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Understanding the mechanisms and significance of the changes in intercellular communication between the non-sensory cells of the ageing cochlea

Reference	BB/V006681/1
Principal Investigator / Supervisor	Professor Walter Marcotti
Co-Investigators / Co-Supervisors	Dr Federico Ceriani, Dr Marta Milo, Dr Mirna Mustapha
Institution	University of Sheffield
Department	School of Biosciences
Funding type	Research
Value (£)	437,978
Status	Current
Type	Research Grant
Start date	01/04/2021
End date	31/03/2024
Duration	36 months

Abstract

Age-related hearing loss (ARHL) is the most common sensory deficit in the elderly, leading to social isolation and depression. Despite the prevalence of ARHL in humans, there are no treatments because we know almost nothing about the disease. A key pathophysiological mechanism that is likely to contribute to ARHL involves changes in the intercellular communication among cochlear non-sensory cells. This intercellular coupling is key to the survival and function of hair cells and their neurons, because it regulates cochlear physiology and metabolic homeostasis. Cochlear intercellular coupling is mediated by gap-junction channels, which are primarily made of connexin 26 and 30, the mutation of which causes nearly half of all congenital hearing loss in many populations, highlighting their key role in cochlear function. Current evidence (including our extensive preliminary data) show that the morphology of gap-junctions, gap-junction permeability and connexin expression change with age. Our overarching hypothesis is that the morphology and functional connectivity of gap-junction channels show progressive deterioration with age, and this occurs prior to changes in the hair cells and their neurons. Our aim is to determine age-related changes in the expression and morphology of gap-junction channels, how these impact on intercellular communication and Ca2+ homeostasis in the aged cochlea, and the networks of genes that regulate these changes. We have devised 4 objectives: 1) to determine the temporal progression of age-related changes in connexin expression in the cochlea; 2) to determine whether the functional coupling between cochlear non-sensory cells is altered with age; 3) to determine whether ageing affects purinergic signalling in cochlear non-sensory cells; 4) to identify the transcriptomic changes in the non-sensory cells of ageing mice. The proposed work will be done using complementary expertise of the applicants and world-expert collaborators.

Summary

Age-related hearing loss (ARHL) is the most common health condition in the elderly. Approximately half of adults in their 70s exhibit ARHL severe enough to affect communication. It is expected that approximately 14.5M people in the UK will be affected by hearing loss by 2030, with ARHL being the single biggest cause. ARHL is a progressive disorder decreasing the ability to understand speech, especially in a noisy environment. ARHL is also associated with social isolation and depression. Although hearing aids and cochlear implants are beneficial, they cannot restore hearing, especially if the cells in the ear are missing or do not function, which are both characteristic features in ARHL. The major obstacle preventing the development of new treatments for ARHL is a lack of understanding about why we progressively lose our sense of hearing with age, making it difficult to prevent, slow down or even reverse ARHL. 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. When sound enters the ear canal it produces minute vibrations of the stereocilia. These vibrations initiate the conversion of sound waves into an electrical current by the movement of charged ions through mechanically-gated channels present in the hair cell stereocilia; a process known as mechano-electrical transduction. These tiny electrical currents, which are a billion time smaller than the current of a phone charger, are sent to the brain via nerve fibres, allowing us to perceive sound such as speech and music. Similar to the brain, the hair cells work constantly and as such they require a lot of energy, which is provided by molecules such as nutrients, travelling in the body through the blood vessels. One problem, however, is that the hair cells are very far from the blood vessels entering the cochlea. This is because the movement caused by the blood flowing through the vessels would be picked up by the hair cells, leading to a pulsating background noise in our ears. Therefore, nature has developed an intricate network of conduits that bring the nutrients from the blood vessels to the hair cells. This network is formed by a large number of cells, called non-sensory cells, that are present all around the hair cells and the blood vessels. When nutrients, such as glucose, are "released" by the blood vessels, they enter the non-sensory cells and travel from cell-to-cell via specialised channels until they reach the hair cells. These channels, also known as gap-junctions, are made by proteins called connexins. Connexins are vital for hearing since nearly half of all cases of hearing impairment present at birth in humans are due to mutations in these proteins. Our preliminary work has identified age-related changes in the way connexins function and how they are distributed in the non-sensory cells. These changes appear to occur before any degeneration is observed in the hair cells, making the non-sensory cells and connexin gap-junctions potentially key instigators of the deterioration of hearing that occurs with ageing. Therefore, the hypothesis we plan to test in this project is that non-sensory cells are a key determinant of the progression of ARHL. In this project we will use aged mice that show signs of ARHL. Mice are an ideal animal because the structure and function of their auditory system is strikingly similar to that of the human, and also because of the high level of concordance between genes critical for hearing function. This project will provide a better understanding of why and how non-sensory cells lead to the development of ARHL. The outcomes will contribute to the identification of targetable genes that will facilitate the development of diagnostic and therapeutic interventions for ARHL in humans.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Neuroscience and Behaviour, Systems Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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