This is a Discovery Research Grant awarded to Professor Jonathan Gale at University College London in 2024.
Background
Some medicines have side effects that can cause damage to the inner ear. This can cause hearing loss, balance problems or tinnitus. As a result, they are known as ototoxic (ear-toxic) medicines. A type of antibiotic called aminoglycoside antibiotics are ototoxic and can cause permanent hearing loss. Currently, aside from restricting their use and dosing, there is no way to prevent the hearing loss associated with these drugs.
Previous work from the researcher’s lab has provided evidence that a cellular process called the stress granule response may play a role in the development of this type of hearing loss. Stress granules are structures which form when a cell is put under some kind of stress (eg exposure to a toxin, an infectious agent such as a virus, or other stressors such as excessive heat) – they collect and sequester various proteins and RNA molecules in response to the stress.
It is thought that cells use stress granules as a way of protecting themselves from harm – and once the danger to the cell has passed, the stress granules usually disperse. However, sometimes, abnormal stress granules may develop which persist in the cell even after it is no longer stressed. This can happen to cells that have undergone repeated or chronic stress.
These abnormal stress granules have been linked to neurodegenerative diseases and hearing loss caused by the anti-cancer drug cisplatin. They may even play a role in the development of hearing loss as we age.
Aim
The research team have two main aims: first, they will investigate how stress granules behave in response to chronic cellular stress, like the accumulated stress that plays a part in age-related hearing loss. Second, they will investigate the role of stress granules in hearing loss caused by aminoglycoside antibiotics. As part of this aim, they will test whether a drug they have identified from previous work on stress granules can protect the sensory (hair) cells of the inner ear.
To better investigate the mechanisms of stress granule function, they will use a technique to insert a new protein into inner ear cells that can be activated by shining light on it. Activating this protein causes stress granules to form, and the researchers will be able to trigger the formation of either normal or abnormal stress granules, and thus to mimic the granules that form normally following either acute or chronic cellular stress.
They will compare the composition of these different stress granules (that is, which proteins and other molecules make them up) to each other and to those that form in response to treatment of the cells with aminoglycoside antibiotics. This will allow them to identify shared and unique molecules in the stress granules. These molecules will provide potential targets for future investigation and drug development to prevent hearing loss.
Benefit
People treated with aminoglycoside antibiotics often develop hearing loss. This work could ultimately lead to ways to reduce or prevent that hearing loss. The findings may also have implications for the treatment or prevention of age-related hearing loss.