through their mechano-electrical transducer (MET) channels situated at the top of the bundles of ‘hairs’ or stereocilia, by acting as permeant blockers. Once inside the cells the drug molecules remain trapped and cannot exit. They then enter the mitochondria by an as yet unknown route, leading to apoptotic cell death. Important research aims in the lab include trying to identify and develop other blockers of the MET channel that might be otoprotective by competing with the drugs for entry into the hair cells, and to determine the mechanisms by which aminoglycosides enter mitochondria and disrupt their function in hair cells.

The student will employ electrophysiological methods  to study the interaction of candidate otoprotective compounds with the MET channels (whole-cell patch-clamp recordings of MET currents elicited by a fluid jet from mouse cochlear hair cells). To search for entry routes of aminoglycosides into mitochondria you will patch clamp mitoplasts and compare their membrane currents in the presence and absence of the drugs. Other approaches (e.g. rapid screening of compounds using zebrafish lateral line; recording of mitochondrial membrane potential and oxygen consumption; confocal and transmission electron microscopy imaging of mitochondria) will be used to address the research questions efficiently and comprehensively.

The project would suit a student with patience and attention to detail who is interested in studying the interaction of aminoglycosides with auditory hair cells, with the long-term aim of preventing ototoxicity of these otherwise clinically useful drugs.

Selected References

(For full list of publications and more details about the lab, please visit:http://www.sussex.ac.uk/lifesci/kroslab/)

Gale, J.E., Marcotti, W., Kennedy, H.J., Kros, C.J. & Richardson, G.P. (2001). FM1-43 dye behaves as a permeant blocker of the hair cell's mechanotransducer channel. Journal of Neuroscience 21, 7013-7025.

Marcotti, W., Netten, S.M. van & Kros, C.J. (2005). The aminoglycoside antibiotic dihydrostreptomycin rapidly enters hair cells through the mechano-electrical transducer channels. Journal of Physiology 567, 505-521.

Netten, S.M. van & Kros, C.J. (2007). Insights into the pore of the hair cell transducer channel from experiments with permeant blockers. In Current Topics in Membranes, Vol. 59: Mechanosensitive Ion Channels, Part B, ed. Hamill, O.P., pp. 375-398. Academic Press, New York.

Goodyear, R.J., Gale, J.E., Ranatunga, K.M., Kros, C.J. & Richardson, G.P. (2008). Aminoglycoside-induced phosphatidylserine externalisation in sensory hair cells is regionally restricted, rapid and reversible. Journal of Neuroscience 28, 9939-9952.