Sphingosine-1-phosphate signalling in hearing loss

Progressive age-related hearing loss is very common in the population, affecting the quality of life of a large proportion of people as they get older and their families. It can start at any age. There is no medical treatment available, and hearing aids have limited value in helping to understand speech in difficult listening conditions or noisy backgrounds or to enjoy music. Hearing impairment can be profoundly isolating, both socially and economically. 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 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 one type of pathology: a failure to maintain the normal electrochemical environment around the sensory hair cells of the cochlea leading to 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. Therefore we anticipate that our findings will apply directly to human hearing loss. The proposal aims to study the role of a pathway that normally maintains lipids including sphingosine-1-phosphate (S1P) in correct balance in the body. S1P is also a bioactive lipid, with signalling properties that influence the behaviour of various cell types. We know the S1P pathway is important in hearing because mutations in three different genes involved, encoding an enzyme in the pathway (Sgms1), a transporter of S1P (Spns2) and a receptor for S1P (S1pr2) all lead to progressive deafness in the mouse. The proposed research will analyse the pathological process in detail to discover the earliest structural and physiological changes in the cochlea, establish which tissue types within the cochlea require S1P signalling to function normally, and use genetic approaches to ask if the hearing loss can be halted or reversed as a proof-of-principle. These findings will lay the foundations for the development of pharmacological approaches to manipulate S1P signalling as a treatment for progressive hearing loss.

We know that sphingosine-1-phosphate (S1P) signalling is required for hearing because mutations in three genes in this pathway lead to progressive deafness in the mouse. Analysis of these mice suggests that maintenance of the normal electrochemical environment of the fluid bathing sensory hair cells of the cochlea is at fault.
The main objective is to ask if manipulating S1P signalling can reverse hearing loss as a proof-of-principle. The specific questions are:
1. What are the mechanisms underlying progressive hearing loss in mice with mutations affecting S1P signalling?
2. Can progressive hearing loss in S1P-associated deafness be halted or reversed?
3. Is S1P signalling involved in deafness resulting from other triggers for hearing loss?
The first question will be addressed by detailed analysis of the time course of structural and physiological changes in two of the affected lines of mouse (one with rapid and one with slower progression of hearing loss) and identification of the cell types within the cochlea that require S1P signalling using a genetic approach to target gene deletion to specific cells and at specific ages. These findings will tell us which cells we need to target for treatment and when.
The second question involves using a genetic approach to restore normal gene function before, during and after the onset of hearing loss to ask if it can be prevented, halted or even reversed after it has become established. These experiments will aim to determine a critical period for treatment to avoid hearing loss.
The third question will bring in a mouse line with a defect in maintenance of the cochlear fluids due to a different cause, unrelated to S1P. In this mouse line, S1P signalling will be manipulated using genetics to ask if boosting S1P activity can improve hearing irrespective of the specific trigger. If so, then manipulating S1P signalling pharmacologically may be beneficial in a much broader range of cases of human deafness.

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 main groups to benefit include health care professionals, including clinical geneticists, otolaryngologists and audiologists, who will benefit by developing a broader understanding of what possibilities will be available in the future to offer their patients.
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.