This is a fellowship grant awarded to Dr Emma Kenyon at the University of Sussex. The project will end in May 2021.
Aminoglycoside antibiotics are crucial for treating a wide range of serious infections. Aside from penicillin, they are the most commonly used drugs in neonatal intensive care units. These drugs save lives; but unfortunately, they can also damage structures in the inner ear and lead to hearing loss, balance problems and/or tinnitus. The rate of hearing loss in premature babies treated with aminoglycosides is estimated to be at least six times higher than in babies born at full-term.
Drugs which damage the ear in this way are known as ‘ototoxic’ (ear-toxic). As well as aminoglycosides, some cancer treatment drugs containing platinum can also damage hearing. Most ototoxic drugs cause the death of hair cells – the sound-sensing cells in our inner ear. They are called hair cells because they have tiny, hair-like projections at the top of the cell which move in response to sound vibrations.
Ototoxic drugs enter hair cells through tiny channels in these projections, or via small, bubble-like sacs (vesicles) that normally carry essential materials, such as nutrients, into the cell. Once inside the hair cell, these drugs cause a chain reaction of events that increases the production of toxic chemicals and damages the structures that generate energy for the cell to use. Ultimately, the cell degenerates and dies – and can’t be replaced.
Previous studies have shown that, whichever way the aminoglycosides get into the cell, they end up in larger vesicles in the cell called lysosomes, where they’re broken down. We know that the longer it takes for them to reach the lysosomes, the more toxic they are to the hair cells. However, what we don’t know is how these antibiotics are moved (trafficked) though the hair cell and delivered to the lysosomes.
In her project, Emma will study how ototoxic drugs are delivered to lysosomes in hair cells. The ultimate aim of her research is to find ways to speed up the process and thus prevent hair cell toxicity.
A group of proteins, called Rab GTPases, act as ‘traffic controllers’ in cells – they control the movement of vesicles within the cell. They are therefore likely to be involved in the movement of aminoglycoside antibiotics within hair cells. Emma will use fluorescent tags to label aminoglycoside drugs and different Rab GTPase proteins. She will then look at how aminoglycoside antibiotics are trafficked through hair cells, and find out which of the many types of Rab GTPase proteins are involved.
She will study both zebrafish and mice. While the latter are often used to create models of human diseases, zebrafish have an edge when it comes to studying hearing. This is because they have a row of hair cells very similar to the ones we have in our inner ear located on the outside of their bodies. This makes the cells very easy to see and image – and, as they’re so similar to our own, they can be used to study the processes happening inside hair cells.
Emma will then carry out similar experiments using mice, which have an inner ear and biology similar to ours. If she finds that the same processes and proteins are involved in ototoxicity in both zebrafish and mice, this will strongly support the idea that her findings apply in humans as well.
These findings will help other researchers working to protect hearing from ototoxic drugs to understand how they affect hair cells. Such information may also help in developing aminoglycoside antibiotics which are just as effective in treating infections but no longer damage hearing.