NIHRDataInsights/HRCSData huggingface dataset:
Title: Telehealth in Motor Neurone Disease
Funder: Motor Neurone Disease Association

Abstract: The Sheffield MND Care Centre team have developed a bespoke telehealth system: the TiM system with the aim of improving access to specialist care in MND. This consists of a handheld tablet computer used by the patient linked via the internet to the MND care centre. Each week the patients and their primary informal carer enter information about their condition. Any change in their condition is alerted to the MND care team in Sheffield. The aim of the project is to improve access to specialist MND care provided by a care centre, between clinic visits and if the patient is unable to travel to clinic. We hope that by detecting problems and intervening earlier and providing better education and communication we can improve both the quality of patients and carers lives and improve clinical outcomes. A grant from the MND Association would enable us to purchase additional weighing devices to enhance the service by measuring patients' weight and balance. It is recognised that nutritional status is closely linked to survival in MND. Patients who experience weight loss have a worse prognosis and a decline in weight can often be a sign of deteriorating swallow or respiratory function. Accurate weekly assessment of weight will can detect declines in weight at an earlier stage enabling the team to implement timely interventions. The proposed weighing devices are wireless and able to instantly send weight measurements whenever patients chose to weigh themselves and the MND nurse will be alerted when the weight falls below pre-specified thresholds. The proposed weighing scales also have a method for measuring patients' balance. Instability and subsequent falls are a major problem to patients with MND and are associated with injury as well as fear and loss of confidence and independence. In patients at risk of falls interventions such as physiotherapy and home adaptions can prevent falls and improve patients' confidence and independence. Our collaborators at the University of Sheffield have demonstrated that using technology to monitor this type of problem has been highly successful in stroke patients. This would be the first time a system of monitoring balance been used in MND. This system could provide a method to detect problems, avoid falls and could potentially even provide feedback to patients to promote confidence and self-management. Given this is a novel approach, the opportunity to test it in an 18 month trial would provide an opportunity to understand more about the natural history and monitoring of balance problems, and how these could be more effectively monitored and treated.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: A randomised controlled trial in patients with respotory muscle weakness due to MND of the NeuRX RA/4 diaphragm pacing trial
Funder: Motor Neurone Disease Association

Abstract: Motor neurone disease (MND) is a devastating illness which leads to progressive muscle weakness and death, usually within 2-3 years of symptom onset. Death usually occurs as a result of breathing problems due to weakness of breathing muscles, including the diaphragm (the main breathing muscle). An important advance in treating MND has been the discovery of an additional survival and quality of life benefit of approximately 7 months, in patients using non invasive ventilation (NIV) therapy. NIV is a treatment for which patients wear a face mask over their nose or mouth or both and as they breathe in, the machine gives an extra push of air to support the patient’s weak breathing muscles, enabling a bigger deeper breath. NIV has problems which include; certain groups of patients do not tolerate NIV due to the type of MND they have, or due to issues such as claustrophobia and mask interface problems; although NIV systems are ideal for overnight use, during the day the mask interface can interfere with communication and feeding, and the ventilator itself although small does restrict mobility; eventually respiratory muscle weakness will progress to a point at which intermittent/overnight NIV is ineffective. Diaphragm pacing (DP) is a means of increasing the strength of the main breathing muscle. The pacing wires are inserted into the diaphragm muscle during a small operation and are connected to a small portable box that the patient can easily carry about. The proposed study will assess if treatment with DP prolongs life and maintains quality of life when given in addition to current standard care. Patients will be allocated to receive either standard care or standard care with additional DP. The main outcome measure to be compared between the two groups will be the survival over twelve months following entry into the study. Quality of life measures will be recorded to ensure that any prolongation of life is not at the expense of quality of life. The study will be conducted at four sites within the UK. The study team has a track record of running clinical trials in MND and particularly the management of respiratory problems in MND.


Research activity codes: 6.4 SURGERY
Health categories: NEUROLOGICAL
Title: Evaluation of the MND awareness tool within primary care
Funder: Motor Neurone Disease Association

Abstract: Patients with motor neuron disease (MND) live on average 3 years. Although there is no cure there are treatments that can prolong life and improve quality of life. On average it takes 1 year for a patient to diagnosed and receive these treatments. The reasons for the delay are complex but one factor is that as MND is rare, awareness of MND is low amongst non specialist doctors. The MNDA and the Royal College of General Practitioners have developed an educational tool to increase awareness of MND, which will be launched towards the end of this year. We intend to interview GP's before and after the launch to understand how they make the diagnosis of MND and if the tool has helped this.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: NEUROLOGICAL
Title: Deciphering non-cell autonomous disease mechanisms in human ALS using inducible pluripotent stem (iPS) cell technology
Funder: Motor Neurone Disease Association

Abstract: The motor neuron disease Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative condition for which there remains no cure and few, if any, beneficial treatments. The lack of medical intervention available for ALS sufferers reflects our poor understanding of the mechanisms that underlie motor neuron loss and fatal paralysis in the disease. It is therefore critical that basic research continues to decipher disease mechanisms which may provide targets for novel treatments of ALS. Many disease mechanisms have been proposed based on studies of animal models of ALS. However, it is now important that such mechanisms are verified in human ALS. The present study will address this need by utilising cutting edge technology which allows is to create stem cells from ALS patients and healthy control subjects and then convert these stem cells into motor neurons and other types of cells found in the spinal cord. We will then utilise state-of-the-art techniques to record the function (electrical activity) of motor neurons and other types of cells derived from these stem cells. This approach will allow us to directly assess the function, and dysfunction, of human, ALS-affected motoneurons and their connections with other nearby cell types. Importantly, unlike studies of ALS patients, we will be able to manipulate these human motor neurons and the environments they are in and we will be able to study their dysfunction during development, at stages prior to disease onset in patients. With increasing evidence of involvement of developmental abnormalities and changes in the communication between motor neurons and their neighbouring spinal cord cells in ALS, we expect our direct analyses of human spinal cord cells to reveal important new targets for the development of novel treatments for this incurable disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Studying the function of c9orf72 in amyotrophic lateral sclerosis
Funder: Motor Neurone Disease Association

Abstract: Some forms of motor neurone disease (MND) are caused by defects in our genes and so the disease can be passed down through families from parents to sons and daughters. A large number of these defective “mutant” genes have now been identified. However, most cause only a very small percentage of MND cases. Recently, a new defective mutant gene was identified and this is now known to be the cause of most familial and also some sporadic forms of MND. This is a major finding since it might be able to tell us how a large number of MND cases arise. The mutant gene is called c9orf72 but it has not been studied before and we know very little about it. However, there are two ideas for how the defective c9orf72 might cause MND and one is that it is loss of c9orf72 protein that causes MND. But what does c9orf72 protein do? This project is to gain insight into the function of c9orf72 since this will help us devise ways of correcting any functional loss in MND. We will use advanced microscopy to find the location of c9orf72 in cells and then use molecular biology methods to see whether loss of c9orf72 induces MND-type damage to cultured cells. We have already obtained an important clue in our pilot studies by finding that c9orf72 is present in the nucleus of cells and this indicates that c9orf72 might function to control how cells make new proteins. This study will therefore tell us about the function of c9orf72 protein and this information is important for devising new treatments for MND that involve therapeutic targeting of either the c9orf72 genetic material or c9orf72 protein.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Molecular reconstitution of cellular machinery essential for neuronal development
Funder: Medical Research Council

Abstract: Human brain development involves the coordinated movement of billions of neurons. Microtubules (MTs) are crucial for this, acting as both a dynamic framework for motility and forming tracks for intracellular trafficking by molecular motors. Disruption of these functions causes aberrant migration, resulting in developmental neurological defects and brain malformations. Understanding neuronal migration is also critical in the context of brain repair therapies for adult diseases, for example in the treatment of stroke and neurodegeneration. MT-associated proteins (MAPs) are essential for regulating and organising MTs. However, our mechanistic understanding of MAP function is limited by a lack of integrated structural and functional information. The aim of this research programme is to shed light on the doublecortin (DCX) family of essential neuronal MAPs (DCX-MAPs). We will elucidate the molecular mechanisms by which they regulate MTs and control cargo trafficking through interactions with molecular motors. Using state-of-the-art cryo-electron microscopy and image processing, we will solve sub-nanometre resolution structures of DCX-MAP-MT complexes to precisely reveal their mechanisms of MT regulation. We will also reconstitute complexes of motor-bound DCX-MAP-MT complexes and determine these structures by cryo-electron microscopy, revealing the molecular details of motor-track cross-talk. Biochemical and biophysical assays will provide a functional context for our structural discoveries and allow us to test our hypotheses using protein engineering. To place our molecular discoveries in a cellular context, we will study the function of DCX-MAPs in neurons using cryo-electron tomography. We will visualise the organisation of MTs in neurons and elucidate the impact of depletion of DCX-MAPs on neuronal MTs. Through this integrated programme of research, we will discover regulatory mechanisms of MT dynamics and trafficking, with important implications for human health.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The basis underlying microcephaly caused by defects in replication or DNA repair.
Funder: Medical Research Council

Abstract: We aim to understand the basis underlying microcephaly in humans. We will study neurogenesis in mouse embryos since this represents a good model system. We will examine neurogenesis in mice deficient in Orc1, a condition recently found to cause microcephaly in patients. We will also examine mice deficient in DNA ligase IV and following exposure to ionising radiation. Mouse embryos at E13.5 to E17 will be obtained from mice and subjected to PCR analysis to assess their genotype. Studies will be performed on heterozygous crosses, allowing homozygous deficient and heterozygous mice from identical litters to be examined in parallel. Our studies with LigIVY288C mice have shown that embryonic neuronal development is similar in wild type and heterozygous mice. This will be established for Orc1-deficient mice. The embryonic neuronal tissues will be snap frozen or prefixed (depending on the analysis to be undertaken), sliced and processed for immunostaining using neuronal markers and/or antibodies to DNA damage response proteins or markers of replication. We have established that p-histone H3 staining, which marks the apical and basal mitotic layers, provides a suitable marker to separate the VZ/SVZ from the IZ. Neuronal markers will include Tbr2, Tuj1 and Pax6. Apoptosis will be assessed by TUNEL staining and DNA double strand breakage identified by gammaH2AX or 53BP1 foci analysis. Where necessary BrdU will be given to the mice by peritoneal injection. Where necessaryembryos mice will be irradiated in utero with low doses using an X-ray source and maintained as necessary prior to sacrifice. These procedures have predominantly been described previously REF. Mouse embryo fibroblasts (MEFs) will be obtained from Orc-1 deficient mice using standard procedures and examined using assays described in our recent publication (Bicknell et al., Nat Genet. 43: 350-355, 2011). Generation of an Orc1-deficient knock-in mice will be undertaken using a standard procedure as described.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Regulation of gene expression in developing cortex by the transcription factor Pax6
Funder: Medical Research Council

Abstract: Aim 1. To test how profiles of gene expression in a defined population of Pax6-expressing cerebral cortical progenitors vary (i) normally with developmental age and (ii) following experimenter-induced removal of Pax6 at different ages. We shall remove Pax6 acutely at different ages using tamoxifen-induced activation of Cre recombinase from an Emx1-CreER allele to delete our new floxed Pax6 allele. Progenitor cells that would normally express the Pax6 gene (whether its sequence is mutated or not) will be isolated from cells that do not express Pax6 using our new YAC reporter transgene (DTy54), allowing comparison of equivalent progenitor populations in cortices that express Pax6 versus those that lose Pax6. For each age of tamoxifen administration, changes in gene expression profiles will be followed by RNA sequencing. Profiles will be analysed using bioinformatics. Aim 2. To study in more detail Pax6's regulation of sets of genes involved in cortical cell proliferation, migration, specification, differentiation and axon guidance. We shall test for direct regulation by Pax6 of genes whose expression levels change when Pax6 is removed and correlate changes in expression with cellular defects. The immediate priority, based on our existing pilot data, is to test whether Pax6 exerts control over progenitor cell proliferation by direct regulation of cell cycle genes. Further sets of genes for testing will be prioritised based on results from work in Aim 1, focussing on clusters of co-regulated genes that change expression rapidly after Pax6 loss and are associated with functions that are disrupted when Pax6 is removed. Methods to be used include chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assays (EMSAs) and in vitro and in vivo reporter assays, as well as proliferation, migration and differentiation assays in vivo.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: The contribution of tanycyte signalling to the function of hypothalamic networks
Funder: Medical Research Council

Abstract: The unremitting rise of obesity has led to intense study of the hypothalamic networks that are central to the regulation of energy balance. The study of these networks has concentrated almost exclusively on the roles of neurons. We have recently shown that hypothalamic tanycytes, cells at the interface between the ventricular cerebrospinal fluid and the brain parenchyma, respond to both neuron-derived and circulating agents that signal energy status and arousal. Other researchers have evidence that processes of tanycytes come into close contact with hypothalamic neurons. An active role for tanycytes in the hypothalamic network is highly plausible. We shall therefore: 1) develop methods to target optogenetic tools to tanycytes to allow selective activation of these cells; 2) establish whether tanycytes communicate directly to neurons; and 3) examine whether tanycyte-neuron communication is depends on metabolic state. We shall develop a lentiviral construct that efficiently drives tanycyte specific expression of a channel rhodopsin (ChR2). The selectivity of expression and efficacy of activation will be verified with cultured cells and tissue. We shall then map activate tanycyte-neuron communication in brain slices. We shall activate tanycytes by optical methods that include use of our new optogenetic tools but also involve multiphoton flash photolysis methods to release intracellular calcium ions within single tanycytes, or uncage ATP next to single tanycytes. Neuronal responses will be assessed via calcium imaging and their identity determined through use of mice with genetically labelled populations of hypothalamic neurons (NPY and POMC). We shall use pharmacological methods and biosensing to identify the transmitters released by tanycytes and the receptors activated on the neurons. Finally we shall examine the whether tanycyte-neuron communication exhibits state-dependent plasticity and can be altered by prior fasting, or diet-induced obesity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Folate metabolism and development of Neural Tube Defects
Funder: Medical Research Council

Abstract: Neural tube defects (NTDs), such as spina bifida and anencephaly, are severe congenital abnormalities caused by failure of closure of the embryonic neural tube. The causes of human NTDs are still largely unknown, but appear to involve multiple genetic and environmental factors. Folic acid supplementation can prevent some NTDs but a significant proportion (at least 30%) are unresponsive, and these defects remain a major health issue in the UK and worldwide. Abnormalities in folate one-carbon metabolism (FOCM) have been implicated in the possible causation of NTDs but the genetic basis of this relationship remains elusive. Key outstanding questions include which components of FOCM may be involved in NTDs, the mechanism by which impaired FOCM influences the morphological process of neural tube closure and whether FOCM-related NTDs can be prevented by folic acid and/or other exogenous agents. Emerging evidence suggests that neural tube closure depends on activity of the glycine cleavage system (GCS), a component of mitochondrial FOCM. We have identified functional mutations in GLDC and AMT in patients with NTDs, while loss-of-function of the corresponding genes has generated NTDs in novel mouse models. In the current project we will build on these preliminary findings by, (1) determining the developmental and cellular basis of NTDs in GCS mutant embryos. Next, (2) the metabolic consequence of impaired GCS activity in mouse embryos and patient cell lines will be analysed by mass spectrometry-based quantification of FOCM components, measurement of flux through FOCM and assay of FOCM outputs. Finally, (3) we will test potential therapies for prevention of GCS-related NTDs. We will follow up pilot data suggesting an ameliorating effect of methionine and additional approaches will be informed by data from metabolic assays and in silico modelling. Therapies will be optimised by an iterative process of testing and evaluation of metabolic and developmental outcome


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Cellular pathophysiology of prion-mediated neurodegeneration - a model for understanding protein misfolding disorders
Funder: Medical Research Council

Abstract: Prion diseases are fatal neurodegenerative disorders whose pathogenesis is associated with a conformational rearrangement of the normal cellular PrP (PrPC) to abnormal conformers (PrPSc) which causes neurodegeneration via a poorly defined mechanism. Understanding these mechanisms has key relevance to other neurodegenerative proteinopathies where both prion-like mechanisms and dysfunction of the proteostasis networks have been suggested to be important. My laboratory has demonstrated that dysfunction of the ubiquitin proteasome system (UPS) is an early event in prion disease pathogenesis in vivo, and that beta-sheet rich PrP oligomers potently inhibit proteasome activity in vitro. Work from my last MRC grant yielded a novel cell model where PrP knockdown neuroblastoma cells have been engineered to express an epitope-tagged PrP-chimera (PrP-Ala224MYC). This novel chimera is unique since it supports prion replication, and generates bona fide epitope-tagged PrPSc. We have used this model system to study the earliest events in prion infection. This proposal has five main aims directed at extending the understanding of the cellular pathobiology of prion disease. Our existing PrP-Ala224MYC cell model will be used to map the cellular trafficking pathways of PrPSc with a view to defining how it accesses the cytosol. We will reconstitute neuronal stem cells derived from PrP KO mice with PrP-Ala224MYC, to study prion formation, UPS dysfunction and cytotoxicity in neurons. Detailed biochemical studies will refine our molecular understanding of the inhibitory interaction between misfolded PrP and the UPS. Lentiviral-mediated knockdown of PrP in vivo will determine whether UPS activity can be modulated in neurons as a viable therapeutic target. A proteomic study of the ubiquitinated proteome in prion-diseased brain will identify substrate proteins that accumulate as the disease progresses with the aim of uncovering new pathways that may contribute to cellular toxicity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL