NIHRDataInsights/HRCSData huggingface dataset:
Title: Understanding prosensory specification for improved regenerative therapies in the inner ear
Funder: Medical Research Council

Abstract: The prevalence of hearing loss is steadily increasing: one in six people in the UK has a hearing disability, rising to one in two for over 70 year-old. The main cause of sensorineural hearing loss is the irreversible loss of the hair cells residing in the organ of Corti, the sensory epithelium of the cochlea. A potential therapy for hearing loss could be to induce in the damaged auditory organ the regeneration of new hair cells - a process that is occurring spontaneously in non-mammalian vertebrates. However the current strategies relying on the manipulation of the molecular signals controlling hair cell differentiation alone are relatively inefficient. An alternative approach might be to re-activate the developmental signals that drive the formation of the 'prosensory' cells, which are the progenitors for both hair cells and their associated supporting cells. The essential step to achieve this is to understand how prosensory specification is regulated during ear development. We have already identified two important signals with opposing effects on prosensory specification: Notch signalling and the transcription factor Lmx1a. Using RNA-Seq screenings in the chicken and mouse inner ear, we have started to uncover some of their transcriptional targets, and several of these are components of the Wnt signalling pathway. The objectives of this project are i) to elucidate the role of Wnt/beta-catenin signalling and its interactions with Notch signalling during prosensory specification, ii) to investigate the function of specific candidate targets of Notch/Lmx1a and iii) to establish a new mouse model (Sox2-tdTomato knock-in) to investigate the transcriptional profile of otic cells at different stages of commitment towards the sensory fate. The outcomes of this research could be exploited in the future to induce hair cell regeneration by means of gene therapies or to improve existing methods for the generation of hair cells from embryonic stem cells in vitro.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EAR
Title: Understanding and alleviating hearing disability: the contribution of natural behaviours
Funder: Medical Research Council

Abstract: People use their hearing in complex and diverse situations. An individual's experience of hearing disability, and benefit from hearing aids, will depend on a unique mix of social activities, importance of success in those activities, and how much hearing aids help in different situations. It remains unclear how these factors interact to drive the experience of disability or benefit for the individual. In parallel, little is known about how people use low-level behaviours to maintain satisfactory auditory communication, and whether those behaviours change with hearing impairment and hearing aids. These knowledge gaps hinder advances in hearing devices and rehabilitation, which increasingly target specific acoustic environments and listening needs. Our research will: -Assemble a model describing how ambient acoustics, hearing impairment, hearing-aid signal processing and body movements affect hearing performance. -Determine whether real-world hearing disability/benefit is driven by key events for the individual or by a 'grand mean' of activities. -Devise and test hearing-aid fitting protocols accounting for listeners' insensitivity to acoustic changes. -Develop hearing device technologies which exploit or support listeners' natural behaviour to provide benefits beyond those currently available, and test them in the laboratory and in the field. We will also test the utility of routine clinical data to inform the prescription of interventions for hearing loss. Using a very large clinical database, we will examine whether known predictive relations are reproduced. A datamining approach will indicate whether other plausible patterns are present. Overall, the knowledge generated will facilitate the development of hearing devices and device fitting processes which provide improved benefits by taking account of individual behaviour at micro and macro-scales.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);5.3 MEDICAL DEVICES
Health categories: EAR
Title: Understanding the Consequences of Recreational Noise Exposure
Funder: Medical Research Council

Abstract: There is increasing concern that young people are damaging their hearing by exposure to recreational noise. The scale of the problem is unclear because exposure can cause damage that is undetectable by conventional audiometry, including: hair cell damage, particularly at high frequencies; cochlear synaptopathy; and retro-cochlear deficits including neural loss and demyelination. It is important to identify the full impact of recreational noise exposure so that we can: 1. Identify at-risk individuals and provide personalised healthcare advice 2. Re-evaluate recreational noise-exposure regulations 3. Adequately assess hearing ability, and provide appropriate treatments The main work package, led by Manchester, will be a longitudinal study on a large cohort of teenagers before and after their first years of potentially harmful exposure. Electrophysiological and listening tests will detect the early signs of damage, and their relation to listening habits. We will also investigate listening habits and relation to tinnitus and hearing ability in a large number of young adults using an internet survey, and we will measure the factors influencing temporary hearing loss in a laboratory-based study. These results will identify the individual factors associated with noise damage, including sex, skin tone, and prior exposure. The fourth work package capitalises on the outstanding facilities at the Sir Peter Mansfield Imaging Centre, University of Nottingham. We will optimise advanced structural MRI to detect damage to the auditory nerve and central auditory pathways, and also study alterations in resting state network connectivity. We will determine the contributions of sub-clinical and clinical deficits to listening ability. Our programme is unique in combining a world-leading audiology research group with a world-leading MRI group. The multidisciplinary approach has great potential to deliver new insights into the consequences of recreational noise exposure.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EAR
Title: Effectiveness and cost-effectiveness of home-based intervention to support early deaf child development in South Africa.
Funder: Medical Research Council

Abstract: The study concerns deaf children under 6 years in South Africa (SA) who have been enrolled the HI HOPES early intervention programme (n=1800). The research objectives are: [A] To evaluate the effectiveness and cost-effectiveness of the HI HOPES programme in order to consider its potential for upscaling throughout SA and into other countries of Sub-Saharan Africa. [B] To provide large scale data on the development of deaf children in SA aligned with the SA Government/UNICEF National Early Learning and Development Standards birth to 4 years (NELDS) as a basis for clearer identification of developmental support requirements for this population. [C] To adapt for use with deaf children, in both spoken and signed languages, the SA Government- adopted tool for the evaluation of early childhood development - the ELOM (Early Learning Outcome Measure) - so it becomes possible for the first time in South Africa accurately to evaluate deaf children's developmental progress and needs in all domains (not just language) at point of school entry. A process evaluation methodology guides the secondary data analysis of the HI HOPES data set and primary data collection on 200 infants. The outcome measures are a criterion-referenced deaf child language development scales (LDS) and early childhood development assessment (NELDS - SA). In addition, the study will adapt the ELOM (SA) to be suitable for deaf children following an online Delphi consensus approach and a test-retest reliability study (n=80). The cost effectiveness study uses a bottom-up, ingredients-based costing analysis and a cost of illness study from a societal perspective. The project will also supply data on the model, impact and costs of intervention at a level of detail to enable feasibility testing of its scalability at national level and its replicability in other countries of Sub-Saharan Africa.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: EAR
Title: Process and non-clinical development of a stem cell therapy for hearing loss
Funder: Medical Research Council

Abstract: Disabling hearing loss has a devastating effect on communication, education and employment. Sensorineural hearing loss is produced mostly by damage to the hair cells and/or their associated neurons. Hearing aids and cochlear implants (CIs) are the only therapeutic option and, although many have benefited from their use, they are not suitable for every patient and cannot fully restore normal hearing. To address these deficiencies, Rinri Therapeutics is developing a first-in-class, stem-cell-derived therapy, Rincell-1, which aims to restore hearing by replacing damaged cochlear neurons. This should provide a true regenerative, biological therapy to patients affected by auditory neuropathy. Work performed at the Rivolta Lab at the University of Sheffield generated protocols to drive the differentiation of human pluripotent stem cells into otic neuroprogenitors and established proof of concept for functional restoration. Further work identified cellular markers to purify the relevant cell types, and is demonstrating the cells biosafety. However, there is now the need to move these processes from the academic lab into an industrial setting. We are requesting funds to support the seconding of Dr Leila Abbas, a highly experienced postdoctoral researcher from the Rivolta lab with expertise in hearing loss and otic stem cells, into Rinri. Rinri has designed a GMP cell manufacture strategy, analytical and quality control (QC) procedures as well as identified key elements to be developed in the preclinical and safety path. Dr Abbas will refine and adapt them to the requirements of cell manufacturing organizations, generating new data. She will help to manage and incorporate outcomes from several work packages into the broader product development plan and interact with process development/CMC, non-clinical safety, regulatory and other clinical advisors at Rinri to build a unified and coherent approach leading to Rinri's first-in-human clinical trial authorisation.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: EAR
Title: Environment and Listener Optimised Speech Processing for Hearing Enhancement in Real Situations (ELO-SPHERES)
Funder: Engineering and Physical Sciences Research Council

Abstract: Although modern hearing aids offer the potential to exploit advanced signal processing techniques, the experience and capabilities of hearing impaired listeners are still unsatisfactory in many everyday listening situations. In part this is because hearing aids reduce or remove subtle differences in the signals received at the two ears. The normally-hearing auditory system uses such differences to determine the location of sound sources in the environment, separate wanted from unwanted sounds and allow attention to be focused on a particular talker in a noisy, multi-talker environment. True binaural hearing aids - in which the sound processing that takes place in the left and right ears is coordinated rather than independent - are just becoming available. However practitioners' knowledge of how best to match their potential to the requirements of impaired listeners and listening situations is still very limited. One significant problem is that typical existing listening tests do not reflect the complexity of real-world listening situations, in which there may be many sound sources which may move around and listeners move their heads and also use visual information. A second important issue is that HI listeners vary widely in their underlying spatial hearing abilities. This project aims to understand better the problems of hearing impaired listeners in noisy, multiple-talker conversations, particularly with regard to (i) their abilities to attend to and recognise speech coming from different directions while listening through binaural aids, (ii) their use of audio-visual cues. We will develop new techniques for coordinated processing of the signals arriving at the different ears that will allow identification of the locations and characteristics of different sound sources in complex environments and tailor the information presented to match the individual listener's pattern of hearing loss. We will build virtual reality simulations of complex listening environments and develop audio-visual tests to assess the abilities of listeners. We will investigate how the abilities of hearing-impaired listeners vary with their degree of impairment and the complexity of the environment. This research project is a timely and focussed addition to knowledge and techniques to realise the potential of binaural hearing aids. Its outcomes will provide solutions to some key problems faced by hearing aid users in noisy, multiple-talker situations.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.3 MEDICAL DEVICES
Health categories: EAR
Title: PERCEPTUAL DIFFICULTIES ASSOCIATED WITH HYPERACUSIS: ASSESSMENTS AND MODEL DEVELOPMENT
Funder: Economic and Social Research Council

Abstract: OBJECTIVE 1: Evaluate the relationship between inferred inner and outer hair cell dysfunction and EEG/psychophysical measures of synaptopathy and hyperacusis. OBJECTIVE 2: Evaluate effect of brainstem-mediated neural feedback on binaural hearing and its role in hyperacusis. OBJECTIVE 3: Evaluate the role of cortical-mediated neural feedback (via attentional networks) on decision-making in psychophysical tasks used to assess hyperacusis. OBJECTIVE 4: Develop an auditory model which can be used to simulate the effects of hyperacusis using human EEG and psychophysical data. OBJECTIVE 5: Use the model to evaluate the role of different auditory nerve fibres in synaptopathy and hyperacusis.

Lay abstract: Some people find sound levels of average volume to be too loud or even painfully loud. This condition is called hyperacusis and affects at least 15% of the population. People with hyperacusis often find it difficult to follow speech in certain situations, especially when there is background noise. This can affect a person's quality of life, such that they may regularly avoid certain social situations. Hyperacusis may arise due to damage at some level of the auditory system. There may be damage to the way in which sounds are processed within the inner ear. There could also be damage to the nerve structures and nerve pathways that convey information from the ear to the brain, or from the brain to the ear. People with hyperacusis may report different problems with their hearing due to varying degree of damage to some, or all, of these auditory structures or nerve pathways. This project will use psychological tests of sound and speech perception and recordings of neural activity from the brain (using sensors) to obtain an understanding of which auditory structures and nerve pathways are involved in the normal perception of loudness. We shall use these tests to measure sound and speech perception in people that do not have hyperacusis and also people that have had hyperacusis for different lengths of time. The data from these tests will then be used to create a computational model that can simulate the auditory processing in different parts of the auditory pathway. The model will be used to improve our understanding of hyperacusis by simulating how different types of damage to auditory structures and neural pathways can interact to contribute to hyperacusis. The model will also be used to simulate the difficulties people with hyperacusis have when listening to speech in noisy backgrounds.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EAR
Title: Incorporating active strategies in speech testing to predict communication performance
Funder: Medical Research Foundation

Abstract: Among the most important consequences of hearing impairment is difficulty with spoken conversations in everyday situations. Spoken conversation is central to humans’ capacity to communicate and is crucial for establishing and maintaining relationships, undertaking meaningful occupations, and fulfilling requirements of daily living. Unlike listening, conversation is dynamic and interactive. A person’s capacity for successful spoken conversation is therefore a function of both hearing sensitivity and the use of active communication strategies, such as eliciting repetitions or moving closer to a talker. In order to improve predictions of outcomes for individuals with hearing impairment it is necessary to quantify the benefit to individuals of using communication strategies and to understand individuals’ willingness and capacity to make use of such strategies. However, measuring conversational behaviour in controlled and repeatable clinical settings is impractical. The proposed project will incorporate active communication strategies into controlled assessment of speech comprehension to quantify the benefit of these strategies and the extent to which taking account of these strategies can improve prediction of outcomes. The proposed project will determine the factors which affect people’s willingness and capacity to employ communication strategies, the impact of communication training, and how communication strategies influence hearing device usage, benefit and satisfaction.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL;7.1 INDIVIDUAL CARE NEEDS
Health categories: EAR
Title: Experimental and theoretical investigation of cochlear hair-cell mechanotransduction
Funder: Wellcome Trust

Abstract: The inner ear is the fastest and most sensitive sensory organ in the human body. It can resolve signals a thousand times faster than the eye, and its receptor cells can detect vibrations at the atomic scale while amplifying them on a cycle-by-cycle basis. The biophysical mechanisms underlying sound detection and amplification by hair cells are, however, not well understood, mainly because of technical limitations in mechanical stimulation probes. To resolve this issue, we have designed and propose to build two new optical instruments. They will allow us to apply mechanical forces to stereocilia of hair cells at arbitrarily high frequencies using laser radiation pressure and to measure evoked motions with a sub-nanometer sensitivity and high spatial resolution using laser interferometry. Thanks to this technological breakthrough, we will be able to study mammalian hair-cell mechanotransduction at any physiologically relevant frequency and we will be able to address, systematically and quantitatively, a range of fundamental questions about the biophysics of mechano-electrical transduction in the inner ear. This work will help us understand the biophysical mechanisms underlying normal hearing. It may also help us understand specific hearing deficits in the deaf and hard of hearing, a prerequisite for rational hearing restoration.

Lay abstract: When speech and music are stripped of their emotional components, they reduce to travelling waves of pressure. Vertebrates convert these waves into intelligible electrical signals using hair cells, the receptor cells of the inner ear. Each hair cell has a bundle of microvilli (stereocilia) interconnected by molecular springs attached to mechanosensitive ion channels. Hair cells not only convert but also amplify sounds, as if equipped with miniature muscles. Unfortunately, we understand poorly how the transduction and amplification processes work. This is because it is technically challenging to apply appropriate mechanical forces to stereocilia, sensitive to atomic-scale vibrations at thousands of cycles/second. Measuring their vibrations accurately is also challenging. We plan to build new instruments to move stereocilia with light, using the same physical principle that causes a comet’s tail to bend away from the Sun. This work promises to shed light on fundamental aspects of the biophysics of hearing.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: EAR
Title: Spatiotemporal single-cell multi-omics to unlock hair cell regeneration
Funder: Wellcome Trust

Abstract: In humans, as with all mammals,, the loss of auditory sensory hair cells (HCs) is irreversible. However, different degrees of HC regeneration occur in vestibular sensory epithelia, at early developmental stages, or in non-mammalian species. HC regeneration results from division and/or trans-differentiation of neighbouring supporting cells (SCs). It is generally accepted that poor/absent HC regeneration relates to the differentiation state reached by SCs and HCs, but the mechanisms behind this are unknown. What dictates HC regeneration potential? Taking on a multi-layered approach, combining single-cell multi-omics, in-situ sequencing and transcriptional manipulations, I will study the vestibular utricle to evaluate the connection between maturation and HC regeneration potential. First, I will identify the cell/tissue level factors that interact during maturation to distinguish the mouse (marginally-regenerating) and chick (fully-regenerating) utricle. Second, I will study the regeneration trajectories of postnatal and adult mouse utricle to zoom-in on the factors driving the age-related decrease in regeneration potential. Finally, I will perform simultaneous transcriptional manipulation of identified targets aiming to overturn the poor HC regeneration of the adult mammalian utricle. My research will generate unprecedented cell/tissue-level insight on the maturation and regeneration of sensory epithelia, identifying potential novel therapeutic avenues for recovery from pathological HC loss.

Lay abstract: Our senses of hearing and balance use highly-specialised cells, located in the inner ear, to communicate sound and head movement information to the brain. These are called hair cells (for their hairy-like protrusions), and are so specialised that it is very difficult to replace them when they are damaged. In fact, auditory hair cells cannot be recovered, while the vestibular ones can be replaced, but very inefficiently. Interestingly, this regeneration is more prominent at young ages. My project will study how the inefficient regeneration of vestibular hair cells relates to age. I will use the latest single-cell genomics techniques to look at the genes each cell uses while maturing and/or regenerating. I will also investigate whether changing the use of key genes can overturn the age-related loss of hair cell regeneration. In this way, we will be one step closer to developing therapies for tackling balance disorders and deafness.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: EAR