NIHRDataInsights/HRCSData huggingface dataset:
Title: Human pluripotent stem cell models of Alzheimer's disease pathology in Down syndrome
Funder: Alzheimer's Research UK

Abstract: Animal models for human dementias have been very useful in helping to understand how the diseases occur and the investigation of potential treatments. However, animal models do not capture many aspects of the disease and there is a pressing need for human models for Alzheimer's disease to understand the disease process and develop treatments. We have used human stem cells to make a cell culture model of the early stages of AD in Down syndrome (DS). People with DS commonly get dementia at a young age, because they have an extra copy of the APP gene, a major risk factor for AD. A useful model of AD would recapitulate the early stages of the disease in the cell type affected in patients. The Down syndrome stem cell model does both, developing amyloid pathology in cerebral cortex neurons. Importantly, the development of the early stages of the disease is blocked in this model by administering drugs that inhibit candidate pathways for the progression of AD in patients, demonstrating the usefulness of this model for drug testing. We now want to expand our work on this model to study events downstream of amyloid in human brain neurons made from stem cells.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;CONGENITAL DISORDERS
Title: Aberrant protein phosphorylation in Down Syndrome and activity-dependent bulk endocytosis - a causal link?
Funder: Medical Research Council

Abstract: Synaptic vesicle (SV) recycling is essential for neurotransmission, the fidelity of which is maintained across a wide range of stimuli by multiple modes of SV recycling in nerve terminals. Activity-dependent bulk endocytosis (ADBE) is triggered during high intensity stimulation via dynamin I dephosphorylation by calcineurin (CaN). Dynamin I rephosphorylation is also essential for the continuation of ADBE. Down syndrome (DS) is a genetic disease caused by a trisomy in chromosome 21. Two genes upregulated in DS are regulator of calcineurin 1 (RCAN1) and dual-specificity Yak1-related kinase 1A (DYRK1A). We predict that overexpression of these enzymes in DS will result in dysfunctional dynamin I phosphorylation, and defective ADBE. In agreement, multiple DS models and patients display neuronal defects consistent with dysfunctional SV recycling. We hypothesise that trisomy causes a dysregulation of dynamin I phosphoryation, leading to defects in ADBE, that contributes towards the symptoms of DS. This hypothesis is supported by key pilot data generated in our laboratory. First, a vesicle trafficking phenotype observed in DS (enlarged endosomes) can be replicated in central nerve terminals by inhibition of CaN. Second, RCAN1 interacts with multiple targets (including CaN) in nerve terminals. Third, manipulation of DRYK1A dynamin I phosphorylation sites alter interactions with nerve terminal proteins. The project has three major aims 1) To establish the role of RCAN1 in dynamin I phosphorylation and ADBE 2) To establish the role of DYRK1A in ADBE 3) To determine a causal link between DS trisomy and ADBE We will integrate state of the art live cell fluorescence imaging of nerve terminal function with protein biochemistry / cell biology techniques in concert with genetic models of DS. This will involve loss/gain of function strategies using overexpression and shRNA silencing of RCAN1 and DYRK1A in primary neuronal cultures to determine their role in both dynamin I phosphorylation and SV turnover. To determine the role of these enzymes in the appropriate disease context, we will monitor the same parameters using an established mouse model of DS trisomy. Establishing a causal link between DS and downstream defects in SV turnover will provide a key conceptual advance in understanding the symptoms associated with the disease. Furthermore, a demonstration that specific ADBE defects contribute towards the DS outcome will potentially provide a range of new and important tools with which investigate and treat the downstream consequences of the disorder.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;CONGENITAL DISORDERS
Title: Deciphering the molecular mechanism linking Ataxia-Telangiectasia and Ataxia-Telangiectasia-Like Disorder
Funder: Action for A-T

Abstract: This project will explore the molecular mechanism linking Ataxia-Telangiectasia and Ataxia-Telangiectasia-Like Disorder

Lay abstract: The team at the University of Birmingham have recently identified a unique ATLD patient who exhibits all the clinical symptoms associated with ATLD, but in contrast cells from this patient can activate ATM efficiently and can repair IR-induced DNA damage normally. This suggests that a global inability to repair DNA double strand breaks may not be the underlying cause of the ataxia in ATLD and A-T patients as previously thought. Interestingly, the MRE11 mutation present in this unique ATLD patient specifically causes a defect in repairing DNA damage induced by the activity of an enzyme called Topoisomerase 2 (TOP2). TOP2 is a protein that resides in the cell and helps to relieve tangles in the DNA, called supercoils, by cutting the DNA and allowing it to unwind, before resealing the break. This activity of TOP2 is very important for regulating the expression of specific genes, particularly genes associated with brain development and function. However, in certain situations TOP2 is unable to reseal the DNA break, and as such the cell requires the activity of other proteins e.g. ATM and MRE11, to repair the damage. Therefore, it is possible that mutations in MRE11 that cause an inability to repair DNA breaks caused by the activity of TOP2, will block the expression of genes that are required for brain development and function, leading to a progressive decline in neuronal fitness. Based on these preliminary observations, this project aims to study how this unique mutant MRE11 protein causes a specific defect in the repair of TOP2-associated DNA double strand breaks and how this can be linked to the neurodegeneration exhibited by patients with A-T and ATLD.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;CONGENITAL DISORDERS
Title: Fragile X mental retardation protein interaction with neuronal voltage-gated calcium channels: mechanism and consequences
Funder: Medical Research Council

Abstract: We will examine a novel molecular interaction involving Fragile X mental retardation protein (FMRP). This may have a bearing on the behavioural deficits that are characteristic of Fragile X syndrome, including mental retardation and autistic behaviour which results from a loss of the expression of FMRP. People with Fragile X also have peripheral symptoms, including heightened tactile sensitivity, and gastrointestinal motility changes. Dynamic regulation of CaV2.2 calcium channel trafficking and turnover is important for the functions of these channels in neurons, and may occur on a rapid timescale. CaV2.2 channels are critical for neurotransmission both in central neurons, particularly early in development, and in the autonomic and sensory nervous system. Thus they are the main mediators of neurotransmission between primary sensory neurons involved in nociception and other modalities, and the spinal cord. Regulation of N-type channel function is highly relevant to neuropathic pain, and self-injurious behaviour is one of the features of Fragile X syndrome. Thus, the newly-identified interaction between FMRP and CaV2.2 may play a role in the pathology and behavioural features of Fragile-X syndrome. We will probe the interaction between FMRP and CaV2.2 (N-type) voltage-gated calcium channels that we have recently identified, which markedly inhibits the functional expression of CaV2.2 currents. We will define the interaction biochemically and biophysically, make peptide reagents to inhibit the association between the two proteins, and examine the role of the interaction, both in terms of the effect of FMRP on N-type currents in DRGs, and the in the contribution of CaV2.2 channels to synaptic transmission. As a subsidiary Aim we will examine the regulation by N-type channels of FMRP localization and its role in regulation of mRNA translation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;CONGENITAL DISORDERS
Title: The role of neural crest cells in olfactory/terminal nerve and GnRH neuron development.
Funder: Wellcome Trust

Abstract: The nerve cells (neurons) that sense smells sit in the lining of the nose and send long fibres (axons) into the brain: together, these axons make up the olfactory nerve. Remarkably, the nasal lining also produces special GnRH neurons that migrate along the olfactory nerve into the brain, where they will eventually stimulate the production of reproductive hormones. People with Kallmann's syndrome have no sense of smell and are infertile, because their olfactory nerves and GnRH neurons never ent ered the brain when they were embryos. Olfactory ensheathing cells (OECs) seem to help olfactory nerves and GnRH neurons enter the embryonic brain. Transplanted OECs can also help restore movement after spinal cord injury in rats. We have recently made a breakthrough in identifying the embryonic origins of OECs and our work will build on this discovery to find out more about the molecules needed for OECs to tell olfactory axons and GnRH neurons to enter the brain. As well as understanding more a bout what happens in Kallmann s syndrome, knowing more about how OECs normally talk to olfactory axons, GnRH neurons and brain cells may help us understand how OECs promote spinal cord repair.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;CONGENITAL DISORDERS
Title: Improving the diagnosis, assessment and outcome in patients with hydrocephalus and raised intracranial pressure.
Funder: Department of Health (England)

Abstract: Unfortunately some children suffer from ‘water on the brain’. This can be due to brain cancer, previous head injury or in some cases the cause is unknown. Without treatment these children may die, or suffer varying degrees of brain damage reducing their chances of success in later life. Modern scanners are now able to assess the causes and effects of water on the brain. We will undertake experiments to develop techniques, using these scanners, to more accurately predict the best type of treatment and also determine when a treatment is failing. We will also develop the means to measure the pressure within the brain without needing to insert a needle into the spine of a child. The overwhelming majority of scanners in use within the NHS today have the potential to undertake these types of scans, but the necessary expertise is unfortunately not always available. To overcome this, this research will also develop computer systems to provide this expertise and support these advanced scans being performed at your district general hospital. This means that children can be assessed faster and more accurately at their local hospital, making full use of existing NHS resources.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: NEUROLOGICAL;DISPUTED AETIOLOGY AND OTHER
Title: Peer support for community dwelling older adults to facilitate self care of chronic lower back pain
Funder: The Dunhill Medical Trust

Abstract: Chronic Low Back Pain (CLBP) is a common and disabling condition among older adults, many of whom are referred to physiotherapy where exercise and self care are promoted. However, several barriers to self care exist, which can adversely affect function, quality of life, and health service utilisation. Thus, there is an urgent clinical and economic need for interventions that support older adults with CLBP to self care. Findings from studies of other chronic conditions suggest peer support is a promising, potentially effective intervention to fulfil this need. This research will first develop a peer support intervention for older adults with CLBP and associated training materials. Peer support volunteers will then receive a moderate amount of training to assist older adults with CLBP to self care following physiotherapy. Finally, the intervention will be tested on a small sample to determine its acceptability and feasibility prior to a subsequent controlled clinical trial.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL;DISPUTED AETIOLOGY AND OTHER
Title: The molecular mechanisms of structural conversion and toxicity in amyloid disease.
Funder: Wellcome Trust

Abstract: Several human disorders involve the formation of deposits made of rope-like protein fibres, called amyloid. These fibres can be isolated from the brain, pancreas and other tissues. These disorders include devastating diseases such as Alzheimer and Parkinson diseases, which are prevalent in older people, and for which there is currently little effective therapeutic help. As our population ages, the need for therapies against these diseases of ageing increases and developing successful therapies a gainst amyloid disease is a major priority for human health both now and in the future. Amyloid is therefore of intense interest both to academics interested in the structures of proteins and how changes in structure cause proteins to assemble into amyloid fibrils, and to pharmaceutical companies who require this knowledge to design drugs able to intervene in amyloid disease. Here we propose to determine precisely how a protein assembles into amyloid, and how the resulting fibrils cause cellular dysfunction. Our overall aim is to generate the fundamental insights that will provide the platform for the development of new therapies able to combat these common and grave disorders.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;DISPUTED AETIOLOGY AND OTHER
Title: Determining the limits for reversing hearing loss
Funder: Wellcome Trust

Abstract: Progressive hearing loss is very common but there are no medical treatments to slow down or reverse it. Histopathological reports suggest three main sites of lesion in the cochlea can be involved: sensory hair cells; synapses of hair cells with cochlear neurons; and the stria vascularis which produces a potassium-rich fluid with an endocochlear potential of +100mV that is essential for hair cell sensitivity. This research has three goals that will provide the scientific underpinning for development of new treatments for hearing loss. Firstly, we will investigate whether hearing loss in each of the three pathological categories can be reversed and hearing improved. Secondly, the research will determine what the limiting factors to reversal of hearing loss are and how these define the critical period for intervention. Thirdly, we will develop new diagnostic tools to distinguish the three sites of lesion using objective measures of auditory responses, to establish the underlying pathological contributions to hearing loss in an individual, and hence determine the optimum treatment. To achieve these goals, we will use mouse mutants with well-characterised cochlear pathology as examples of each site of lesion, and a new approach to reactivating a mutant gene after the onset of hearing loss.

Lay abstract: Hearing loss is very common as we get older, and it can isolate affected people from society. We have no treatments to reverse hearing loss or even to slow down its progression. In this project, we will investigate whether some types of hearing loss can be reversed and develop new methods for diagnosing which structures within the inner ear are malfunctioning. This knowledge will be important to focus our efforts on developing new treatments for the types of hearing loss that are most likely to respond, and to select the best treatment for each individual depending on what the problem is. For this research we will use mutant mice with similar types of dysfunction as in human deafness. In the mouse we have the advantage of knowing exactly what is going on inside the ear including the primary site of the pathology, while in humans currently we can only guess.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;EAR
Title: Neural coding in the central auditory system: spectrotemporal processing, hearing loss and tinnitus
Funder: Medical Research Council

Abstract: The aim of this research group is to understand the way in which sound is processed by neural circuitry in the brain, and how it underpins auditory perception. We do this through the integration of physiological, behavioural and computational techniques. This work is essential if we are to properly understand how we hear; for example, how we are able to perceive distinct sound sources in complex listening environments, and how neural processing is affected by hearing impairments. Basic research into hearing has traditionally been dominated by two distinct branches: psychoacoustics measures subjects' ability to detect and discriminate sounds by, for example, pressing buttons; auditory neuroscience studies the response of neurons to sound.These separate approaches have led to considerable advances in treating hearing disorders. However, it was always difficult to relate these two types of measurement.Part of our goal is to better relate perception to neural coding, by studying them together in integrated experiments. For example, by recording directly from neurons in the auditory brain during active listening. We are currently attempting to understand the relationships between the frequency resolution of hearing measured perceptually, in the cochlea, and at different nuclei in the central auditory system. Other recent work includes investigating cortical correlates of the way we perceptually group sequences sound sounds, or the way a loud sound renders a quiet sound following it undetectable. These techniques can also be used to study the effects of deficits in hearing, and even changes following implantation of hearing prostheses. How do we adapt to a loss of hearing, or to the change in auditory inputs when we receive a cochlea implant? The other goal of this research is to understand the underlying computations that lead to the neural representations of sound. We do this through theoretical and computational models of auditory processing. We simulate, in computer programmes, neurons' responses to sound in order to generate and test theories about underlying mechanisms, and also use them to predict as yet untested properties of neurons. For example, it has long been known that the timing of spikes is important in auditory coding – neurons tend to fire precisely in time to specific features in a sound. However, we have recently shown that neurons in the auditory brainstem encode the stimulus with much more complex temporal patterns of spikes – and furthermore were able to relate these back to the mathematics of non-linear oscillators, and show how simple computer models of neurons replicate these complex behaviours


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;EAR;MENTAL HEALTH
Title: Auditory Learning and Development
Funder: Medical Research Council

Abstract: Auditory processing is fundamental to effective communication, particularly in challenging listening conditions. However, there is considerable variation in ability to efficiently process and use auditory inputs across the lifespan. Most of this variation is thought to reflect cognitive factors associated with the central auditory system rather than sensory processes located at the periphery of the system. This programme aims to further understand how central and peripheral mechanisms interact to modulate individual listening efficiency across the lifespan. We consider listening efficiency in both typical individuals and individuals with some form of listening difficulty. Ultimately, we hope to translate this learning into clinical benefit by developing more effective assessment tools and auditory training regimes to assess and treat patients with listening difficulties. Primary outcomes from our work to date are, (i) a new scale (the ECLiPS) to profile children’s listening abilities, (ii) a test of auditory attention (the TAIL) (iii) supra-threshold auditory and cognitive age-norms, and (iv) a delineation of important regimen specific factors modulating auditory learning efficiency. The ECLiPS is proving to offer valuable insight into the nature of listening difficulties in children. Research in auditory training underlines the importance of carefully structured training regimens involving positive not negative feedback. The test of auditory attention is providing insights into the differences between auditory and visual attention. In other research this year, we showed how training beat perception in older adults resulted not only in improved beat perception but importantly, improved speech-in-noise listening. Interestingly, in this context older adults show greater reliance on cognitive abilities when listening in noise. In children with auditory processing disorder, we demonstrated deficits in auditory specific sustained attention. Moreover, we showed how relative strength in sustained attention acts as a protective factor for supporting normal development of language and listening abilities. In summary, our research highlights the need for an individualised approach to training and rehabilitation. Our findings provide converging evidence that auditory perceptual abilities in younger and older populations depend on cognitive factors such as attention, working memory and general IQ. Aspects of cognition, and in particular attention appear to be more important than bottom-up channel sharpening to improve perception through training. These findings inform our endeavours to appropriately tailor training programmes to improve speech perception not only in children with auditory and language-learning disorders, but also in older hearing-impaired individuals and cochlear-implant users.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL;EAR;MENTAL HEALTH
Title: Functional gaze control in young children with severe cerebral palsy
Funder: SPARKS

Abstract: It is extremely difficult to assess the extent to which young children with severe physical disability also experience impairments such as learning disability. One way of doing this is to monitor how they move their eyes during tasks. However, in order for observation of children’s eye movements during assessment to be informative, we first need to establish the extent to which children can use their eyes to fulfil basic functions such as fixing and shifting gaze. This project will develop effective procedures to assess eye control in this group of children who are often labelled as ‘unassessable’.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;7.1 INDIVIDUAL CARE NEEDS
Health categories: NEUROLOGICAL;EYE