NIHRDataInsights/HRCSData huggingface dataset:
Title: The role of BMP/Smad signalling in motor neuron connectivity
Funder: Medical Research Council

Abstract: We have revealed that BMP-Smad signalling is involved in motor neuron (MN) axon elongation and identified Arkadia2C (Ark2C) as a positive regulator required for this (Kelly et al Nat. Neurosc. resubmitted). Ark2C is an E3 ubiquitin ligase specifically expressed in the nervous system that enhances BMP-Smad signalling by ubiquitin-mediated degradation of negative regulators. Expression analysis showed that MN harbour activated Smads and treatment of a MN cell line with BMP inhibitor diminished axon growth in culture. Genetic reduction of BMP signalling, by removal of a BMP-receptorII allele or loss of Smad8 BMP effectors in Ark2C+/- mice causes the emergence of innervation defects otherwise observed only in Ark2C-/-. Ark2C-/- mice are born but progressively thin and die before weaning, suggesting that BMP/Ark2C are involved in maintenance of the neuromuscular synapse. To explore the importance of motor axon elongation at postnatal stages, the involvement of BMP signalling, and mechanisms: 1. We will generate chimaeras with mixtures of Ark2C-/- and wild type ES-cells that will, respectively, express GFP and RFP in MN, allowing side-by-side comparison of pre-synaptic terminals, branching and synapses. The chimaeras should survive but exhibit defects dependent on contribution of mutant cells. If all Ark2C-/- MN are outcompeted by wild type MN we will pursue a conditional knockout strategy. Smad8-/- mice also exhibit MN defects and these will be analysed to explore BMP-Smad requirements independently of Arkadia2C. 2. Using high throughput sequencing we have identified BMP/Ark2C dependent target genes in ES-cell derived MN that are expected to be relevant to axon elongation. Functional studies on candidate targets will be performed by knockdowns in MN axon elongation assays that we have developed in culture, focusing on genes implicated in axon guidance, adhesion, cytoskeleton remodelling, signal reception and transcription.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Contribution of Wnt signalling to Amyloid Beta-mediated synaptic dysfunction
Funder: Medical Research Council

Abstract: Alzheimer's disease (AD) is devastating disease that leads to cognitive decline and dementia. It has been estimated that the number of cases of dementia will double in 20 years. Although extensive efforts have been made to find a treatment for this condition, no effective therapies are available. AD is associated with synaptic dysfunction, the early loss of synapses and the progressive accumulation of Amyloid-Beta (AB) resulting in cognitive decline. Soluble forms of AB decrease the number and strength of synapses before evidence of neuronal cell death. However, the mechanisms by which AB triggers the loss of synapses are poorly understood. We have recently found that AB interferes with Wnt signalling by inducing the expression of an effective secreted Wnt antagonist. Importantly, this antagonist is required for AB-mediated synaptic loss. In the current proposal, we will examine the contribution of compromised Wnt signalling to AB mediated synaptotoxicity. We will first characterize the role of the Wnt antagonist in AB toxicity by evaluating the integrity of synapses at the cellular and electrophysiological level. We will then examine the in vivo role of this molecule in transgenic mouse models of AD. We will test our hypothesis that expression of the Wnt antagonist in the adult brain might enhance or accelerate synaptic loss and dysfunction in transgenic mouse models of AD. The impact on synapses will be evaluated using a combination of cellular, electrophysiological and behavioural approaches. We will also screen for small molecules that block or interfere with the Wnt antagonist. Our studies could make a significant contribution towards unravelling the mechanisms that trigger synaptic loss in AD, and in the discovery of effective treatment for AD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Detecting, tracking & modelling structural and functional brain imaging changes in Alzheimer's disease
Funder: Medical Research Council

Abstract: This proposal aims to assess cerebral structural and functional changes in Alzheimer's disease (AD). I will develop models for structural and functional changes and structure-function relationships using magnetic resonance imaging (MRI). Novel modelling approaches have the potential to yield scientific insights into the disease process and to provide improved biomarkers with impact on clinical studies and trials of candidate disease-modifying therapies. Specifically, I first propose to enhance the widely used statistical parametric mapping framework with a new spatio-temporal Bayesian model for serial MRI data, which will enable efficient modelling of the trajectories of volume change at every voxel in the brain, allowing direct localisation of regions with significant group differences or associations with clinical measurements, in terms of local volumes, rates of change of volume, and acceleration or deceleration. Secondly, I will investigate the application to AD of a recently developed method for Bayesian estimation and comparison of dynamical system models of brain connectivity (dynamic causal modelling; DCM) using functional MRI acquired at rest. Finally, I will explore the inter-relations of structural and functional changes, developing and evaluating biomarkers that combine their unique strengths. The methods will be widely applicable to imaging of dementia, but are particularly motivated by data from the Dominantly Inherited Alzheimer Network, available at the Dementia Research Centre, which includes longitudinal structural MRI and resting-state functional MRI in subjects at risk of familial AD, including presymptomatic mutation-carriers.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Positive Allosteric Modulators (PAMS) of Strychnine-Sensitive Glycine Receptors - A New Concept in Treating Chronic Pain
Funder: Medical Research Council

Abstract: Our project addresses the longstanding unmet need of chronic pain. This debilitating condition affects about 20% of adults in Europe and in the USA, one key issue being the fact that patients struggle to maintain the balance between adequate pain relief and their ability to cope with the substantive side effects caused by the symptomatic medication available. We have successfully progressed from target validation/hit identification to the discovery of a novel class of compounds with low nM positive allosteric modulating activity at alpha1 glycine receptors. Such an action compensates for the loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord, which plays a key role in central pain sensitisation. Here we propose to advance these early leads through lead development/optimisation to realise a quality lead molecule appropriate for further exploitation, aiming at a causal treatment for chronic pain. Significant progress has been made so far funded by NESTech and the EPSRC/KTA leading to the filing of a composition of matter patent. For the first generation of compounds we have obtained successful proof-of-efficacy/selectivity in neuronal network models and proof-of-concept in vivo in a neuropathic pain rat model (intrathecal as well as oral administration). Moreover we have generated further hits while synthesising new optimised compounds. As our main objective is an optimised lead series we will: 1) sequentially and systematically remove chemical liabilities 2) run SAR analysis and ligand-based design to create new analogues with improved potency, specificity and physico-chemical characteristics 3) evaluate the most promising leads with appropriate in vivo and ex vivo screens and derisk them by standard pharmacokinetic and toxicology experiments. Two pharmaceutical companies, Grunenthal and B.Braun have confirmed their desire to collaborate with our group, and each other, in the event of a successful completion of this programme


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: REPAIR OF SPINAL ROOT LESIONS BY TRANSPLANTATION OF OLFACTORY ENSHEATHING CELLS CULTURED FROM THE ADULT OLFACTORY SYSTEM
Funder: Medical Research Council

Abstract: Reparative cells will be cultured from samples of stem cell containing tissue from the adult olfactory system. Dorsal (sensory) and ventral (motor) spinal roots will be detached from the spinal cord. We will re-appose these roots to the spinal cord. Using a specific endogenous matrix system which we have devised we will determine the effect of including these cells into the site of re-apposition. The results will be analysed in terms of the ability of severed nerve fibres to cross the transplants and the restoration of pain, touch and temperature sensation, and the degree of return of control over muscle function. This will provide an animal model for future translation to clinical application.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: DEMTEST
Funder: Medical Research Council

Abstract: Rapidly progressive dementia (RPD), in contrast to the more common forms of dementia, is a subset that follows an accelerated course of cognitive, behavioural and motor decline over a period of less than 2 years. An important cause of RPD is sporadic Creutzfeldt-Jakob Disease (sCJD). The clinical diagnosis of sCJD is supported by detection of biomarkers in blood or CSF, including the indirect markers 14-3-3, AB-amyloid 1-40 AB-amyloid 1-42, and the direct marker PrPSc, abnormal disease specific prion protein. In the differential diagnosis of neurodegenerative disorders, elevated levels of 14-3-3 and/or tau support the diagnosis of sCJD with a sensitivity of 85-94% and specificity of 80%. The availability of a reliable assay for the sensitive detection of PrPSc in human body fluids would provide a much needed disease specific test during the patient lifetime. Assays based on initial amplification of PrPSc protein aggregates show great promise for achieving specific and sensitive premortem testing for CJD. Studies on prion disease diagnosis have shown that rapidly progressive Alzheimers dementia (rpAD) as a major differential diagnosis. In addition, about one third of the referred cases actually suffer from a potentially treatable and reversible dementia caused by autoimmune, metabolic or (para)neoplastic conditions. Thus, achieving a correct diagnosis in RPD cases has important implications for distinguishing prion disease from other, potentially treatable diseases, preventing infectious material from being distributed via blood transfusions, surgery or organ donations and selecting homogeneous population for upcoming drug trials in AD and prion diseases.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Sampling and biomarker OPtimisation and Harmonisation In ALS and other motor neuron diseases (SOPHIA)
Funder: Medical Research Council

Abstract: Amyotrophic Lateral Sclerosis (ALS) is one of the most devastating diseases in neurology affecting some 50,000 individuals at any time in Europe, and causing around 10.000 deaths each year. The motor system (upper motor neurons in the motor cortex and lower motor neurons in the spinal cord) is preferentially affected. Whilst correlation between clinical and autopsy diagnosis is close to 100%, validated neurochemical biomarkers for monitoring disease activity, earlier diagnosis and defining prognosis are lacking. Thus, standardized protocols for clinical data and sample collection are now urgently required for optimization and harmonization of biomarker development. The overall aim of this proposal is to provide a common European strategy for the prioritization and selection of candidate biomarker domains for optimization and harmonization. This will in turn provide a long term platform by which existing collaborative structures that are relevant to neurodegenerative disease biomarkers (including academic initiatives, co-funding strategies, biobanks, industrial efforts, private-public alliances) are integrated within an inclusive web-based virtual biobank. Samples and clinical, imaging, neurophysiologic and neuropathological datasets provided by participating members can then be optimally utilized to enable state of the art collaborative analyses. The established platform will act as an important communication channel between this consortium and the broader international ALS/Neurodegeneration field, to ensure that the optimization efforts are consistently applied. Ultimately, the platform will establish a permanent Interactive European ALS biomarker tool for all researchers, and will enable ongoing optimization/harmonization of novel biomarkers using an integrated and robust pan-European ALS methodology. The platform will allow interaction with those of other cognate groups (e.g the NEALS group within the US), with patient groups and other relevant stakeholders.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: NEUROLOGICAL
Title: Sampling, biomarker OPtimization and Harmonization In ALS (SOPHIA)
Funder: Medical Research Council

Abstract: Tasks in the MRI component of SOPHIA: T1. Registration of participating EU ALS centres to the Jena MRI database. T2. Establish bidirectional interface to the core clinical data management. T3. Assessment of acquisition parameters driving variability in T1W and DTI datasets T4. Comparison of group-level results from different analysis platforms (SPM versus FSL versus TIFT). T5. Identification of a standardised protocol for T1W and DTI acquisition. T6. Linkage of core dataset and non-MRI biomarkers to individual MRI datasets to explore the additional value of a multimodal profile. T7. Implementation of standardised protocol prospectively in ALS and healthy control subjects. T8. Publication and international challenge of neurodegenerative disease research groups to test protocol against non-ALS neurodegenerative disease cases. T9. Re-assessment of variability of both pre-processed MRIs and results post-analysis in prospective data, through multi-site data sharing (inter and intra-site variability). T10. Correlation with post-mortem neuropathology reports in a subset of centers adhering to the standards of established European brain banks. T11. Application of quality control systems to other MRI modalities i.e. resting state fMRI, MR spectroscopy and advanced fibre track analysis tools of DTI. T12. Implementation of a continuous quality control framework which feeds back to participating centres.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: NEUROLOGICAL
Title: Bone marrow stem cell therapy in multiple sclerosis: potential mechanisms of repair and protection
Funder: Medical Research Council

Abstract: Cell therapy offers new possibilities for reducing tissue damage, and progressive disability, in multiple sclerosis [MS]. We hypothesise that autologous bone marrow [BM] cell therapy in chronic MS offers durable benefit; and that the mechanisms are multiple, but include the reparative and/or neuroprotective effects of more than one BM cell sub-population. On a background of our own and others' experimental BM stem cell studies, we completed a Phase 1 trial of intravenous BM cell therapy in 6 patients with chronic MS (www.nature.com/clpt/journal/v87/n6/full/clpt201044a.html). Safety was confirmed, and intensive serial neurophysiological tests showed statistically significant improvements at 12 months in every patient. While uncontrolled and highly preliminary, these results are consistent with a beneficial effect within the damaged CNS. We believe this urgently requires further testing - both to accelerate benefit towards patients, and to improve therapeutic efficacy. We therefore propose a programme of translational and clinical stem cell research, aiming (1) to continue translation with a Phase 2 controlled trial of autologous BM cells in 80 patients with chronic MS; and (2) in parallel to explore potential mechanisms of action by studying BM cells from recruited MS patients and non-MS controls, aiming to establish what the various BM sub-populations might contribute to efficacy; which reparative mechanism(s) might be important; whether monocytes contribute to the effect; and whether there are differences in therapeutic properties between BM cells from MS patients and those from non-MS controls. Our trial has been funded by a grant from a USA foundation; this application seeks MRC funding to exploit the unique back-translational opportunity presented by the trial to explore how this therapy might work - and, potentially, provide the basis for improving the magnitude and impact of this treatment.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL
Title: Integration strategies of GABAergic interneuron subtypes in the normal and dysfunctional neonatal cerebral cortex
Funder: Medical Research Council

Abstract: The inhibitory interneurons of the cerebral cortex are fundamental to normal cognitive function and deficits in interneuron signalling have been implicated in a wide range of neurological disorders. However our understanding of the precise role of interneurons within the developing cortex has been to a large degree hampered by their diversity. To address this question we are taking an approach that combines developmental genetics, physiology and optogenetics to probe the contribution of individual interneuron subtypes to the emergent network in both the normal and dysfunctional brain. Our recent work suggests that a transcriptional code acts to specify interneurons at the moment of neurogenesis. We intend to use our knowledge of the developmental origin of interneurons to track and determine the role of specific interneuron cohorts within the nascent neocortex. The benefit of using developmental genetics is that it provides an efficient means of identifying and interrogating interneuron function in a highly dynamic developing structure. Specifically, we will use an inducible Cre/LoxP strategy in combination with fluorescent and optogenetic reporters to track distinct populations of interneuron as they integrate into the nascent circuit both in the normal brain and those in which known molecular determinant of integration have been perturbed. To provide a comprehensive picture we will adopt a multi-faceted electrophysiological approach utilising a range of photostimulation techniques to examine the integration and downstream physiological targets of interneuron in the primordial network. These experiments will enable us to distinguish when interneuron subtypes become actively involved, and the timeframe over which they are engaged in early cortical function. The result will provide a valuable platform for researchers to go on and further dissect and understand the role of individual interneuron subtypes within the context of the emergent and mature cerebral cortex.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Structural and functional fronto-hippocampal maturation and neurodevelopmental outcome following very preterm birth in adulthood
Funder: Medical Research Council

Abstract: Individuals who were born very preterm are at greater risk of brain damage and consequent neurological disorders, neuropsychological, and behavioural impairments in childhood and later in life. A number of studies to date have used MRI at term to predict childhood outcome, but little is known about the nature and course of neurodevelopment in preterm individuals when they reach adulthood. We propose to study 153 individuals who were born very preterm (VP; <33 weeks of gestation) in 1979-1984, with varying degrees of neonatal distress, for whom we have acquired detailed longitudinal neuroimaging and developmental data from birth up to adolescence, and 89 age matched controls. This will allow us to undertake the first study on how VP birth affects the longitudinal trajectories of brain development from mid-adolescence (14-15 years) to adulthood (28-33 years), and to determine the relationship between brain maturational patterns, cognition and behaviour. As functional and structural alterations in frontal, temporal and hippocampal regions have been described in VP samples and have been associated with neurodevelopmental outcome, we will specifically focus on studying maturation in these brairegions. We propose a multimodal neuroimaging study, which will use voxel-based morphometry, region of interest volumetric and shape analysis, diffusion and functional MRI and a novel technique (mcDESPOT), which will allow us for the first time to assess myelin fraction in a VP sample in adulthood. We hypothesise that VP individuals will show altered dynamic sequences of brain maturation (slower growth rates and accelerated cortical thinning) in frontal and temporal brain regions compared to controls from mid-adolescence to adulthood. We further hypothesise that exaggerated or/and dysregulated dynamic patterns of frontal and temporal maturation will be associated with neurodevelopmental "risk", while early alterations which normalize by adulthood will be associated with "resilience"


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The role of Miro and PKC signalling in axonal transport defects in amyotrophic lateral sclerosis.
Funder: Medical Research Council

Abstract: Amyotrophic lateral sclerosis (ALS) is a lethal motor neuron disorder without a cure. Impaired axonal transport is one of the earliest pathological features observed in ALS models, suggesting that transport defects might be a primary cause of ALS. We showed that mutations in SOD1 and VAPB that cause familial ALS inhibit anterograde but not retrograde axonal transport of mitochondria. The mitochondrial kinesin-1 receptor Miro regulates anterograde transport of mitochondria in response to calcium and mitochondrial damage. Furthermore, several groups including us have shown a role for phosphorylation in regulation of the transport process. We hypothesise that inhibition of anterograde mitochondrial axonal transport by a calcium/Miro and kinase-dependent pathway is a primary cause of motor neuron death in ALS and a potential therapeutic target. The specific objectives are: (1) To determine if a calcium/Miro signalling pathway underlies the mitochondrial axonal transport deficit in ALS. We will evaluate if a calcium insensitive mutant Miro can restore the transport deficit in mitochondrial transport assays. (2) To investigate the involvement of kinase signalling. We will test kinase inhibitors for their effect on axonal transport in mitochondrial transport assays. (3) To establish if axonal transport defects are a primary cause of cell death in ALS. We will restore axonal transport of mitochondria using a calcium insensitive Miro mutant or kinase inhibitors in motor neurons expressing ALS mutant proteins and monitor motor neuron survival. Summarised, this research will increase our understanding of the mechanisms underlying defective mitochondrial transport and motor neuron death in ALS, and will establish if restoration of axonal transport has therapeutic potential. Furthermore, the results obtained here are likely to be transferable to other neurodegenerative diseases that involve axonal transport defects, including Alzheimer's and Parkinson's disease.


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