Cochlear stress granules - a therapeutic target for auditory protection?

An age-related decline in hearing is so common that in the UK, by the age of 70, some 70% of people suffer from a hearing loss. Both ageing and damage from environmental agents such as noise contribute to this sensory loss but because it is commonplace, the effects of hearing loss on health and wellbeing and on the economy are often overlooked.
Detecting and processing sound is a very sensitive and sophisticated process which also generates a great deal of cellular stress within the inner ear. To cope with such intrinsic stress, cells have evolved special mechanisms, one of which is the stress granule pathway. Stress granules are dynamic and highly-regulated cytoplasmic complexes of protein and RNA that have been compared to a hospital triage system, as they put cells into an emergency state to deal with stress. When they are formed the stress granules cause the cell's resources to focus on producing those proteins that can help overcome the stress. Once the stress subsides, the granules disassemble and the cell can then return to its normal state. Our own work has shown that these stress granules do form in the inner ear in response to external insults such as toxic drug treatment and noise trauma as well as in older animals that are beginning to lose hearing. Our hypothesis is that the stress granules play an important role in protecting sensory hair cells and therefore they could be an important and novel therapeutic target for hearing protection and preservation.
This research project will study the function of stress granules by a multi-disciplinary and multi pronged approach to provide evidence of their role in protection of hair cells and their viability as therapeutic target for auditory protection. Firstly, we will target two key genes that we know are part of the complexes formed in the cochlea. We will delete them specifically in the sensory cells and then assess the result of this manipulation on hearing ability and cell survival under normal conditions and after noise and ototoxic trauma. Secondly, we will test the effect of two different pharmacological treatments, that we have shown can enhance and prevent stress granule formation in a simpler cellular system, in our in-vitro models of the cochlea. If the in vitro data show hair cell protection we will extend this approach to testing their efficacy in animal models. Thirdly, we will investigate which proteins are triaged for the response to stress in the inner ear at the molecular level, using RiboTag technology. This will provide information on what the critical survival proteins are in the sensory cells of the inner ear.

The project will thus provide: (i) insight into the mechanisms underlying the hair cell response to stress, (ii) it will test whether stress granules are crucial factors for hair cell survival, (iii) whether they are a potential therapeutic target, and (iv) it will derive novel, unbiased data on the critical components that are actively translated by hair cells in response to trauma. The outcomes of this project hold both translational potential and resources to advance discovery science in this area with the development of a new database of survival factors along with new models for both stress granule biologist, neuroscientists and auditory research.

The WHO estimates that 360 million people worldwide have a disabling hearing loss. A primary cause of this sensory deficit is permanent loss of sensory receptor hair cells resulting from exposure to noise or ototoxic drugs, infection, or through ageing. No medicines are available to treat hearing loss, and hearing aids fails to provide a benefit for the majority (~90%). This leaves a clear, unmet need for a biological-based therapy that prevents hearing loss by preventing hair cell death.
Stress granules are cytoplasmic complexes of mRNA and RNA-binding proteins that form in cells undergoing stress. We have shown that stress granules form in cochlear hair cells after exposure to ototoxic drugs or noise. Our hypothesis is that stress granules play an important role in sensory hair cell survival. This project takes three approaches to test this: (1) Conditional gene deletion will be used to determine the contribution of two stress granule components, TIA-1 and Caprin-1, to hair cell survival in normal hearing and when the cochlea is challenged by acoustic or ototoxic trauma. Auditory system function will be assessed by auditory brainstem response measurement, combined with histological and immunohistochemical assessment of cell survival, stress granule formation and protein constitution. (2) Cochlear explant models will be used to test the effect of drugs that can enhance or inhibit stress granule formation on hair cell survival. Drugs that increase hair cell survival will then be further studied in animal models. (3) Conditional RiboTag mice and RNAseq will be used to determine the effects of trauma on the translational profile of sensory hair cells in vivo, and after conditional deletion of stress granule components.
The research will determine whether stress granules can regulate hair cell survival, and it has the potential to generate novel therapeutics for the protection of those sensory cells and thus the prevention of hearing loss.

Who will benefit from this research?
The primary aim of the research is to provide a significant breakthrough in the amelioration of the most common forms of hearing loss- adult onset progressive hearing loss. Without the identification of new biological based therapies it is difficult to envisage the status quo in patient experience changing. Currently, there is a lack of translational research in this area and no medicinal-based treatment for hearing loss. The only current treatment for hearing loss of this type is the use of hearing aids which are widely accepted as an inadequate treatment, with many patients not using the devices they have been prescribed. The MRC has recently identified this as an issue and put out a joint call for research networks to improve hearing aid technology (http://www.mrc.ac.uk/funding/browse/joint-mrc-epsrc-call-for-hearing-aid-research-networks/). In this call the MRC states "Hearing loss is an area of unmet clinical need that affects a large proportion of the adult population". Ageing, lifelong health and well-being are also highlighted areas in the MRC research strategy. Age-related hearing loss is the most common sensory loss in the ageing population and has effects communication leading to social isolation and depression. Clearly any breakthrough in the understanding or amelioration of acquired hearing loss which might lead to the development of therapeutic strategies will have massive qualify of life benefit and economic potential. A direct outcome of this project would be to answer the question of whether targeting a cochlear stress pathway has therapeutic potential (timescale 2-3 years). It will also provide research tools for investigating cochlear stress (timescale 2-5 years). If successful, it could form the basis of the development of drugs to protect the auditory system from damage and reducing the incidence of acquired hearing loss (timescale to clinical use 10-15 years).

Raising the profile of hearing loss and research (timescale 1-5 years). The UCL Ear Institute has a strong connection with Action on Hearing Loss, the leading UK charity concerned with hearing loss. Drs Gale and Dawson regularly takes part in presentations of their work to publicise the need for research on various visits to the UCL Ear Institute arranged through charities. Visitors are from a wide range of backgrounds from members of the public who suffer from hearing loss to members of government, journalists and policy making bodies eg discussion were held with the Surgeon General about the impact of hearing loss in the military. Dr Dawson has attended a ceremony at the House of Commons aimed at publicising the need for hearing research. In our experience patients affected by hearing loss have a great interest in understanding the cause of their hearing loss and increased understanding and dissemination of these processes will add to this knowledge basis. These visits also help such interested parties appreciate the need for scientific research and the use of animals in research.

Research staff development (1-4 years). As part of this project we will also mentor and foster the career development of Dr Lisa Nolan the post-doc on this project. The specialist nature of auditory science, particularly the unique physiology of the cochlea means scientists in this field require specialist skills. The Ear Institute has an excellent track record of mentoring young scientists from early career progression to fellowships and finally to tenure and it is expected that Dr Nolan will be applying for her own funding by the end of the project. Retention of these skill sets within hearing research is a significant outcome both in terms of supporting this project and in particular in keeping one of the few auditory scientists with a profound hearing disability within hearing research.