NIHRDataInsights/HRCSData huggingface dataset:
Title: Non-invasive real-time bioluminescence imaging in living mice to interrogate transcription factor activity and fate of engrafted stem cells
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: This project is based on developing technologies to increase the information generated per mouse in order to reduce cohort sizes and also to include refinements of existing animal procedures to minimize stress to animals involved in the study. During this project we will: 1) Develop mouse induced Pluripotent Stem cell (iPSc) lines transgenic for transcription factor activated reporters (TFAR) that express both FLuc and eGFP (iPSc-TFAR) and constitutively expressing reporters (CER) that express VLuc and mCherry (iPSc-CER) from Gba1-/- and Gba1+/+ mouse embryonic fibroblasts. iPSc-TFAR will be developed that are responsive to NFkB (inflammation), NRF2 (reactive oxygen), HIF (hypoxia), STAT3 (potency), FOXO (metabolism) and NFAT (Ca2+ signaling) transcription factors, all of which we hypothesise are involved in neural stem cell (NSC) differentiation and Gaucher's disease (GD) pathology. 2) TFAR/CER-iPSc will be differentiated to NSC in vitro using established methodologies and compare Gba1-/- and Gba1+/+. 3) Intracranially inject TFAR/CER-NSC into Gba1-/- and Gba1+/+ mouse fetuses and assay for FLuc versus VLuc expression as neonates develop and disease progresses over a 14-day period. The data generated in this study will address the following sub-hypotheses: Gba1-/- and Gba1+/+ NSC differentiate readily to all neural cell-types in vitro. Gba1-/- and Gba1+/+ NSC employ the same cellular signaling pathways during neuronal differentiation in vitro. Gba1+/+ NSC successfully engraft in the fetal brains of Gba1+/+ mice. Gba1-/- NSC successfully engraft and signal normally when engrafted into the brains of Gba1+/+ mice. Gba1+/+ NSC successfully engraft and signal normally when engrafted into the brains of Gba1-/- mice. For the first time this technology will allow us to see whether normal neurons are affected by a Gba1 knockout environment or vice versa whilst concurrently giving us new information as to how the cells react at the sub-cellular level.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Volcanic mercury: local deposition or global dispersion?
Funder: Natural Environment Research Council

Abstract: Mercury is a toxic metal released to our environment through mankind's activities (e.g., coal burning) and natural processes. Once it gets into the sea or other aqueous environments it can be transformed into toxic forms, which can then get into the food chain and can cause damage to the central nervous systems of animals. Mercury pollution is a grave human health concern and so it is important to understand its different global sources. Recent work has shown that continuously degassing volcanoes represent a significant source of mercury to the atmosphere compared to other sources on the global scale. Recent measurements at active volcanic craters have also shown that volcanic mercury is primarily emitted as a gas. This gas is not very soluble (e.g., in rainwater) and so would not be very efficiently removed from the atmosphere meaning that it could be transported very long distances from its source making volcanic mercury a global environmental hazard. However reactive bromine compounds have also been observed in volcanic plumes downwind from the point of emission. In the Polar Regions and at the Dead Sea reactive bromine compounds are thought to lead to the rapid transformation of gaseous mercury (present in these environments at low levels due to remote sources) into more soluble form that are then rapidly deposited to the local environment. If similar chemistry occurs in volcanic plumes then they will represent a significant mercury hazard to local ecosystems as this chemistry would not only lead to the rapid deposition of low levels of atmospheric mercury from remote sources but also the very significantly enhanced levels present in volcanic plumes. We want to understand the behaviour of mercury in volcanic plumes and the balance between local deposition and global dispersion. We will make measurements of the levels and types of mercury found in the persistent non-explosive volcanic plume from Masaya volcano in Nicaragua at the crater rim and at two locations downwind of the volcano where the plume is known to ground regularly. We will also measure reactive bromine levels and other constituents of the volcanic plume at these locations and will put out a network of samplers to measure the deposition flux of mercury to the local downwind environment from the volcano. These measurements will allow us to test our hypothesis that in volcanic plumes, gaseous mercury will be rapidly transformed to more reactive forms that are then deposited to the local environment. These measurements will then be used to adapt existing computer models of the atmospheric chemistry occurring in volcanic plumes to include mercury chemistry. This will allow us to further our understanding of volcanic mercury processing as well as to build up a picture of the fate of the mercury emitted from active volcanoes and specifically to understand whether volcanic mercury emissions pose a local or global hazard.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: NEUROLOGICAL
Title: Developing and evaluating an online psychoeducation package for adolescent depression
Funder: Division for Social Care and Health Research (Wales)

Abstract: This study aims to develop and evaluate a complex home based exercise intervention for people with Huntington's Disease (HD). Components of an existing intervention will be refined in terms of methods of delivery and appropriate support mechanisms and incorporated into a 16 week randomized and controlled multi-centre Phase II study where functional, motor, cognitive and behavioural outcomes will be evaluated. Adherence will be documented and exploratory health economics analysis undertaken. If successful, this intervention has potential to prevent the need for expensive hospital admissions and intensive input from community reablement teams in this devastating neurodegenerative disease.


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: NEUROLOGICAL
Title: Improve the health and wellbeing of older people and the quality of community care they receive, especially for people living with dementia.
Funder: Department of Health (England)

Abstract: Dementia presents one of the major care challenges for the 21st century. Prof. Robinson's research aims to improve the quality of community care for people with dementia and create a skilled and motivated NHS workforce to deliver such care.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: NEUROLOGICAL
Title: Improve recovery from traumatic brain injury by enhancing the function of intact brain regions so people can regain independence and improve their quality of life.
Funder: Department of Health (England)

Abstract: Dr Sharp's research focuses on diagnosing and treating the effects of head injury on the brain. He works with civilians and soldiers, aiming to minimise the long-term disability that traumatic brain injury often produces. His research will allow treatment to be targeted and recovery enhanced.


Research activity codes: 4.3 INFLUENCES AND IMPACT;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Function and pathology of spatacsin/ALS5 using a novel Drosophila model
Funder: Motor Neurone Disease Association

Abstract: Ultimately the best prospect for therapies to delay the course of motor neurone disease is to understand the disease mechanisms, but unfortunately our knowledge of these is still patchy. To date our best insights have come from genetic variants of the disease, but the fact that novel genetic forms of ALS are still emerging shows how far we still have to go. One recently identified form of inherited juvenile ALS is ALS5, found in at least 12 families from widely dispersed geographic origins. However, we know nothing of the processes that ALS5 is affecting in the disease. To address this problem we will study the function of the ALS5 gene in the fruitfly Drosophila. These offer a more natural system than cultured cells, and powerful genetics and many experimental approaches that can be applied more conveniently and rapidly than in mice. By understanding the defects in flies that lack the ALS5 protein, we expect to make predictions about what goes wrong in human ALS5 patients, and potentially in a wider range of ALS patients too. We have generated flies that lack normal ALS5 function. Like human ALS5 patients, these survive to adulthood, and preliminary results suggest a progressive loss of motor function. We will use these flies to understand the consequences of ALS5 loss for nervous system function. First we will test whether manipulating ALS5 affects the severity of other fly ALS models, to determine whether ALS5 may affect similar pathways to known ALS genes. Second, we will look for defects in the brains of flies that lack ALS5. In particular we will test for some kinds of cellular stress. Third, we will look for other proteins that might be are affected in ALS5 mutant nerve cells. In summary, our ALS5 flies offer a unique opportunity to investigate the disease mechanisms, in a whole organism where we can draw on a wealth of information on other neurodegenerative conditions. While the main outcome will be basic understanding of ALS5, which is currently lacking, it may also suggest therapeutic possibilities if loss of ALS5 affects any stress pathways that are amenable to drug treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Understanding prescribing of opioids for chronic, non-cancer pain in general practice
Funder: Department of Health (England)

Abstract: Background The management of chronic pain in general practice is problematic. The World Health Organisation (WHO) ‘analgesic ladder’ was originally developed for cancer pain but its use has spread to chronic, non-cancer pain. There are growing concerns that: (1) patients are being moved up this ladder towards potent opioids inappropriately and without considering other drug and non-drug aspects of care; and (2) the potential social and medical harms of opioids have been significantly underestimated. Local pilot work suggests that around 5% of adults currently receive repeat prescriptions for opioids, with almost 1% of these people receiving strong opioids. We urgently need to improve our understanding of how and why patients receive long term opioids as well as the epidemiology of such prescribing. Aims AIM: To improve understanding of the use of long term opioids for chronic, non-cancer pain in general practice. OBJECTIVE 1: To examine patterns and trends in long term prescribing of opioids in general practice. OBJECTIVE 2: To explore the experiences, beliefs and expectations of patients and general practitioners (GPs) in relation to long term prescribing of opioids, and delineate the trajectories by which patients become established on ‘Step 3 (‘strong’) opioids. Plan of Investigation OBJECTIVE 1: Analysis of centrally-held computerised general practice records covering the majority of practices in Bradford and Leeds. We shall examine associations between long term opioid prescribing and practice and patient characteristics (e.g. coded diagnoses and demographics). We shall also examine temporal trends in prescribing. OBJECTIVE 2: Qualitative interview study examining the perspectives of patients and GPs. This will include one set of patients on ‘weak’ opioids and another on ‘strong’ opioids, so that we can explore the knowledge, attitudes, experiences and expectations for patients and doctors at varying stages in their trajectories. Sampling will be based partly on diagnostic groups but also on other features identifiable through Objective 1. Potential Impact By examining the nature of opioid prescribing, we shall improve our understanding of its prevalence and of the factors associated with it. We will characterise ‘red flag’ trajectories in which patients are escalated to strong opioids outside of recommended practice. By exploring the trajectories by which people become established on opioids, we will gain insights into resistance to change and identify opportunities for intervention. This work will inform strategies to promote appropriate practice in the clinical management of chronic, non-cancer pain. We will seek further funding following this study to evaluate the cost-effectiveness of an improvement strategy.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: NEUROLOGICAL
Title: C9ORF72 hexanucleotide repeat dsRNA and ADAR mutant neurodegenerations with aberrant immune induction
Funder: Motor Neurone Disease Association

Abstract: The ADAR RNA editing enzymes first came to attention in MND research because of the key role of glutamate excitotoxicity in the disease and because of a report that ADAR2 expression is lost in MND motor neurons. More recently ADARs have been identified as major proteins binding C9Orf72 hexanucleotide repeat dsRNAs. ADARs are adenosine deaminases acting on RNA and they deaminate individual or multiple adenosines in dsRNA regions of transcripts, depending on the length of the dsRNA formed. ADAR2 is known to site-specifically edit a particular adenosine in the GRIA2, (formerly called GluR B) transcript, leading to an amino acid change in the AMPA channel that blocks calcium entry. Loss of editing leads to aberrant excitability and neurodegeneration. We have felt since early on in our MND work that the excitotoxic effect of glutamate in the disease might be linked to other aberrant immune induction or neuro-inflammatory spreading effects that could also arise due to reduced ADAR expression or activity. This grant will provide short-term support for a post-doc (salary and expenses) to complete ongoing work for publication and generate additional data to support a project grant application.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Multimorbidity in the ageing human brain - assessment by quantitative neuropathology
Funder: The Dunhill Medical Trust

Abstract: Multiple pathologies are frequently seen in the brains of demented elderly suggesting that the clinical picture of dementia usually results from a multimorbid condition in the CNS rather than from one single disease process. However, data on cerebral multimorbidity is largely based on semi-quantitative assessment and hence it's role in age-associated dementia is poorly understood. We hypothesize that quantitative analysis of various neuropathological lesions in multiple regions will better estimate the combined impact of different pathological lesions on clinical dementia. Using a fully motorised microscope we will quantitatively evaluate a range of discrete neuropathological lesions in over 200 cases of the Brain-Bank material from the Newcastle Brain Tissue Resource (NBTR). Quantitative neuropathological data will be correlated with clinical data to determine the best model predicting dementia status. Our results should lead to a better understanding of age associated cerebral multimorbidity and will be helpful in formulating targeted therapeutic strategies against dementia.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Online dizziness intervention for older adults
Funder: The Dunhill Medical Trust

Abstract: More than 1 in 5 people over 60 have current dizziness, which can lead to falls, reduced quality of life, disability and loss of independence. Vestibular or multisensory dysfunction is a common cause of dizziness in later life, and is treated safely and effectively by booklet-based vestibular rehabilitation, i.e. booklets that teach patients to carry out at home exercises that promote neurological adaption, but very few patients currently gain access to these booklets. Our multidisciplinary team will work closely with older people to develop an accessible online intervention that includes videos illustrating the exercises, advice personalised to symptoms and progress, and psychological strategies to help overcome fear and avoidance. Among older people, Internet use for health information is already common and growing rapidly. We will test the intervention compared to usual care in a randomised controlled trial in primary care (N = 160 patients), and conduct formal cost-effectiveness analyses.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: NEUROLOGICAL
Title: Decision-making concerning eating and drinking for people with progressive neurological disease with and without decision-making capacity: patient, public, professional and family perspectives
Funder: The Dunhill Medical Trust

Abstract: The prevalence and incidence of progressive neurological disease is predicted to rise, as the age of the UK population increases. Those with Motor Neurone Disease, Parkinson’s Disease, Huntington’s Disease and Alzheimer’s Disease often experience dysphagia and feeding difficulties as their disease advances. Decisions concerning feeding interventions, e.g. Percutaneous Endoscopic Gastrostomy are complex, particularly when individuals lack decision-making capacity. The review and withdrawal of the Liverpool Care Pathway highlighted nutrition and hydration as an area of concern. Research questions: With respect to neurological conditions in the community: (a)Which factors and principles are taken into account in decisions about eating/drinking interventions? How are these factors balanced? (b)What effect does possible loss of decision-making capacity have on decision-making? What strategies are used in this situation? Study-One: Face-to-face public opinion survey. Study-Two: Interview and observation study with patient, relative, health and social professionals. Study-Three: Focus groups developing a toolkit improving decision-making and healthcare.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: NEUROLOGICAL
Title: Identification of progressive neuronal stress from early development to adulthood and utilisation of the readout in a pharmacological screen for disease modifiers in the SOD1 zebrafish model of ALS/MND
Funder: Motor Neurone Disease Association

Abstract: A familial form of motor neuron disease (MND) caused by mutations in the SOD1 gene produces disease that is indistinguishable from the sporadic form of MND. The mechanisms that underlie MND are unknown and the mechanism of sod1 toxicity is not completely understood. Despite the availability of mouse models of MND, they are not suitable for undertaking large drug screens due to costs, space and time required. Screening of 2000 drugs in the MND mouse model would require over 20 years (@100 drugs/year) and involve huge sums of money. Our zebrafish model of MND serves as an ideal platform for drug screening to identify compounds that protect neurons from injury. Zebrafish like mice and humans is a vertebrate and many genes are similar in human and fish. In fact 87% of the amino acids mutated in human SOD1 patients are identical in the fish. The zebrafish sod1G93R MND model that we recently published shows that these zebrafish reproduce most aspects of disease seen in mice and humans. Transgenic zebrafish expressing mutant Sod1G93R but not WT Sod1 show muscle atrophy paralysis, and premature death. When we generated the transgenic zebrafish, we incorporated a red fluorescent protein gene (DsRed) that is sensitive to cell stress. We show that in the mutant sod1 fish neuronal stress is initially induced during embryonic development within neurons that connect to the motor neurons and inhibit them. In symptomatic adult fish we see the propagation of stress to motor neurons. The stressed motor neurons also show abnormal connectivity to the muscles and this may directly affect their function and cause paralysis. This suggests that the neurons in MND are constantly in a state of stress that predisposes them to greater damage and eventual death. We believe that stopping this stress at an early stage will provide a greater chance of correcting the disease onset and progression and address the root cause of damage in MND. When we treated the mutant fish with riluzole, a drug that is used to treat MND, we see a reduction in neuronal stress. This validates our assay and now allows us to utilize our sod1 zebrafish model for drug screens to rapidly identify drugs that may be of eventual benefit to patients with MND. Our new zebrafish model also provides a new tool to better understand the mechanisms of neurotoxicity in MND. We will perform a drug screen (2000 drugs) using this model system and try to identify neuroprotective and stress reducing drugs that could slow or arrest MND. The drugs that we will screen include a large number of already approved drugs and if any of these show promise, translation into human clinical trials could be developed in a relatively rapid time scale.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Cognitive rehabilitation for Parkinson's disease dementia: a pilot trial
Funder: Division for Social Care and Health Research (Wales)

Abstract: Parkinson’s disease is a common condition that causes problems with movement. It also causes memory problems which can develop into dementia. People with a similar condition called Dementia with Lewy Bodies also have memory and movement problems For both conditions drugs are the main form of treatment but are limited by side-effects and not everyone can take them. There is growing interest in developing treatments that do not use drugs so that more people with memory problems may receive these treatments. A treatment which focuses on improving memory has been shown to be useful in Alzheimer’s disease but there are no studies that have used the same treatment with people with Parkinson’s disease or people with Dementia with Lewy Bodies. This study aims to find out whether this treatment can improve memory performance in people with Parkinson’s disease and Dementia with Lewy Bodies. To make sure that the treatment is useful, people with Parkinson’s disease or people with Dementia with Lewy Bodies will receive either the treatment which focuses on improving memory, a form of relaxation therapy or just carry on with their usual drug treatment. Everyone who takes part in the study will choose up to three activities or problems that trouble them and that they wish to improve. The measure of success of the treatment will be based mainly on the peoples’ experiences and satisfaction with their success in achieving their own aims A number of other measures of success will also be used. The information from the study will be assessed to decide on the effectiveness of the treatment compared with relaxation therapy and treatment as usual. The results will help design larger studies of non-drug treatments that improve memory so that more people with Parkinson’s disease or Dementia with Lewy Bodies can benefit.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: NEUROLOGICAL