Title: Understanding the role of hair cell mechanoelectrical transduction in age-related and noise-induced hearing loss
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Age-related hearing loss (ARHL) is the most common sensory deficit and one of the most prevalent chronic diseases in the elderly. The progression of ARHL is shaped by external factors such as exposure to damaging noise. The effects of ageing and noise exposure can be exacerbated by underlying genetic abnormalities in the auditory pathway. The tip link protein cadherin-23 is essential for gating the hair cell mechanosensitive ion channels. Mutations in the cadherin-23 gene (Cdh23ahl) have been linked with early onset ARHL and a greater susceptibility to noise insult. However, we currently do not know how the Cdh23ahl mutation affects the susceptibility of the hair cells to ageing and noise insult, nor whether these two processes exacerbate hearing loss by affecting the same mechanisms at the level of hair cell mechanoelectrical transduction (MET)._x000D__x000D_ _x000D__x000D_ We will investigate MET in hair cells from a strain of mice harbouring the Cdh23ahl mutation (6N) and another where it has been repaired (6N-Repaired). The aim of this proposal is to identify the functional and structural changes to the MET apparatus that result from ageing and noise exposure (in isolation or in combination). We will establish how the mutation in Cdh23 exacerbates the progression of ARHL and whether it is a primary target during noise insult._x000D__x000D_ _x000D__x000D_ To address this aim we will 1) determine how Cdh23ahl affects the biophysical properties of the IHC MET current during ageing and whether it leads to an increased susceptibility to noise exposure; 2) identify the effect of Cdh23ahl on the mechanical and morphological architecture of the hair bundle during ageing and following noise exposure; 3) investigate how Cdh23ahl affects the Ca2+ dynamics and homeostasis in IHC hair bundles during ageing and after noise exposure._x000D__x000D_ _x000D__x000D_ Understanding the cellular mechanisms underlying ARHL is key to develop future treatments for the disease. This project requires the complementary skills present in the applicant's laboratories.

Lay abstract: Age-related hearing loss (ARHL) is a progressive sensorineural hearing loss representing the most common sensory deficit and one of the most prevalent chronic diseases in the elderly. About 12 million people in the UK and ~500 million worldwide have disabling hearing loss, with ARHL being the single biggest cause (>900 million people expected by 2050). ARHL excludes people from basic day-to-day communication, which is associated with significant psychological and medical morbidity, including social isolation and depression. Hearing loss in mid-life is the largest modifiable risk factor for dementia._x000D__x000D_ _x000D__x000D_ The progression of ARHL is shaped by our genes, which can predispose an individual to developing hearing loss. It can also be influenced by environmental factors, such as exposure to damaging noise levels, which can exacerbate the progressive decline of hearing with age. However, it is not clear whether noise exposure exacerbates ARHL by affecting the same mechanisms governing the normal intrinsic ageing process, or whether it causes additional pathologies that superimpose onto it._x000D__x000D_ _x000D__x000D_ Sound is detected by extremely sensitive sensory cells named hair cells that are located inside a bony structure called the cochlea in the inner ear. Their name derives from the hair-like elements (stereocilia) that project from their apical surface to form an intricate structure called the hair bundle. When sound enters the ear, it produces minute vibrations of the hair bundle. These vibrations initiate the conversion of sound waves into an electrical signal within the hair cells that is relayed onto nerve fibres. This electrical signal is received by the brain, allowing us to perceive speech and music for example._x000D__x000D_ _x000D__x000D_ The pivotal role of the hair bundle in sound transduction makes it a target for the damaging effects of ageing and noise. One of the key proteins present in the hair bundle is cadherin-23, which is required to initiate the conversion of sound into an electrical signal. Alterations in this protein, through genetic mutation, have been linked with early onset ARHL and a greater susceptibility to noise insult. However, we still know very little about how mutations in this protein affect the susceptibility of the hair cells to ageing and noise insult, nor how these distinct processes of hearing deterioration interact at the level of the hair bundle._x000D__x000D_ _x000D__x000D_ In this project we will investigate the function of the hair bundle in mice that have a mutation in cadherin-23, as well as normal mice, and compare how the bundle properties change with ageing and in response to damaging noise levels. By doing this we will identify the functional and structural changes to the hair bundle that result from the combination of ageing and noise exposure and establish whether this is a key contributor to the initiation and progression of ARHL in the mammalian cochlea. The project will also establish how mutation in cadherin-23 exacerbates the progression of ARHL and whether it is also a primary target during noise insult._x000D__x000D_ _x000D__x000D_ Currently, the only options available to ameliorate hearing loss are hearing aids and cochlear implants, which are beneficial but far from able to restore normal hearing. Without a fundamental understanding of why we progressively lose hearing following noise exposure and during ageing, we will not be able to develop effective treatments to either prevent or cure hearing loss. Recent developments in gene replacement technologies in mice have highlighted potentially promising therapeutic avenues. However, the success of these types of approaches relies on having a basic scientific understanding of the pathology underlying noise and age-related hearing loss, which is within the remit of this proposal._x000D__x000D_

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EAR