NIHRDataInsights/HRCSData huggingface dataset:
Title: Stem Cell Therapy for Sensorineural Hearing Loss - How Do Glial Cells Interact With Auditory Stem Cells in the Peripheral Auditory System?
Funder: Medical Research Council

Abstract: The ability of sensory hair cells and auditory neurones of the human cochlea to regenerate is lost soon after birth, hence later damage to these structures results in an irreversible sensorineural hearing loss. Otic neural progenitors (ONPs) derived from human embryonic stem cells have the potential to restore function in the damaged auditory nerve. However, the interaction between ONPs and glial cells is yet to be described. Furthermore, with the recent finding that auditory nerve damage results in glial cell prolieferation, it is unclear whether this is conducive or inhibitory for ONPs to differentiate into auditory neurone-like cells. Objectives 1.To determine whether auditory stem cells have the capability of producing glial-like cells 2.To identify whether auditory stem cells are able to interact with primary glial cell cultures in vitro 3.To define the nature of glial responses to injury of the auditory nerve in vivo 4.To understand if auditory stem cells are able to survive in an environment of 'cochlear gliosis' Design of study 1.ONPs will be expanded in vitro, and reverse transcriptase PCR and immunolabelling will be used to determine the presence of glia-like cells 2. Co-cultures of glial cells and ONPs in vitro will enable the deduction of the inductive influence of the former on the latter. 3. Auditory neurons will be selectively damaged using Oubain in vivo, and the ensuing glial response will be determined through immunohistology. 4. Following exposure to Oubain, ONPs will be surgically inserted into the cochlea in vivo, and their ability to differentiate in a pathological glial environment will be assessed. Medical opportunities Understanding the interaction between cochlear glial cells and ONPs is paramount in demonstrating stem cell therapy as a viable solution to SNHL and it will bring us a step closer to clinically translating potential stem cell therapies for SNHL


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EAR;NEUROLOGICAL
Title: Transcription factors for promoting sensory hair cell differentiation
Funder: Medical Research Council

Abstract: Sensorineural deafness most often results from loss of or damage to hair cells in the inner ear. Understanding the developmental biology of hair cell formation may provide strategies leading to potential therapeutic avenues to tackle deafness through: (1) gene therapy - to reactivate hair cell development in the adult inner ear; (2) stem cell therapy - to promote differentiation of stem cells for transplantation; (3) stem cell models for in vitro investigation - to use stem cells as a source of hair cells for drug screening and disease modelling. The bHLH transcription factor Atoh1 triggers hair cell formation during development and is a key factor in all the strategies outlined above. However, its function appears to be limited by as yet unknown cofactors. Our previous work on Drosophila auditory and proprioceptive sensory cells (which are homologous to vertebrate hair cells) has led to the implication of Gfi1 and SUMO as potential Atoh1 cofactors in vertebrates. Here we propose to garner critical preliminary information on the role of these factors in promoting Atoh1 function in a mouse ESC model and in zebrafish development. We shall then apply this knowledge to the development of stem cell models of hair cell formation. Firstly we shall investigate whether forced expression of Atoh1 and cofactors can promote transcriptional programming of mouse ESCs to induce hair cell differentiation. Using mouse ESCs (rather than human) allows us to take advantage of new genetic tools that we have previously developed for forced expression. We shall then apply the strategy to mouse embryonic fibroblasts. Finally, if forced expression alone is not sufficient, we shall determine whether it can be used to improve current protocols for generating hair cell-like cells from ESCs by directed differentiation using extrinsic factors, which currently have many limitations.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: EAR;NEUROLOGICAL
Title: Damaged Ears at the Cocktail Party - Investigating How Cochlear Damage Impairs the Neural Representation of Speech in Background Noise
Funder: Medical Research Council

Abstract: The ability to understand speech in complex noisy environments is considerably degraded for those with hearing impairment. Hearing thresholds alone are insufficient to explain the range of speech in noise performance seen in patients, and amplification through hearing aids only provides limited benefit. Additional factors at the peripheral as well as central level might therefore play a role. Recent data suggest that a range of hearing problems, including speech-in-noise deficits, may arise as a result of deafferentation of auditory nerve fibres (ANFs). Moreover, it is likely that neural adaptive processes, such as adaptive coding, contribute to the processing of signals in a noisy background. We hypothesize that A) deafferentation of high-threshold ANFs decreases understanding of speech in noise due to a degraded representation of the signal and B) that hearing loss decreases the capability for adaptive coding, resulting in a reduced capacity of neurons to average out mean background intensities which may be critical to separate speech from noise. To test these hypotheses, we will employ an animal model to study the neural representation of speech in noise, how it is affected by hearing loss, and the role of adaptation to sound level statistics in the central auditory system. Specific types of hearing loss will be induced using noise exposure, ototoxic drugs, or earplugs. We will then investigate the effects of these manipulations using single unit as well as intracellular recordings in the inferior colliculus. We will analyze a) how well speech tokens can be discriminated based on the neuronal activity, b) the adaptive coding capability of the neurons and how it is related to speech disciminability, and c) the influence of hearing loss on these measures. This will provide powerful insight about the peripheral and central factors contributing to speech in noise performance.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EAR;NEUROLOGICAL
Title: Imaging brain structures in children with auditory neuropathy spectrum disorder
Funder: Department of Health (England)

Abstract: This study will investigate whether advanced magnetic resonance imaging techniques can be used to find abnormalities in children diagnosed with a hearing problem called auditory neuropathy spectrum disorder (ANSD). Babies and children diagnosed with ANSD face an uncertain future as conventional hearing testing is unable to show how well they can access spoken language. The research will benefit children with ANSD as it will identify possible abnormalities in brain structure and function in people with this condition. This will increase scientific knowledge and eventually allow treatment options to be targeted towards the patient’s specific difficulty leading to more successful outcomes.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: EAR;NEUROLOGICAL
Title: Facilitating reading in posterior cortical atrophy.
Funder: The Dunhill Medical Trust

Abstract: Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterised by progressive visual impairment and posterior brain atrophy. A common and debilitating early symptom of PCA is acquired dyslexia, which likely arises from specific visual deficits. This project aims to circumvent such deficits by manipulating the presentation of text in order to facilitate reading in PCA; preliminary data (N=15) has identified an average improvement in accuracy from 57% to 96% using one manipulation. Behavioural, qualitative and eyetracking data from 24 PCA patients will inform the development of a reading intervention. The efficacy of the intervention will subsequently be assessed in home-based trials involving 48 PCA patients. Alpha- and beta- testing will shape the final intervention, which will allow users to stream digital text via a website. The intervention will be the first software-based reading tool designed for dementia-related reading impairment, allowing patients to read more effectively further into the disease course.


Research activity codes: 5.7 PHYSICAL;6.7 PHYSICAL
Health categories: EAR;NEUROLOGICAL
Title: Coding and plasticity in the adult auditory system.
Funder: Wellcome Trust

Abstract: This research is intended to improve our understanding of the neurophysiological basis for perception and behaviour by investigating the changes in neuronal response properties that accompany perceptual learning, the improvement with practice in the discrimination of sensory stimuli. We will examine the relative plasticity of different areas in the auditory cortex as ferrets improve their performance with practice in sound localization, pitch discrimination and pattern discrimination tasks. Using functional imaging, reversible inactivation and multi-site electrophysiological recordings techniques, we will identify which brain regions are activated during and are essential for the execution of those tasks. We will also investigate the role of descending corticofugal pathways and neuromodulatory inputs from the basal forebrain in learning-induced plasticity. Recordings will be made before, during and after learning takes place in order to determine how behaviourally-significant information is encoded and stored in the firing patterns of ensembles of cortical neurons and whether different sound attributes are processed in separate cortical networks. In addition to studying the effects of behavioural training in animals with normal hearing, we will investigate the capacity of the mature auditory localization system to adapt to altered spatial cues produced by introducing a reversible conductive hearing loss into one ear. We will examine the role of vision in auditory adaptation and the neurophysiological changes by which it is brought about. We will also study cortical processing and auditory localization in animals fitted with bilateral cochlear implants, in order to investigate the role of training in promoting the recovery of function in previously deaf individuals.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: EAR;NEUROLOGICAL
Title: Adaptive coding and plasticity in the auditory system.
Funder: Wellcome Trust

Abstract: The auditory scene changes all the time as voices and other sound-producing objects come and go and we move from an empty room to a busy street. Our perception of the world is therefore critically dependent on the capacity of the brain to adapt rapidly to changes in incoming stimuli and to focus attention toward sounds of interest. In addition to these transient effects, which depend on the prevailing stimulus conditions or current perceptual demands, lasting improvements in the ability to detec t or distinguish different sounds can be brought about by training. In this project, we shall investigate which brain networks are responsible for these adaptive changes when different sounds are localized or compared, and measure how the response properties of nerve cells found there are modified in response to alterations in the acoustic environment or as learning occurs. We shall also examine whether the adaptive capabilities of the brain allow auditory functions to recover when hearing becom es impaired or is restored following a period of deafness. This research will therefore improve our understanding of what happens in the brain during normal everyday hearing, and how those processes are affected by hearing loss and its restoration.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: EAR;NEUROLOGICAL
Title: Cortical bases for auditory perception.
Funder: Wellcome Trust

Abstract: The work addresses how we make sense of the sound world and how this can go wrong in common human disorders. I would test a model based on higher brain centres communicating their best guesses of what is heard to the part of the cortex that first receives the sound. We would measure human brain activity in these centres. This can be done in patients with brain electrodes to locate seizures, in whom the electrodes can also measure electrical responses to sound. Parallel work would assess bra in activity without electrodes using scanning. Both types of measurement inform us how the brain centres in the cortex influence each other, to test the model. The model might go wrong in common human disorders including tinnitus, where abnormal communication from higher centres to auditory cortex might allow spontaneous activity there, as a cause for the experience. We can also scan monkeys to test whether they perceive sound like us. Because we use sounds without meaning the work is a simp le test of whether the monkey is a useful model for human listening that might help us to understand common human disorders such as tinnitus or loss of speech due to stroke.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: EAR;NEUROLOGICAL
Title: Pleiotropic disorders of mitochondrial translation
Funder: Medical Research Council

Abstract: Perrault syndrome (PS) is a clinically and genetically heterogeneous genetic disorder presenting with profound sensorineural hearing loss (SNHL), ovarian insufficiency, and often progressive neurological impairment. The variable onset and severity of features provides a window of opportunity for therapeutic intervention. Over the past decade we, and others, have identified biallelic hypomorphic variants in 7 genes that definitively cause PS. These genes almost exclusively affect protein translation in the mitochondria. Importantly, we have discovered, more deleterious variants in PS-associated genes result in early-onset, often fatal, multi-system disorders, with neurodevelopmental delay and lactic acidosis, consistent with mitochondrial dysfunction. Our recent studies of families affected by PS have identified variants in 6 additional genes, including individuals ascertained through the 100,000 Genomes Project. Three of these new PS genes have not previously been linked to mitochondrial translation, whereas the other three are key to this process. This proposal provides a unique opportunity to determine the molecular mechanisms resulting in this pleiotropic clinical disorder and how these mechanisms can be exploited for therapeutic control. We specifically aim to i) undertake functional studies to define the effects of variants in three novel disease associated genes, DAP3, MRPL49 and ERAL1; ii) undertake studies to define how NOP14 and GPN2 result in disease through mitochondrial dysfunction; iii) determine whether altered prenylation through DAP3 results in mitochondrial disease; and iv) identify additional genes associated with PS.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EAR;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Genedrive MT-RNR1 ID Kit for detecting single nucleotide polymorphism m.1555A>G in neonates [DAP66]
Funder: Department of Health and Social Care

Abstract: Disease background _x000D_ Infection is a common cause of serious illness and death in newborn babies receiving intensive care. Infection can develop into sepsis which is a life-threatening response to an infection. _x000D_ _x000D_ Current practice _x000D_ About 1 in 2000 newborn babies will experience sepsis. But a larger group with suspected sepsis receive antibiotics. _x000D_ It is important to start antibiotics within an hour of the decision to treat. Since standard investigations for sepsis take time, antibiotic treatment is often started before receiving test results. The decision to continue treatment can be reviewed once the result comes back from the laboratory. _x000D_ Aminoglycosides are the first choice antibiotics for treating sepsis in newborn babies. But these treatments can cause hearing loss in some newborns. People with a particular genetic variant called m.1555A>G who receive aminoglycosides are at a very high risk of hearing loss. _x000D_ _x000D_ Rapid testing to identify m.1555A>G _x000D_ There are potential benefits to identifying this genetic variant in newborns, or the mother pre-birth as a proxy for the newborn, before aminoglycoside treatment. For example, a different type of antibiotic could be provided to reduce the risk of hearing loss in this group. _x000D_ Genedrive MT-RNR1 ID Kit is the first point of care test developed to identify m.1555A>G in newborns. The company that developed the test have stated the kit can provide a result in 26 minutes. So, the test has the potential to inform decisions about antibiotic treatment within the recommended start time. _x000D_ _x000D_ Current diagnostic assessment _x000D_ This diagnostic assessment will consider whether the Genedrive MT-RNR1 ID Kit has the potential to provide an effective and safe alternative to current practice for initial assessment and monitoring in new-born babies with a suspected infection. In addition, we will identify evidence gaps to support further evidence generation.

Lay abstract: We will summarise and critically appraise existing evidence on the clinical-effectiveness and cost-effectiveness of the Genedrive MT-RNR1 ID Kit for identifying the gene m.1555A>G variant in neonates.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: EAR;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Structural and biophysical basis of Connexin26 channel mediated disease
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Connexin26 (Cx26) forms both hemichannels and gap junctions, which are important for intercellular communication. We established in the brainstem that CO2 binds to and opens Cx26 hemichannels, allowing them to release ATP, which then activates the neural circuits that control breathing. Surprisingly, we have now found that CO2 closes Cx26 gap junctions. This closing action on gap junctions may be mediated by CO2-binding at the same motif that causes the hemichannel opening. Many different Cx26 mutations are linked to human pathologies that range from hearing loss to syndromes that involve serious disorders of skin, vision and hearing. Unexpectedly, some of these Cx26 mutations also alter the CO2-sensitivity of Cx26 hemichannels. As both Cx26 gap junctions and hemichannels co-exist in tissues affected by Cx26 mutations, understanding the differential modulation of gap junctions and hemichannels by CO2 is fundamentally important. We shall therefore analyze whether CO2 does indeed bind to the same site on Cx26 gap junctions and hemichannels. We shall mutate the key amino acids that comprise the CO2-binding site in hemichannels, and test whether this also alters the CO2-sensitivity of the gap junction. We shall test whether pathology-causing mutations of Cx26, which alter the sensitivity of hemichannels to CO2, also change the sensitivity of the gap junction to CO2. To demonstrate at an atomic level how CO2 binds to Cx26 and opens the hemichannel, we shall use X-ray crystallographic methods on Cx26 (with and without CO2 bound). Human mutations that alter the CO2 sensitivity of Cx26 do not directly affect the CO2 binding site. Therefore we shall crystallize Cx26 mutants, with and without CO2 bound, to see how the structure has been altered and whether this can explain the altered CO2 sensitivity. We shall utilize a complementary method, cryoEM, to examine the conformational changes that follow CO2 binding.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: EAR;SKIN
Title: Over three years to investigate the role of glasses wearing in amblyopia treatment
Funder: Action Medical Research

Abstract: Background Amblyopia (also called lazy eye) is the most common disease affecting vision in childhood. If left untreated, it can lead to serious visual impairment in one or sometimes both eyes. It affects between 2 and 5 per cent of the population and is responsible for 90 per cent of visits to children's eye clinics. Currently 30 per cent of children treated for amblyopia do not reach normal vision after a year or more of treatment. Amblyopia is usually treated firstly by wearing glasses to improve focussing, followed by patching the better eye to make the 'lazy eye' work harder. There is controversy as to whether a long period of glasses wearing (also called refractive adaptation) before patching benefits children with amblyopia. The research project This study will be the first randomised controlled trial to test whether wearing glasses before patching improves the number of successfully treated children with amblyopia. The researchers will compare the effects of either 3 weeks or 18 weeks of glasses wearing before patching on treatment success. In addition, they will use a newly-developed electronic monitor to record how long children wear their glasses each day and will then determine if this relates to their improvement in vision. They will also investigate whether different types of amblyopia respond better to different treatments. The results will clarify whether glasses wearing before patching leads to greater treatment success than patching alone in amblyopia. It will also provide valuable insights into how long children wear their glasses each day and if this is a factor which significantly affects the outcome of treatment.


Research activity codes: 6.3 MEDICAL DEVICES
Health categories: EYE
Title: RAFT: Corneal Stem Cells - First in Man Safety Study
Funder: Innovate UK

Abstract: TAP Biosystems and UCL Institute of Ophthalmology are developing a novel, patented technology (RAFT) that enables 3D tissue equivalents to be manufactured from collagen simply and reproducibly. The RAFT process creates tissue-like architectures that we are using to develop a corneal therapy - with embossed surface topography to replicate the in vivo stem cell niche - to support ocular surface regeneration. Results are very promising; we can reproducibly make multilayered ocular epithelia with morphology and protein markers very like the normal human cornea. We have advanced preclinical work, defining safety testing, regulatory pathway and the basis for QC assays. Our aim in this project is to complete preclinical testing, obtain regulatory and ethical approval, then manufacture the therapy in GMP conditions and perform a small first in man safety study at Moorfields Eye Hospital under Specials Hospitals Exemption arrangements. The data from this study would enable us to progress towards phase I/II clinical trials.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;5.2 CELLULAR AND GENE THERAPIES
Health categories: EYE