This is a Discovery Research Grant awarded to Professor Walter Marcotti at the University of Sheffield in 2019.
Background
There are extremely sensitive sound-sensing cells, called hair cells, in the inner ear. They’re called hair cells because they have hair-like structures, called stereocilia, at the top of the cell.
When sound enters the inner ear, it causes these ‘hairs’ to vibrate. This is the first step in converting a sound wave into an electrical signal – tiny channels made by proteins located in the hair-like structures are pulled open by the vibrations. This allows charged ions to move through the channels into the hair cell, a process known as ‘mechano-electrical transduction’.
The electrical currents generated are a billion times smaller than those used to charge an iPhone – nonetheless, they are the basis of our hearing. The signals are then sent to the brain along specialised nerve fibres, where they are perceived as sounds like speech and music.
The hair-like structures are arranged in a staircase-like fashion on the top of hair cells – they resemble the staggered pipes on a church organ. A large number of proteins are involved in the formation of these structures and their correct arrangement. 2 such proteins are called myosin 7a and harmonin.
Mutations in the genes for these proteins can cause Usher syndrome (deaf-blindness), which is a very debilitating condition causing hearing loss in both people and mice. The researchers have obtained data suggesting that these proteins may be playing a different role in hearing than previously thought. They now want to understand how mutations in these genes lead to hearing loss.
Aims
The researchers aim to better understand the role of myosin 7a and harmonin proteins in how the hair-like bundles in hair cells form and work normally. They’ll also study why their loss causes severe-to-profound hearing loss.
They’ll assess how well hair cells are working in mice which have been genetically engineered to lack either myosin 7a or harmonin. To do this, they’ll use a technique called ‘electrophysiology’. They’ll measure the tiny electrical currents produced by hair cells when their hair-like bundles are moved with a jet of fluid. This mimics what happens in the inner ear when sound waves make the hairs vibrate.
They’ll also measure how well the mice can hear using methods similar to those used to test hearing in people. Finally, they’ll look at what happens to these hair-like structures when the above key proteins are missing, using various microscope imaging techniques. They’ll then use their results to generate a computer model of hair cells to better understand the roles of myosin 7a and harmonin.
Benefit
Currently, there are no treatments available that can reverse hearing loss or restore hearing. Recent developments in gene therapy technology have highlighted its potential to treat hearing loss.
However, to develop effective gene therapy approaches, we need to have a detailed understanding of the molecules involved in hearing loss.
This project will identify processes involved in the development of Usher syndrome and other types of hearing loss. In the long term, it’ll help to identify molecules in the inner ear that could be targeted by treatments to restore hearing.