Understanding the role of hair cell mechanoelectrical transduction in age-related and noise-induced hearing loss
Award Number
BB/X000567/1Status / Stage
ActiveDates
1 October 2022 -30 September 2025
Duration (calculated)
02 years 11 monthsFunder(s)
BBSRC (UKRI)Funding Amount
£467,029.00Funder/Grant study page
BBSRC UKRIContracted Centre
University of SheffieldPrincipal Investigator
Dr Stuart JohnsonPI Contact
s.johnson@sheffield.ac.ukPI ORCID
0000-0001-8357-797XWHO Catergories
Understanding Underlying DiseaseDisease Type
Dementia (Unspecified)CPEC Review Info
| Reference ID | 695 |
|---|---|
| Researcher | Reside Team |
| Published | 07/07/2023 |
Data
| Award Number | BB/X000567/1 |
|---|---|
| Status / Stage | Active |
| Start Date | 20221001 |
| End Date | 20250930 |
| Duration (calculated) | 02 years 11 months |
| Funder/Grant study page | BBSRC UKRI |
| Contracted Centre | University of Sheffield |
| Funding Amount | £467,029.00 |
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). 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. 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. 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.
Aims
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).