The underlying mechanisms of aging in the inner ear

Summary for a lay audience:
Many people lose their hearing as they get older, and deafness is the most common sensory loss. Progressive hearing loss can begin at any age, even in the first few years of life. Hearing impairment can be profoundly isolating, both socially and economically, and has a major impact on the quality of life of those affected. People often first show difficulty in following conversations in a noisy background, followed by a high tone hearing loss further affecting communication. Later, the disease progresses to lower frequencies affecting the ability to detect and localize sounds. The only remedial options are hearing aids and cochlear implants, but although these may provide some benefits they do not restore normal function. We know that noise exposure can have a serious impact on hearing, and certain drugs and infections can also cause deafness, but genetics also plays a role. The variants that we carry in our DNA can make us particularly sensitive to damaging environmental factors like noise, or can lead to progressive hearing loss directly through what we presume is "poor housekeeping" of the ear. However, despite efforts to understand the underlying biological processes leading to deafness in humans, we still have very little knowledge of these processes, making it difficult to think of how to develop alternative treatments to stop or reverse the progression of hearing loss. In this project, we have turned to the mouse to get a better understanding of the causes of deafness. Mice have inner ears that are very similar both in structure and in physiology to human ears, and many of the genes we have found to be involved in deafness in mice also are involved in deafness in humans, and vice versa. The advantage of using mice is that we can control the environment to ensure they are not exposed to damaging sound levels, and we can study groups of mice that have all the same genetic variants as each other except for a single genetic variant, or mutation, that causes deafness in some of them. We have three different groups of mice each with a separate mutation in a different gene, all showing progressive hearing loss. We plan to study these in detail to understand the physiological and cellular changes of the inner ear as they lose their hearing, as well as analysing how all the genes in the genome of the mice are expressed (which means the gene is used in the first step towards making a protein) by a method called transcriptomics. We can then look for common patterns of expression of genes in the three groups of deaf mice to ask if there is a common molecular mechanism leading to hearing loss even when there are three different triggers. In addition to these analyses, we will look at multiple substances in the blood of the mice by a process called metabolomics, to discover if there are any indicators of abnormal metabolism associated with hearing loss. Both the transcriptomics and metabolomics will allow us to look for common molecular features of progressive hearing loss which may reveal points in these pathways that could be modified by drug treatment to slow down or stop the progression, which is our ultimate long-term goal.

Summary for a specialist reader
Age-related progressive hearing loss is very common in the human population and yet we know very little about the underlying mechanisms. Environmental factors like noise exposure, ototoxic drugs and infections can lead to hearing loss, but there is a significant genetic contribution and estimates of heritability are as high as 0.7 or more. However, human population studies have not yet led to any confirmed causative genetic factors. We propose to use the mouse to investigate the pathological processes. From a large-scale screen, we have recently detected three new mouse lines with targeted mutations that show normal development but progressive increase in Auditory Brainstem Response (ABR) thresholds: Ocm, with late onset progressive high frequency hearing loss, Synj2, with early onset slowly progressive high frequency hearing loss, and Zfp719, with early onset rapidly progressive high frequency hearing loss. Whilst the functions of these genes are not well understood, these three lines have the common feature of progressive hearing loss primarily affecting high frequencies. We propose to use these mouse lines to investigate the molecular networks that are required for maintenance of normal hearing and result in hearing loss when disrupted. We will define the pathological mechanisms underlying the hearing loss using electrophysiological and structural/ultrastructural analyses, and use transcriptomic and metabolomic data to construct functional and regulatory networks. We will ask if these different mutations lead to a common molecular pathway to hearing loss by analysis of these networks, and also look for potential therapeutic targets in the networks. This knowledge will allow us to select potential therapeutic targets for investigation in future studies.

Pathways to impact summary:
The proposed project is intended to produce scientific data of excellent quality that will be at the leading edge of efforts to understand the effects of aging on the ear and progressive hearing loss. The main route to academic impact will be through regular talks at scientific and clinical conferences aimed at a wide range of relevant audiences together with publication in widely-read journals in open access format.
The societal and economic impact will result from the application of our anticipated findings to the identification of new targets for development of therapies that will slow down or reverse the progress of hearing loss. The benefits to society will be realised by the people directly affected by the increasing isolation that accompanies hearing loss as well as their families who struggle to communicate with them. Economic benefits will come in the longer term from the development of new therapeutic areas within pharmaceutical companies and small biotechs, as well as from improved economic activity opportunities for the individuals affected by hearing loss.