NIHRDataInsights/HRCSData huggingface dataset:
Title: Non-invasive electrical stimulation of cervical spinal cord to facilitate arm & hand functional recovery in incomplete traumatic cervical spinal cord
Funder: Medical Research Council

Abstract: Manual dexterity is indispensable for carrying out the vast majority of our normal daily activities, ranging from object manipulation to nonverbal communication. Damage to the connectome controlling the upper extremities inflicts devastating consequences, as the patient's lifestyle becomes dependent on supportive devices, which drastically reduce their freedom to perform activities of daily living. From all the physio-pathological symptoms developed following a cervical SCI, patients have emphasized a high priority for finding therapies to restore arm/hand function. Bioengineering is opening a new opportunity in restorative neuroscience. These technologies aim to facilitate or to enhance residual function without the need for long-distance regeneration of severed axons. This project will investigate a new transcutaneous spinal cord stimulation technique that aims to boost spinal cord excitability and facilitate beneficial plasticity in order to produce lasting improvement to upper-limb function using a non-invasive approach. A combination of animal and patient studies will be used to optimise stimulation parameters, explore the mechanisms of facilitation and demonstrate this exciting new technique.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Altered Chloride homeostasis in Reactive plasticity upOn BrAin Trauma
Funder: Medical Research Council

Abstract: Progressive network reorganization and altered proliferation are major events leading to traumatic brain injury (TBI)-related complications, such as post-traumatic pharmaco-resistant epilepsy and cognitive impairment. The underlying mechanisms are not well understood, making research in this field mandatory. The proposed project aims at exploring the contribution of altered chloride homeostasis and GABAergic transmission to TBI-triggered reactive plasticity mechanisms, from cellular to system levels. The working hypothesis of our consortium is that TBI induces changes in the chloride regulatory proteins KCC2 and NKCC1, leading to altered intracellular chloride homeostasis and changes in the polarity of GABAA receptor-mediated responses. Those may then be responsible for the resistance of therapies targeting the GABAergic system. According to preliminary data from our partners, TBI-induced chloride transport malfunction leads to hyper-excitability as well as deficits in BDNF trophic support. With our partners, we aim to target the underlying mechanisms with a specific focus on how GABAA receptor-mediated depolarization alters proliferation in affected neurogenic niches through p75NTR pro-apoptotic effects on interneurons. Given the role of different interneuron subtypes in microcircuit activity, a major focus of this project will be to understand how these processes contribute to acquired rhythmopathies and epileptogenesis at the functional level. We and our partners will address these questions using a combination of state-of-the-art transgenic tools for both temporal and cell-specific control and monitoring of intracellular chloride as well as chloride regulatory proteins after TBI. ACRoBAT incorporates several innovative dimensions aimed at designing novel tools, biomarkers and intervention strategies. Ultimately, we will test the therapeutic relevance of novel compounds modulating KCC2 function in TBI experimental models.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: New therapeutic strategies in the treatment of traumatic brain injury by targeting the LEctin Activation Pathway of complement
Funder: Medical Research Council

Abstract: The present research programs aims to define the therapeutic utility of an inhibitory antibody that specifically inhibits a plasma based serine protease called MASP-2 (for Mannan binding lectin Associated Serine Protease-2) of the lectin activation pathway of the complement system, a component of the innate immune system. Inhibiting MASP-2 proved to significantly reduce post ischaemic reperfusion injury (IRI) and post-traumatic inflammation in experimental mouse models of stroke, renal transplantation, renal ischaemia and gastrointestinal ischaemia resulting in a significant reduction of tissue loss and loss of organ functions. MASP-2 inhibition also proved to be an effective treatment for thrombotic pathologies first shown in model of LPS induced thrombosis and FITC-dextran and light induced model of endothelial injury leading to thrombosis in the low pressure blood circulatory system. A clinical candidate inhibitor for MASP-2, a recombinant therapeutic antibody called OMS721 has been assessed in phase 2 and 3 clinical trial in patients with life-threatening microangiopathies, such as thrombotic thrombocytopenic purpura (TTP) and atypical Haemolytic Uraemia Syndrome (aHUS). The treatment proved to be highly successful and significantly improved the clinical outcome of these severe clinical conditions improving all clinical parameters of disease severity without increasing the risk of blood loss by interfering with plasma agglutination. The present research programme will define the windows of therapeutic efficacy to improve the outcome of traumatic brain injury by reducing post-traumatic inflammation and inflammatory loss of CNS tissue and CNS functions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: A glucose-responsive network
Funder: Medical Research Council

Abstract: The brain protects itself from low glucose levels by initiating a hierarchy of endocrine and behavioural counter-regulatory responses (CRR). This is particularly important for diabetic patients on insulin, who often experience hypoglycaemic events. Repeated "hypos" can lead to an impaired CRR and patients becoming unaware of their symptoms. Impaired awareness of hypoglycaemia is the major barrier preventing successful glycaemic control in diabetic patients and, therefore, it is critical that we understand how the brain normally senses and responds to hypoglycaemia. As with other systems regulating homeostatic function, the discovery of a distinct, primary-sensing neurone in a key brain region is often the catalyst to unravelling complex circuits (viz Agrp neurones and appetite or orexin neurones and sleep/wakefulness). We have discovered such a neurone: the PACAP-containing cell in the ventromedial hypothalamic nucleus, which is intrinsically sensitive to reduced glucose. We found that PACAPVMH neurones are "glucose-inhibited", respond to other relevant inputs and project to areas of the brain, each of which has been implicated in different CRR. We will confirm functional projections using channel-rhodopsin-assisted circuit mapping (CRACM) and cre-sensitive designer receptors (opto- and chemo-genetics). By mapping efferent outputs, as well as afferent inputs from other glucose-sensitive brain regions, we will demonstrate that PACAPVMH neurones are part of a robust and redundant glucose-responsive network. We will also use transcriptomic analysis of these and other VMH cells (based on their projections and physiological responses) to identify separate sensing and integratory neurones (such as "glucose-excited" or "presynaptically-excited" neurones). The network will be analysed by CRACM to dissect specific core pathways controlling different endocrine and behavioural CRR to hypoglycaemia.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Repair of the corticospinal tract
Funder: Medical Research Council

Abstract: The overall aim of the project is to develop a method to reconstruct the corticospinal tract in the damaged spinal cord, The project follows on from recent work showing that long distance sensory axon regeneration can be stimulated by transducing sensory neurons with the tenascin-C-binding integrin alpha9beta1 together with integrin-activating kindlin-1. Tenascin-C is the main integrin ligand of the adult spinal cord, upregulated by injury. Kindlin-1 overcomes inactivation of integrins by CSPGs and NogoA. Activated integrin treatment promotes long-distance regeneration of sensory axons, but a further intervention is needed for corticospinal regeneration. The issue is that transport in mature CNS neurons becomes polarised, sending some molecules to dendrites, some to axons. Many growth-related molecules are carried in Rab11 recycling endosomes, and these are excluded from axons as they mature. We have developed four effective and probably synergistic methods that can restore Rab11/integrin transport to mature cortical axons, and promote regeneration. These have been validated in an in vitro model in which cortical neurons mature, developed polarised transport excluding Rab11/integrin and lose the intrinsic ability to regenerate. The four interventions are: a) knockdown of the Arf6 GEF Efa6, b) dominant active transport adaptor protrudin, 3) constitutively active PI3K delta, 4) demolition of the axon initial segment. The plan for the grant is: 1) Develop AAV vector tools for each of the for regeneration methods and validate them in vitro. 2) Test combinations of the treatments to find additive effects and effective combinations. 3) Four short proof-of-principle experiments to find the most effective combination of AAV vectors, including alpha9 integrin, kindlin-1 and two of the four candidate treatments injected into cortex to trace corticspinal regeneration. 4) A definitive regeneration experiment with behaviour to validate the most effective treatment.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Paediatric Brain Monitoring with Information Technology (KidsBrainIT): Using Information Technology (IT) Innovations to Improve Childhood brain trauma
Funder: Medical Research Council

Abstract: Aims: We aim to set up a new multi-centre, multi-disciplinary, multi-national intensive care informatics group for paediatric brain trauma (KidsBrainIT) for current and future hypotheses testing. We then aim to use the KidsBrainIT data-set in this proposal to test two clinically relevant hypotheses: After sustaining traumatic brain injury (TBI), paediatric patients with a longer period of measured cerebral perfusion pressure (CPP) maintained within the calculated optimal CPP (CPPopt) window have (1) an improved global clinical outcome, and (2) better tolerance against raised intracranial pressure (ICP). Methods: A 2-year prospective observational study is planned in the current proposal. Paediatric TBI patients requiring intensive care will be recruited from 10 contributing centres in 4 different countries. We will collect their anonymised routinely collected bedside physiological monitoring data in minute resolutions linked with anonymised clinical and outcome data and store it to the central KidsBrainIT data-bank. CPPopt is calculated using the LAx-CPP plots and DATACAR methodology and ICP dose response analyses will be performed on the KidsBrainIT dataset. These will be correlated with global outcome at 6 months. Age-maturation effects are studied by grouping patients into three previously described age-bands. In addition, a centralised informatics based quality assurance infrastructure is in place to generate treatment compliance reports to our contributing units for clinical care and patient safety improvement.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Developing and validating blood and imaging BIOmarkers of AXonal injury following Traumatic Brain Injury
Funder: Medical Research Council

Abstract: Outcomes after traumatic brain injury (TBI) remain hard to predict. This is partly because axonal injury, which is of fundamental importance, is difficult to measure clinically. Advances in magnetic resonance imaging (MRI) now allow axonal injury to be sensitively detected after TBI. Fluid biomarkers provide a complementary measure, as cytoskeletal proteins are released from damaged axons. We will perform a multicenter study of adult TBI investigating the relationship between plasma, microdialysis and neuroimaging markers of axonal injury. An advanced bioinformatics will be used across the difference parts of the study, building on the CREATIVE system for integrated collection of multi-dimensional clinical data. We will test the relationship between the most promising fluid biomarkers, in particular neurofilament light (NFL) and tau protein, and MRI measures of axonal injury including diffusion MRI (N=250). Longitudinal neuroimaging and blood biomarker data will be collected, allowing us to assess biomarker dynamics their relation to neurodegeneration measured by brain atrophy. A subgroup of patients will be assessed using microdialysis (N=40), which will allow local production of NFL and tau to be investigated. Biomarkers most closely linked to outcome will be identified from our first cohort (N=250) using logistic regression to model mortality and clinical outcome. These results will be validated using a larger cohort of patients from CREACTIVE (N=~1000), where we will also investigate the diagnostic utility of CT head imaging. The project will allow us to: (a) cross validate in vivo methods for assessing axonal injury following TBI; (b) test whether combining measures of axonal injury provides improved diagnostic and prognostic information; (c) gain insights about the underlying mechanisms of axonal injury.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Spinal cord repair: releasing the neuron-intrinsic brake on axon regeneration
Funder: Medical Research Council

Abstract: Problem: Spinal cord injury (SCI) leads to permanent disability and is a significant clinical problem with 130.000 new cases/year worldwide. Following SCI long axon tracts fail to regenerate. This is the primary reason for the sustained loss of bodily functions. Objective and added value: AxonRepair aims to develop a strategy to promote long-distance axon regeneration and functional recovery after SCI by reprogramming neurons into a regenerative state and by overcoming the axon transport block that is a barrier to axon regeneration. The added value of AxonRepair is that we bring together world-class experts on the transcriptional control of axon regeneration, axon transport and therapeutic gene delivery. Individually, we have identified factors that promote CNS axon regeneration and modest sensorimotor recovery in animal models of SCI. Collectively, we now seek to combine these factors to deliver greater axon regeneration and clinically significant functional recovery. We will use clinically translatable adeno-associated vector-based gene delivery, novel techniques to quantify axon trajectories in cleared spinal tissue and innovative, automated methods for assessing dexterity in rats. Workplan: Work package (WP) 1 aims to reprogram neurons into a regenerative state by testing the effect of combinatorial delivery of key transcription factors identified in our collective's discovery pipelines. WP 2 aims to restore axonal transport of growth-related receptors (integrins) to injured spinal axons. WP 3 aims to provide novel mechanistic insight into how interventions at the transcriptional and axon transport level work and whether these interventions act synergistically in rat models of SCI. WP4 defines the management structure, including a data management and sharing plan. A research steering group will direct, coordinate and monitor progress of AxonRepair.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Investigating neuronal RNA localisation and translational deficits as gain of function mechanisms in ALS.
Funder: Medical Research Council

Abstract: RNA binding proteins (RBPs) are crucial in ALS and mutations in RBP FUS cause ~5% familial cases. New evidence supports cytoplasmic gain of function as the pathomechanism in RBP-ALS, but its nature is unknown. Here, we use our new FUS-ALS mouse to dissect changes in FUS cytoplasmic functions: in RNA localisation and in regulating local translation. These functions are crucial for maintenance and response to injury of motor neuron (MN) axons -- the majority of the neuronal cell mass. So far, technical hurdles limited this research so we know little of the composition of RNAs translated in axons, in health or disease. Here, we take combine new molecular tools to overcome these hurdles. We use the RiboTag system to precipitate RNAs bound to ribosomes in MN cell bodies and axons from the mature mouse nervous system. Thus, we study the axonal translatome in vivo at pre-symptomatic and early disease timepoints of our FUS-ALS model. We follow our preliminary data showing reduction in ribosomal genes in this model by studying ribosome quantity and localisation in motor axons, and polysome profiling in spinal cord and nerve. Then, in vitro, we physically separate axons from cell bodies to gain insight into processes linking FUS mutation to altered translation. We use both FUS ALS and Fus knockout MNs for polysome sequencing: a technique enabling us to calculate translation efficiency of all transcripts - to gain understanding of how FUS mutations cause alterations in local translation. We complement these molecular data by visualising protein translation by fluorescent labelling of nascent protein chains detected by confocal microscopy. Finally, in Year 3, we validate our findings using a unique clinically and molecularly well-characterised bank of relevant human post-mortem material. Thus, we address the molecular dysfunction that arises in FUS-ALS, using novel techniques and mouse resources, ultimately moving towards realistic translational approaches.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Environmental enrichment-dependent neuronal activity pathways for axonal regeneration and recovery after spinal cord injury
Funder: Medical Research Council

Abstract: Injury to the adult mammalian nervous system leads to permanent deficits in sensory and motor function. This is partly due the inability of neurons to initiate an effective molecular regenerative response, resulting in failed axon regeneration. Sensory neurons in the dorsal root ganglia (DRG) are essential for sensorimotor function as they receive and convey sensory information from the environment to motor circuits in the spinal cord and brain. We have recently found that exposing mice to environmental enrichment (EE) prior to an injury induces a long-lasting increase in the regenerative potential of DRG neurons, including when combined with a conditioning lesion, priming them for robust axon regeneration in both the peripheral and central nervous system after injury. Therefore, we propose EE as a novel "injury free" paradigm priming sensory neurons for axon regeneration. Mechanistically, our recent combined RNAseq and proteomics studies suggest that EE may enhance neuronal activity and creb binding protein (CBP)-dependent histone acetylation leading to gene expression for a long-lasting enhanced axonal regenerative ability. Here, we will investigate (1) whether EE-dependent proprioceptive input from muscle spindles is required for EE-dependent modulation of neuronal activity and DRG sensory growth by studying EGR KO mice that have an impaired muscle spindle feedback signalling. (2) Second, we will explore whether EE-dependent neuronal activity is required for EE-dependent DRG outgrowth (DREADD based approaches), CBP and histone acetylation. Lastly, 83) we will ask whether a small molecule activator of CBP will enhance axonal regeneration and (neurophysiological and sensorimotor recovery after SCI mimicking the effects of EE and EE in combination with a conditioning lesion. In summary, this proposal aims to provide both mechanistic and translational advancements for the understanding and treatment of experimental and clinical SCI.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: A novel adaptive sampling technique for mapping brain function
Funder: Medical Research Council

Abstract: Patients with a range of neurological and psychiatric disorders have cognitive impairments associated with abnormal activity and connectivity within fronto-parietal brain networks. Cognitive tasks (performed either behaviourally or in the scanner) that can sub-classify patients based on different types of brain network dysfunction have great potential value in clinical research and assessment. However, achieving this aim is non-trivial. The proposed project will develop and apply a novel neuroadaptive approach for identifying the optimal tasks that differentially engage two important frontoparietal brain networks, with the aim of developing more sensitive cognitive tasks. There are four work packages. WP1, we will use meta-analytic approaches based on the large existing literature of FMRI studies to identify cognitive tasks that form an ordered experimental parameter space. This will be the starting point for optimisation. For demonstration purposes, we will seek to find tasks that differentiate between two important functional networks involved in cognitive control. WP2 will use closed-loop neuroadaptive Bayesian optimisation with real-time functional MRI to find the tasks that maximally dissociate between these two functional brain networks. WP3 will involve a further fine-tuning round of Bayesian optimisation to refine the task parameters of the best candidate cognitive tasks from WP2. WP4 will validate the cognitive tasks behaviourally, using internet-delivered cognitive testing on a large number of participants followed by factor-analysis. The neuroadaptive tools developed in the project and the optimised cognitive tasks will be shared with the research community and form the basis for subsequent clinical translational grant applications.


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