Sphingosine-1-phosphate signalling in hearing loss
Lead Research Organisation:
King's College London
Department Name: Wolfson Centre for Age Related Diseases
Abstract
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.
Technical Summary
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 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.
Planned Impact
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.
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.
People |
ORCID iD |
Karen Steel (Principal Investigator) | |
Neil Ingham (Researcher) |
Publications
Bowl MR
(2017)
A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction.
in Nature communications
Corns LF
(2018)
Mechanotransduction is required for establishing and maintaining mature inner hair cells and regulating efferent innervation.
in Nature communications
Ebrahim S
(2016)
Alternative Splice Forms Influence Functions of Whirlin in Mechanosensory Hair Cell Stereocilia.
in Cell reports
Eckert MA
(2021)
Translational and interdisciplinary insights into presbyacusis: A multidimensional disease.
in Hearing research
Ingham NJ
(2019)
Mouse screen reveals multiple new genes underlying mouse and human hearing loss.
in PLoS biology
Ingham NJ
(2016)
S1PR2 variants associated with auditory function in humans and endocochlear potential decline in mouse.
in Scientific reports
Ingham NJ
(2021)
Inner hair cell dysfunction in Klhl18 mutant mice leads to low frequency progressive hearing loss.
in PloS one
Karp NA
(2017)
Prevalence of sexual dimorphism in mammalian phenotypic traits.
in Nature communications
Lewis MA
(2020)
Hearing impairment due to Mir183/96/182 mutations suggests both loss and gain of function effects.
in Disease models & mechanisms
Description | Membership of Royal Society Science Policy Committee |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
Description | Determining the limits for reversing hearing loss |
Amount | £1,947,704 (GBP) |
Funding ID | 221769/Z/20/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2021 |
End | 02/2026 |
Description | Discovery grant |
Amount | £200,000 (GBP) |
Funding ID | G100_STEEL |
Organisation | Action on Hearing Loss |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2021 |
End | 08/2025 |
Description | Exploration of lipidomics as a diagnostic tool for different forms of hearing loss |
Amount | £10,000 (GBP) |
Funding ID | F97 |
Organisation | Action on Hearing Loss |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2019 |
End | 03/2020 |
Description | MRC project grant |
Amount | £640,097 (GBP) |
Funding ID | MR/N012119/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 06/2016 |
End | 06/2019 |
Title | Developing a treatment method to reduce hearing loss |
Description | We developed a method for treating a mouse mutant with a substance to reduce the progression of hearing loss. |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Year Produced | 2018 |
Provided To Others? | No |
Impact | We developed a treatment route that did not adversely affect the health of the mouse, carried out the dosing, and assessed the outcome using electrophysiological measurements. |
Title | Developing the protocol for lipidomics analysis of mouse inner ear |
Description | We developed a protocol to assay lipid composition in a very small sample, the mouse inner ear. |
Type Of Material | Technology assay or reagent |
Year Produced | 2017 |
Provided To Others? | No |
Impact | We succeeded in getting useful information about lipid changes during hearing deterioration in a mouse mutant inner ear. |
Title | Flow cytometry of inner ear cells |
Description | We developed a method for isolating and quantifying immune cells within the inner ear using flow cytometry. |
Type Of Material | Technology assay or reagent |
Year Produced | 2018 |
Provided To Others? | No |
Impact | We continue to develop this tool but have promising pilot data. We plan to apply this protocol for cell sorting for other projects. |
Title | Deafness gene list |
Description | Manually-curated catalogue of genes known to be involved in hearing impairment in humans and/or mouse |
Type Of Material | Database/Collection of data |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | This list has been used to prioritise candidate genes for further analysis. |
Description | Human diagnostic tools using electrophysiological and psychophysical approaches |
Organisation | University of Manchester |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are carrying out the primary research on mouse mutants with well-characterised cochlear pathologies. |
Collaborator Contribution | Our collaborator in Manchester is advising on potential human techniques for differentiating different forms of cochlear pathology. |
Impact | Involves both mouse and human electrophysiology and human psychophysics. No outputs yet. |
Start Year | 2017 |
Description | Human exome sequence analysis for age-related hearing loss |
Organisation | Medical University of South Carolina |
Country | United States |
Sector | Academic/University |
PI Contribution | We are analysing the exome sequence, selecting candidate variants, knocking these into mice and investigating the effects on hearing. |
Collaborator Contribution | The collaborators have assembled a large cohort of people with very well-characterised hearing function, mostly with hearing impairment, and collected samples for exome sequencing. |
Impact | One publication, Lewis et al 2018. Yes, highly multi-disciplinary. |
Start Year | 2017 |
Description | Industry collaboration on S1P signalling as a potential drug target for hearing loss |
Organisation | Decibel Therapeutics |
Country | United States |
Sector | Private |
PI Contribution | We have studied the effects on hearing of three different small molecules (one antagonist, two antagonists) in a mouse mutant line. |
Collaborator Contribution | The partner has provided expertise and information on pharmacokinetics. |
Impact | None yet |
Start Year | 2019 |
Description | Lipidomics analysis of multiple classes of lipids in mutant mouse samples |
Organisation | Babraham Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have collected samples for a pilot study to check the feasibility of carrying out lipidomics analysis on very small samples. We have discussed and agreed the overall experimental design. We continue to collect samples ready for the full study. |
Collaborator Contribution | The Babraham group have tested the small samples as a pilot and found that the analysis is possible. They bring their expertise in mass spec and lipid analysis to the collaboration, and contributed to the agreed experimental design. |
Impact | This collaboration is in its early stages so nothing to report yet. |
Start Year | 2018 |
Title | Popcorn, a software for linking genes to upstream regulators in a network |
Description | Popcorn, a software for linking genes to upstream regulators in a network. Used for analysis of networks, linking genes that are not otherwise discoverable using existing software. The details will be published soon, but it is available on GitHub now. Software written and developed by Dr Morag Lewis. |
Type Of Technology | Software |
Year Produced | 2020 |
Open Source License? | Yes |
Impact | We have used this software to draw up a network, soon to be published (Lewis et al). |
Title | Popcorn, a software for linking genes to upstream regulators in a network |
Description | Popcorn, a software for linking genes to upstream regulators in a network. Used for analysis of networks, linking genes that are not otherwise discoverable using existing software. The details will be published soon, but it is available on GitHub now. Software written and developed by Dr Morag Lewis. |
Type Of Technology | Software |
Year Produced | 2020 |
Open Source License? | Yes |
Impact | We have used this software to draw up a network, soon to be published (Lewis et al). |
Description | AoHL supporters laboratory visit |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Supporters |
Results and Impact | We hosted a visit of around 30 active supporters of the charity Action on Hearing Loss plus 6 charity staff, who visited the labs, watched demonstrations of research methods, listened to talks and posters, and discussed our research. |
Year(s) Of Engagement Activity | 2018 |
Description | Participation and presentation of a talk at a Zellweger syndrome patient group support weekend |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | I attended a weekend retreat organised for families affected by Zellweger disease, presented a talk about hearing loss in Zellweger and answered questions at the formal session as well as informally during the weekend. |
Year(s) Of Engagement Activity | 2019 |
Description | RNID supporters' visit to laboratory |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Supporters |
Results and Impact | Around ten supporters of the charity RNID visited the laboratory |
Year(s) Of Engagement Activity | 2023 |
Description | RNID supporters' visit to laboratory |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Supporters |
Results and Impact | Three people attended a visit to my laboratory including two RNID (charity) staff and one key supporter of the charity, to hear a talk about hearing and deafness followed by a laboratory visit with demonstrations from the team. |
Year(s) Of Engagement Activity | 2022 |
Description | RNID supporters' visit to laboratory |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Supporters |
Results and Impact | Ten people attended a visit to my laboratory including two RNID (charity) staff and eight supporters of the charity, to hear a talk about hearing and deafness followed by a laboratory visit with demonstrations from the team. |
Year(s) Of Engagement Activity | 2022 |
Description | Women in Science event |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Supporters |
Results and Impact | Around 40 people attended an evening event on "Women in Science" organised by Action on Hearing Loss. Many were scientists supported by the charity, others were active or potential supporters. There were 4 talks and Karen Steel gave one of these. There was lively discussion afterwards, and the supporters expressed appreciation of the work done. |
Year(s) Of Engagement Activity | 2018 |