NIHRDataInsights/HRCSData huggingface dataset:
Title: Defining the role of Wnt-Fz7 signalling in long-term plasticity in health and disease
Funder: Medical Research Council

Abstract: The structural and functional plasticity of synapses underlies fundamental brain functions including learning and memory. Defects in synaptic plasticity are correlated with cognitive decline in neurodegenerative conditions such as Alzheimer's disease (AD). Great progress has been made in unravelling the mechanisms controlling synaptic plasticity at central synapses. However, our understanding of how synapses are modulated in the healthy and diseased brain remains limited. Wnt secreted proteins are emerging as key modulators of synaptic connectivity. Our lab has made significant contributions to this field. Our latest studies revealed a crucial role for Wnt signalling in synaptic plasticity, as inhibition of endogenous Wnts blocks long-term potentiation in the hippocampus. We also showed that Wnt7a signals through the Frizzled-7 receptor to promote synaptic plasticity. Wnt-Fz7 signalling triggers similar pathways as NMDAR activation. Based on extensive pilot data, we propose that Wnt signalling together with activation of NMDARs regulates synaptic potentiation. We also found that Fz7 is affected in AD mouse models when synaptic deficits begin to emerge. These results suggest that deficiency in the levels of Fz7 receptor may contribute to synaptic plasticity defects in AD. The central aim of this proposal is to unravel the function of Fz7 in synaptic plasticity in the hippocampus, and to examine how deficiency in Fz7 affects synapses in AD models. We will address three main objectives: 1) To determine the molecular mechanisms by which Fz7 regulates NMDAR-mediated synaptic plasticity; 2) To examine the impact of Amyloid-Beta on Fz7 and associated proteins during synapse degeneration; 3) To investigate whether enhanced Fz7 signalling protects synaptic plasticity and memory in AD models. Our studies will provide new mechanistic insights into how synaptic modulators regulate synaptic plasticity and whether they protect synapses in AD models.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Valium without the sedation: Anxioselective GABAA receptor modulators for the treatment of anxiety disorders
Funder: Medical Research Council

Abstract: This proposal seeks follow-on funding to identify and develop a novel non-sedating anxiolytic drug ready for testing in man. We will identify a single clinical candidate from a chemotype in which we are able to consistently identify molecules that are positive allosteric modulators (PAMs) at GABAA receptors containing either an alpha2 or alpha3 subunit (a2/a3-GABAAR; "anxiolytic" GABAARs) but which have minimal effects at the a1 subtype ("sedating" GABAARs). Based upon proprietary chemical starting points and structure-activity relationships originating from our AstraZeneca collaborators, we have significantly improved the pharmacology of these compounds to the point where we can demonstrate a non-sedating anxiolytic pharmacology in rodent species. We are now requesting funding to further fine tune our lead compounds and balance the current excellent pharmacological profile with emerging issues (such as solubility, CYP450 inhibition and PXR activation) in order to deliver the strongest possible clinical candidate. More specifically, we will identify 2-4 pre-candidate molecules from which a single candidate molecule will be selected to undergo full IND-enabling, GLP preclinical safety and toxicity testing. The outcome of this 33-month project will therefore be a drug ready for Phase 1 clinical studies. Subject to further clinical development, such a compound would be a first-in-class, non-sedating anxiolytic - "Valium without the sedation" - with the potential to transform the treatment of anxiety disorders, and more specifically generalised anxiety disorder (GAD), a debilitating and poorly-treated disorder with a lifetime prevalence of 5% and an estimated annual cost to the UK economy of around £10 billion.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Enabling Caribbean people to live well with dementia: Developing 'dementia-friendly', community hubs with Black Majority Churches
Funder: Medical Research Council

Abstract: Background: Caribbeans have higher dementia prevalence than White British peers; developing symptoms on average 8-10 years earlier (7). Despite greater morbidity, Caribbeans access dementia-related services later in their illness trajectories with more advanced symptoms . Eschewing mainstream services; they tend to be cared for by families, increasing the risk of adverse effects on carer health and wellbeing . Outside the family, Caribbeans seek help from local culturally-aware sources of support such as Black Majority Churches (BMCs) rather than more mainstream dementia services. However, BMCs and church leaders lack appropriate structures, knowledge and experience to support people to live well with dementia or to advise church and community members on dementia. There is currently little understanding of what 'living well with dementia' looks like from Caribbean people's perspectives. Aim: Co-produce a manualised intervention ("how to resource") for developing dementia-friendly BMCs as 'community hubs' where people with dementia and their families can access information, advice and support to improve wellbeing, reduce social isolation, and ultimately increase access to early diagnosis and timely and appropriate care and support. Design: Mixed-methods in 3 stages: 1) Systematic literature review to identify the key elements for culturally-appropriate, dementia-friendly church hubs 2) Focus groups with people with dementia (n=6-8) using creative arts-based methods, carers, church leaders, healthcare professionals (n=6-10 per group). to inform what 'living well' with dementia means for Caribbean people and what they feel a community hub should provide. 3) Co-production/design of the intervention and identification of desired outcomes, using Stage 1 & 2 findings Analysis: Realist synthesis (literature review) and thematic analysis.


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: NEUROLOGICAL
Title: Mechanisms underpinning human neocortical development and neurodevelopmental disorders: The novel role of Extracellular Matrix.
Funder: Medical Research Council

Abstract: I propose to elucidate the function of the extracellular matrix (ECM) in human neocortex development and neurodevelopmental disorders, using the human fetal neocortex explant systems and ex vivo folding assay I have developed. Aim 1: Determine the function of ECM in human neurodevelopmental disorders, using i) human fetal neocortex tissue with neurodevelopmental disorders, and ii) introducing known ECM perturbations linked to such disorders in healthy human fetal neocortex tissue. Cell behaviour, such as proliferation and migration, and tissue morphology, such as folding, will be analysed using live imaging and immunofluorescence. Atomic force microscopy (AFM) will be used to analyse changes in ECM stiffness alongside cell behaviour. Aim 2: Characterise ECM composition during human neocortex development, using proteomic analysis of the ECM within the different zones of the developing human neocortical wall in combination with AFM to analyse ECM stiffness. This will be performed at several key time points throughout neurogenesis and at the onset of folding (9-22 GW) to assess the dynamics of the ECM network. Aim 3: Elucidate the function of ECM and related signaling on human neocortex development and folding. The ECM candidates identified in Aim 2 will be perturbed/modified in human fetal neocortical explants using ECM-modifying enzymes, signalling pathway inhibitors, electroporation to manipulate gene expression and recombinant ECM proteins. The effect of modifying the ECM will be analysed by AFM, live imaging and immunofluorescence to assess ECM stiffness, cell behaviour, such as proliferation and migration, and tissue morphology, such as folding. Interesting candidates can then be tested in the mouse, to examine the effects of humanizing the ECM during neocortical development. Together, these aims will enable me to elucidate the function of the ECM network in human neocortex development and folding, and how disruption of this leads to neurodevelopmental disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Long-term consequences of silencing pain pathways with novel Botulinum constructs.
Funder: Medical Research Council

Abstract: There is an urgent need for new pain-relieving therapies. We have previously shown in mouse models of persistent pain that a single injection of novel Botulinum toxin constructs silenced pain-processing neurons in the spinal cord and decreased mechanical hypersensitivity. We targeted either NK1R-expressing neurons that relay pain-related information from the spinal cord to the brain or the mu opiate receptor (MOR) expressing dorsal horn neurons that modulate activity in the dorsal horn. To silence NK1R- expressing neurons, we used an SP-Botulinum (SP-BOT) construct, whereas MOR expressing neurons were silenced using a dermorphin-Botulinum (Derm-BOT) construct. We found that the new constructs were selectively internalized after binding to their target receptors and observed a long-term effect on mechanical pain sensitivity on both inflammatory and neuropathic pain states after a single injection of the constructs. We also found that Botulinum construct treatment was as effective as giving an intrathecal opiate. The local paralysis caused by injections of Botulinum neurotoxin A into muscle is reversible over a period of months and may be repeated if desired. The aim of the current proposal is to establish the point at which Botulinum-construct based silencing of pain pathways is lost and whether reinjection of the Botulinum constructs will re-silence these key pain-signaling neurons without damaging neurons. We will also examine the influence of sex in our models as recent research has suggested that the efficacy of morphine-mediated analgesia may be sex dependent and Botulinum based constructs may therefore be more effective in one sex than the other. The evidence for the translational potential of these Botulinum constructs is strong. But while we have demonstrated that the silencing of pain-signaling neurons lasts at least 40d in mice we need to know at what point the treatment reverses and whether it can be repeated without causing damage to spinal neurons.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Elucidating early stage ALS pathomecanisms that drive mitochondrial dysfunction
Funder: Medical Research Council

Abstract: In regards to molecular disease mechanisms, ALS is a poorly understood disease. However, we recently identified that (1) mutant FUS Delta14 protein accumulates in the mitochondrial fraction to a greater extent than wildtype FUS, (2) the level of wildtype FUS in mitochondria is significantly altered in the FUS Delta14 mice and (3) lipidomic analysis of CNS tissues suggest significant mitochondrial dysfunction through key alterations in mitochondria-associated lipids in FUS Delta14 mice before MN loss. All together these data suggest that mutant FUS is likely to play key roles at mitochondria and that mitochondrial dysfunction has an important role in early stage disease processes. To dissect the role of mitochondria in FUS-ALS we have designed five independent, yet inter-related aims. Aim 1.Identify FUS wildtype, and mutant, protein-protein interactions through tissue fractionation and immunoprecipitation Aim 2.Visualise key interactions of mutant and wildtype FUS associated with mitochondria using super resolution microscopy (SIM and STORM) Aim 3.ssess structural changes in ER-mitochondrial tethering and mitochondrial morphology by electron microscopy (EM) Aim 4.Generation of human FUS Delta14 frameshift iPSC line Aim 5.In vitro functional studies using human iPSC derived MN We combine comparable in vivo and in vitro systems, with the same genetic modifications, in order to identify key disease pathomechanisms. Our mouse model allows working in vivo with multiple cell types, throughout aging and disease development, while our cellular systems will allow detailed mechanistic investigation of disease-associated pathways. Overall these experiments take advantage of our novel FUS frameshift model systems, provide fundamental new insight into earliest pathological events in FUS-ALS. As mitochondria dysfunction has been reported in many neurodegenerative diseases, it may also provide important insights for the whole ALS and neurodegeneration research field.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Uncovering the neural basis of movement transitions
Funder: Medical Research Council

Abstract: Animals naturally perform movements as a continuous sequence, smoothly transitioning from one to the next. We know much about the neural correlates of isolated movements, about how the periodicity of population activity in motor centres encodes rhythmic movements, and about how cortical population activity encodes discrete movements like reaching. But we know little about the neural correlates of transitions between rhythmic or discrete movements. In this project, we will take advantage of newly available datasets of population activity during transitions in rhythmic and discrete movements to determine how a neural population reconfigures its dynamics to support multiple end-goal movements. For rhythmic movements, we have dense single-neuron, single-spike resolution imaging data from the motor circuits of the marine mollusc Aplysia during their transitions from quiescence, to an escape gallop to exploratory crawling. For discrete movements, we have microelectrode array recordings from the motor cortex of monkeys performing a task with multiple, sequential arm movements. Our proposed work will determine if distinctly observable movements map onto distinct dynamics of the neural population. We will use a dynamical systems framework to compare hypotheses for how transitions between discrete and rhythmic movements are encoded by the population. And we will define the contribution of single neurons to test the hypothesis that movement transitions are encoded by the joint activity of a population, and not by individual neurons. Finally, we will fit network models to the recorded population activity to infer how the underlying circuits change to create the transition in movement. Collectively, our findings will place strong constraints on theories for the neural control of movement, and on future designs of invasive brain-machine interfaces.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: REGULATION OF ER-MITOCHONDRIA CONTACTS IN NEURODEGENERATION
Funder: Medical Research Council

Abstract: An estimated 5-20% of mitochondria are closely associated with a subdomain of the endoplasmic reticulum (ER) called mitochondria-associated ER membranes (MAMs). Inter-organelle communication at these contact sites has been shown to regulate several physiological processes including calcium homeostasis, autophagy/mitophagy, mitochondrial dynamics, phospholipid synthesis, the unfolded protein response, apoptosis, and inflammasome activation. Disruption of ER-mitochondria contact sites has been implicated in amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) and Parkinson's disease (PD). We and others have shown reduced ER-mitochondria coupling in mutant SOD1, TDP-43, FUS, and Sigma-1R-associated ALS/FTD. Similarly, decreased ER-mitochondria contact has been reported in mutant a-synuclein-related PD. The purpose of this proposal is to further our insight into the pathogenic pathways underlying ER-mitochondria contact defects in ALS/FTD and PD and to leverage that knowledge to validate ER-mitochondria contacts as a therapeutic target. We have uncovered a novel kinase pathway that regulates ER-mitochondria contacts, and have data that suggest that upregulation of this pathway may be the underlying cause of ER-mitochondria contact disruption in SOD1-related ALS and a-synuclein-related PD. We will further investigate this novel pathway and determine its involvement in ALS/FTD and PD. Building on this data we will validate ER-mitochondria contacts as a therapeutic target by determining if restoring contacts in ALS and PD models is neuroprotective and can improve disease-associated dysfunction. This project may mark a crucial step in the translational pathway towards novel strategies to treat neurodegenerative conditions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: A 5 year prospective follow-up clinical and imaging investigation of demyelinating clinically isolated syndrome (CIS)
Funder: Medical Research Council

Abstract: We wish to study at five years a cohort of 50 people, who originally presented and were studied at baseline with CIS. This longitudinal assessment will allow us to ascertain the imaging correlates of risk of conversion to MS, disease activity and progression. Participants will attend UCL Institute of Neurology and undergo 1) Magnetic Resonance Imaging (MRI), 2) Optical Coherence Tomography (OCT), 3) Clinical assessment. 1) 3T MRI Conventional and advanced MRI acquisitions will be employed: a) T1/T2-weighted images brain and spine - for white matter lesions, and T1 parcellation volumes b) Phase Sensitive Inversion Recovery (PSIR) brain - for grey matter lesions c) Diffusion weighted imaging brain - for (i) Tractography and diffusion connectivity metrics, (ii) Metrics of neurite dispersion and orientation and neuronal density d) Sodium MRI (NaMRI) - for sodium metric e) Resting-state fMRI brain - for functional connectivity 2) OCT Acquisition A Heidelberg Spectralis high resolution OCT system will acquire: a) Optic nerve scans (peripapillary) - for peripapillary RNFL (pRNFL) b) Macular volume - for Macular RFNL (mRNFL) and Macular ganglion cell layer (mGCL) 3) Clinical assessment a) History b) Physical disability recorded with EDSS, MSFCS, MRC power/sensory. c) Cognitive assessment with MACFIMS d) Visual assessment - high and low contrast acuity charts, colour vision e) Lifestyle questionnaires Statistical models will be constructed using mainly mixed (mulit-level) regression models to address (i) longitudinal changes over time in imaging measures of OCT and MRI, (ii) imaging and OCT predictors of five year clinical outcomes e.g. conversion to MS, disease activity, disability, (iii) associations between imaging and clinical metrics at five years. The results will inform our understanding of neurobiological processes responsible for disease activity and progression in early MS.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Is Alzheimer's disease triggered by a failure of the brain's blood supply?
Funder: Medical Research Council

Abstract: Cardiovascular risk factors and APOE4 expression increase the risk of Alzheimer's disease (AD), possibly by decreasing brain blood flow. Our data show that brain capillaries are constricted and neurovascular coupling is impaired in APOE4 mice. Such decreased cerebral blood flow could trigger a vicious cycle of beta amyloid production, accumulation and progressive impairment of brain blood flow. If this "vascular hypothesis" of AD is correct, improving cerebrovascular function at early stages should reduce beta amyloid accumulation and subsequent neurodegeneration. We will track the time course of the development of cerebrovascular, neuronal and behavioural dysfunction in mice that carry APOE4 and produce beta amyloid in a controllable manner, testing the prediction that beta amyloid should accumulate preferentially around already dysfunctional blood vessels, before discovering if improving cerebral blood flow reduces beta amyloid accumulation. To do this, we will generate mice expressing human APOE3 or 4, and doxycycline-suppressible human APPSwe/Ind. After baseline characterisation, doxycycline will be removed, enabling production of beta amyloid. First, we will track beta amyloid accumulation and neurovascular function in vivo, using 2-photon imaging to test whether it first aggregates in tissue surrounding blood vessels that already show impaired flow and neurovascular coupling. Second, we will immunohistochemically label unaggregated forms of beta amyloid at different time points, alongside markers of the vasculature, hypoxia, beta amyloid degradation and lysosomes, to test whether production and aggregation both start in hypoxic locations. Finally, we will pharmacologically increase cerebral blood flow and test if this reduces beta amyloid accumulation and improves neurovascular reactivity and cognitive function. Our project will test whether decreased brain blood flow could trigger AD, suggesting potential new therapeutic strategies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: The development of gene therapy for infantile neuroaxonal dystrophy
Funder: Medical Research Council

Abstract: We aim to develop AAV-mediated gene therapy to treat infantile neuroaxonal dystrophy (INAD). INAD is a devastating and fatal inherited neurodegenerative disease of children caused by mutations in the PLA2G6 gene. Patients suffer neurodegeneration, severe spasticity and progressive cognitive decline leading to death within the first decade of life. No treatment is available, and patients receive only palliative care. There is an overwhelming need to develop an effective therapy for INAD. AAV-mediated gene therapy holds great potential as a treatment for INAD. This is based on our preliminary data using AAV9 to deliver a functional copy of the PLA2G6 gene to neurons of a mouse model of INAD. This neonatal intervention provided significant improvements in lifespan, locomotor function and quality of life and extensive amelioration of neurodegeneration in the brain and spinal cord. While promising, there is considerable room for optimization of the gene therapy vector itself before potential translation to the clinic. Following a meeting with the UK Medicines and Healthcare products Regulatory Agency (MHRA) and based on their feedback, we propose a pre-clinical study in older early symptomatic INAD mice to model the clinical scenario of providing therapy after diagnosis. This will include further optimization of INAD gene therapy by (A) comparing the use of a clinically used ubiquitous promoter in the AAV9 vector to our original neuron specific promoter, (B) comparing different routes, or combination of routes, of administration of the optimal vector to assess therapeutic response, (C) conduct biodistribution studies using the optimal vector and route(s) of administration in a larger brain. This proposal is supported by (i) our preliminary proof-of-concept data (ii) our experience in pre-clinical gene therapy studies in mouse models of neurodegeneration (iii) feedback and guidance from the MHRA.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL