NIHRDataInsights/HRCSData huggingface dataset:
Title: Neuronal and glial AMPARs: auxiliary subunits as targets for ion channel regulation
Funder: Medical Research Council

Abstract: We will examine how pharmacological, biophysical and molecular properties of neuronal and glial AMPARs are regulated by TARP and cornichon (CNIH) proteins. The identity and role of these auxiliary subunits will be dissected by comparing recombinant and native AMPARs, by examining mutant and transgenic mice, and by targeted molecular intervention to manipulate protein expression or structure. We will use: (1) recombinant AMPARs expressed with specific TARPs and/or CNIHs in tsA201 cells; (2) identified neurons and glia in dissociated cultures, prepared from wild-type (WT) and mutant or transgenic mice; (3) neurons and glia in acute brain slices. We will use patch-clamp methods to record pharmacologically isolated AMPAR-mediated macroscopic and single-channel currents, and synaptic currents. We will determine defining kinetic properties, voltage-dependence, calcium-permeability and conductance of recombinant, synaptic and extrasynaptic receptors, as well as the efficacy of blockers and allosteric potentiators. We will use a variety of molecular approaches, and antibody-linked quantum dot single particle tracking to explore the influence of specific auxiliary subunits on AMPAR targeting/trafficking. In collaboration with the groups of Dickenson (UCL) and Diamond (NIH) we will examine the contribution of auxiliary subunits to the properties and regulation of calcium-permeable AMPARs in retinal amacrine cells, and in the processing of nociceptive signals in dorsal horn of the spinal cord. Roger Nicoll (UCSF) will collaborate in provision of TARP knockout mice, and related experiments. Experiments using lentiviral constructs will be carried out in collaboration with Stephanie Schorge (UCL). Our research will provide fundamental information about the regulation of AMPARs in neurons and glia. It will contribute to our understanding of normal brain function, highlight potential strategies for treatment of debilitating conditions and inform new efforts in drug discovery.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Cortical networks underlying primate choice behaviour
Funder: Medical Research Council

Abstract: The aim is to elucidate the nature of the causal influences that cortical regions interacting in large-scale networks have upon each other at the level of neuronal activity (as measured by electrophysiological recordings of spiking activity and local field potentials using a combinations of multi-unit micro-electrode arrays implanted into cortex and multiple electrodes lowered daily through recording chambers) and at the level of functional and structural connectivity (as measured by MRI). Specifically we will determine the causal effects that inputs from prefrontal cortex, retrosplenial cortex, and medial temporal lobe cortex have upon frontopolar cortex which sits at the top of a hierarchy of prefrontal brain regions in a position in which it can integrate diverse sets of inputs so as influence decisions. We will achieve this by means of making permanent lesions (and reversible inactivations in pilot investigations) to these input structures and recording activity in frontopolar cortex before and after the inactivation or lesions. We will also examine the nature of the influence that frontopolar cortex makes upon posterior brain regions by inactivating or lesioning frontopolar cortex before and after recording neuronal activities in these target regions using electrophysiological techniques and in the rest of the brain using structural and functional imaging techniques. The outcome of this project will provide advances in basic scientific understanding of how networks of brain regions operate for a wide range of beneficiaries primarily including other basic research neuroscientists, applied scientists, and clinicians. The work will be done in an appropriate animal model.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Structural and Functional Connectivity of the Human Basal Ganglia in Health and Disease using High Resolution MRI at 7T
Funder: Medical Research Council

Abstract: The circuits of the basal ganglia are a massive centre of convergence for cortical information. To date however, only invasive animal studies have been able to look at the basal ganglia at the scale required to investigate their connections, challenging most recently the classic model of the organisation of these circuits. Our goal is to characterise in vivo the connectivity of the human basal ganglia. This should ultimately allow us to better understand the mechanisms of two devastating movement disorders caused by degeneration in the basal ganglia: Parkinson's and Huntington's disease. Unfortunately, conventional MRI, which allows the in vivo study of the human brain anatomy and function and the follow-up of degenerative processes, lacks the necessary resolution to investigate the connections of these very small structures composing the basal ganglia. In this proposed project, I will combine cutting-edge imaging techniques and behavioural measures in 30 healthy, 30 Parkinson's and 30 Huntington's participants to study the structural and functional connectivity of the basal ganglia at a high resolution only achievable with our MRC-funded 7T scanner available at the Oxford FMRIB Centre. I will carry out both a cross-sectional and a longitudinal study testing the latest hypothetical models of the basal ganglia connectivity using (i) diffusion imaging to infer the structural connections of the basal ganglia, (ii) functional imaging at rest to determine the connectivity of all functionally-distinct basal ganglia networks and (iii) functional imaging during a finger tapping task to examine the effective motor connectivity of the basal ganglia. These three complementary approaches will allow me to elucidate the human basal ganglia circuits based on predictions drawn from the most recent animal literature, to test the role of each pathway in the execution of movement and to uncover the impact of Parkinson's and Huntington's disease on these connections.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Developing The Oxford Study for Biomarkers in Motor Neuron Disease (BioMOx): Capturing pre-symptomatic events and advancing clinical translation
Funder: Medical Research Council

Abstract: The aims of this project are: 1. To understand the earliest, pre-symptomatic changes in those carrying genetic mutations linked to MND, and how they link to spread of symptoms in affected individuals. 2. The refinement, validation and clinical translation of a multimodal biomarker diagnostic signature for MND. The objectives of this project are: 1. The longitudinal study of pre-symptomatic individuals at risk of MND, particularly those carrying expansions of the C9ORF72 hexanucleotide repeat, as well as those with pathological SOD1, TARDBP and FUS gene mutations. It will uniquely combine the spatial resolution of very high-field 7 Tesla MRI of the brain and cord (including GABA and glutamate MR Spectroscopy, MRS), with the temporal resolution of cerebral magnetoencephalography (MEG) to explore changes in cortical neurophysiology that pre-date symptom onset, and with the hope of capturing the transition to disease in a small proportion of individuals. Incident MND cases will also be studied longitudinally in comparison. 2. To perform multivariate analysis of existing candidate neuroimaging, biofluid and eye-tracking biomarkers acquired through BioMOx, and to test performance in undiagnosed patients with focal weakness referred for electromyography and established mimics of MND ('disease controls') referred to me in the Oxford MND Centre. The discovery that pre-symptomatic individuals have changes in brain function or structure compared to healthy individuals with no family history of MND profoundly influences the scientific thinking about this condition. As well as raising the possibility of preventative therapies for familial cases, there would be the hope of additional value when similar treatments are applied earlier to apparently sporadic cases. Such cases would be detected at an earlier stage through the development of a robust biomarker signature for MND, and the BioMOx resource offers a unique opportunity to develop this.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Investigating the mechanisms of axonal degeneration in amyotrophic lateral sclerosis using Drosophila and mouse transgenics
Funder: Medical Research Council

Abstract: Introduction ALS is an incurable motoneuron disease characterised by pathological TDP-43 inclusions. TDP-43 models are emerging as important tools to understand the fundamental causes of ALS and will be important to develop treatments. Significantly, axonal degeneration is one of the earliest processes in ALS and is therefore important to target therapeutically, as early treatment is likely to be the most effective strategy. The Coleman and Freeman labs are pioneers in axonal biology and have recently characterised two ways of potently protecting axons: Ax-NMNAT1 and dSarm/Sarm1 knockout. Significantly, both are conserved in flies and mice and have never been tested in TDP-43 ALS models. Aims and objectives We aim to identify molecular pathways that can protect axons in animal models of amyotrophic lateral sclerosis (ALS). Methods We will use cutting-edge technologies invented by the Freeman lab to develop novel TDP-43 transgenic fly models of ALS, which permit single motoneuron/axon resolution analysis using mosaic animals. These flies will be used to test the axon-protective potential of Ax-NMNAT1 and dSarm-knockout and to perform a sophisticated Drosophila forward-screen (using wing-blade cut) for novel candidates ameliorating TDP-43-mediated axonal degeneration. The top genetic candidates from Drosophila studies will be validated at Babraham using: 1) TDP-43 transgenic mice with fluorescently-labelled upper and lower motoneurons/axons; 2) human post-mortem tissue; 3) induced pluripotent stem cell-derived human ALS motoneurons. Scientific and medical opportunities Our forward screen will be comprehensive, utilising new technologies that will change the way other Drosophila biologists perform screens. My results could benefit researchers working on Parkinson's and Alzheimer's disease, which involve axonal degeneration (in many cases with TDP-43 pathology). Finally, this research holds great promise for identifying new therapeutic avenues for ALS


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Further defining the genetic architecture of Alzheimer's disease
Funder: Medical Research Council

Abstract: Approximately half a million people have Alzheimer's disease (AD) in the UK, incurring an annual care cost of £23 billion. 35 million have dementia world-wide and it is estimated that these numbers will double by 2040. Identifying genes that affect the development of AD is important in pin-pointing potential disease mechanisms, testing new therapeutics and in predicting individual risk of disease development. Our programme of research will focus on identifying rare, exonic susceptibility variants of moderate/strong effect, using novel, powerful, genome-wide approaches and extended and enriched clinical samples. We will undertake a case-control association study comprising 20,000 AD cases and 49,000 controls focusing on coding regions throughout the genome, using the Illumina exome chip. We will also collect a sample of 500 cases with early-onset AD (EOAD), an uncommon form of the disease (<5% cases) that manifests before the age of 65, and in which heritability is especially high (92-100%). We will sequence the exomes of the 500 EOAD individuals and analyse them together with 500 EOAD exomes available to us through collaboration. Susceptibility variants identified will be replicated in an independent sample of 10,000 AD cases and 10,000 controls. We aim to detect rare variants of larger effect than those observed for common susceptibility variants; these effects should prove easier to model and will facilitate the further understanding of disease mechanisms and the development of new therapeutics. We will combine all genetic data we have generated to extend and develop complex analyses including pathway analysis, sub-phenotypic analysis and cross-disease analysis. Finally, we will establish and extend research resources such as DNA and additional sample banking from all EOAD cases collected, and iPSC programmable cell lines from 50 EOAD cases to facilitate functional analyses. This resource will be made available to research and pharmaceutical communities.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Brain networks in epilepsy: Endophenotypes and generative models
Funder: Medical Research Council

Abstract: We aim to explain the emergence of epileptic seizures from the interplay between dynamic properties of localised brain regions and network structures connecting them, using a combination of methods from connectomics and dynamic modelling. We will develop MRI methods to describe distributed abnormalities of grey matter, structural connectivity and functional connectivity in the human brain, using T1-weighted MRI, diffusion tensor imaging and resting-state functional MRI. We will develop EEG methods to describe brain networks. From these data, we will identify candidate brain networks which generate seizures. We will employ our successful phenomenological and physiological models of EEG, which capture the patterns of onset and evolution of human ictal EEG activity. We will adopt a novel formalism to investigate brain networks: generalized dynamic graphs with active network topology. We will combine forward modelling (physiological generative models), and backwards modelling (Bayesian inversion of generative models) to determine which candidate network is most likely to explain imaging and EEG observations. We introduce the new concept of Brain Network Ictogenicity (BNI) - the propensity of brain networks to generate seizures. We will implement and further develop our novel approach to estimating BNI in real brain networks, based on combining a dynamic model with real network structures inferred from data. In data from human patients with epilepsy, their relatives, and normal controls, we will investigate networks which generate seizures and the BNI of these networks. In appropriate subject groups, we will examine the familial basis of brain network properties; we will explain how a familial ictogenic network endophenotype may be further modified to allow seizures to be manifest; and we will reveal the network-level effects of successful drug treatment, natural remission and epilepsy surgery.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: MICA: ET-1-mediated reduction of cerebral blood flow in Alzheimer's disease: therapeutic potential of zibotentan
Funder: Medical Research Council

Abstract: Cerebral blood flow (CBF) is reduced in Alzheimer's disease (AD) before the onset of dementia. More severe reduction predicts more rapid cognitive decline. In mouse models the reduction in CBF greatly exceeds the decline in neuronal metabolic activity. The distribution differs from that of structural vessel disease and is probably mediated by functional vascular abnormalities. AD is thought to be initiated by the intracerebral accumulation of amyloid beta (Abeta). We have shown that Abeta42 upregulates neuronal endothelin-converting enzyme (ECE)-2 and angiotensin-converting enzyme (ACE). ACE catalyses production of angiotensin II (Ang II) and ECE that of endothelin-1 (ET-1), both potent vasoconstrictors. ET-1 concentration is significantly elevated in AD cortex. In addition, Abeta40 increases ECE-1 activity in endothelial cells, and both ECE-1 activity and ET-1 level are elevated in blood vessels from AD brains; this is likely to contribute to impairment of functional hyperaemia in AD. Cerebral vasoconstriction reduces CBF, impairs the delivery of oxygen and nutrients and slows the removal of waste products (including Abeta). Brain ischaemia also increases Abeta production. We and others reported the use of Ang II blockers (ARBs) to be associated with a reduced incidence of AD. No comparable human data are available for ET-1 receptor blockers. In a rat model of AD, injection of ET-1 exacerbated Abeta accumulation and neurodegeneration and impaired memory test performance. We suggest that Abeta40- and Abeta42-mediated increases in ET-1 and/or ACE are at least partly responsible for reduced CBF in AD. ET-1 mediates its cerebrovascular effects through ET-A receptors. We propose to compare the effects of zibotentan, a specific ET-A blocker, and losartan, an ARB, on CBF, autoregulation, functional hyperaemia and other vasoregulatory pathways, in a rat model of Abeta-mediated cerebral vasoconstriction, with a view to zibotentan usage in AD.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL
Title: Modelling the Development of Complex Brain Networks
Funder: Medical Research Council

Abstract: Graph theoretical methods are increasingly being used to study biological and medical problems at a systems level. In the brain, understanding the network structure of neurons at the microscopic level, and of brain regions at the macroscopic level is crucial to elucidating the mechanisms underpinning both healthy and impaired brain-function. While we now possess a sophisticated set of measures to describe the topology of static brain networks, the driving forces that shape the networks into these characteristic topologies remain largely unknown. More generally, the temporal evolution of networks has so far received very little attention both theoretically and in its applications to neuroscience. My proposed research aims to fill these gaps by studying the temporal evolution of brain networks in two developmental epochs of particular clinical interest: (i) the maturation of brain networks during adolescence and (ii) the changes in network structure associated with ageing. My key hypothesis is that many complex network-level changes in human brain organization can be parsimoniously explained (and therefore modelled) in terms of simple trade-offs between cognitive function, spatial constraints and energetic costs. To test these ideas, I will first characterize developmental changes in brain networks using both novel and existing graph theoretical methods. Second, I will correlate the changes observed in various network features with changing abilities in several cognitive domains. This will allow me to consider the functional role of network properties that may offset energetic cost in a trade-off model of human brain development. Based on these insights, I will then build computational models that predict the pattern of network growth and degeneration in terms of biologically plausible rules and simple physical constraints.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: NEUROLOGICAL
Title: PET Call: Development Of Quantitative CNS PET Imaging Probes For The Glutamate and GABA Systems
Funder: Medical Research Council

Abstract: Our interpretation of this specialist training call is that in the UK there is a primary unmet need for PET scientists who can design, develop, evaluate and interpret new PET probes for CNS imaging. The paradigmatic example is the lack of availability of PET radiotracers for the GABAergic and Glutamatergic systems that have been strongly implicated in many CNS disorders so that they are now primary targets for therapeutic strategies. Consequently, the primary deliverable of this proposal is to generate, through a novel integrative approach to training, talent that can think, communicate, innovate and make a tangible impact in this interdisciplinary field. The existence in the UK of cross-disciplinary post-doctoral programs has created a substantial pool of young talent with problem solving abilities in this area. We will select candidates with a core competency in a chemical or biological discipline and take them through 6 months of foundation training that will cover the basic aspects of radiochemistry/pharmacology/quantitative modelling/methodology that are relevant to the modern PET scientist. Core skills will then be expanded with 'on the job' training while performing longer projects in collaboration with our research partners (Karolinska, Toronto, Imanova, GE-Healthcare, Lilly). The second aim of this proposal, is to synergize the talent elicited by this training program with the partners' research activities and bring into man and disease cohorts at least two new PET radioligands to be chosen from [18F]GE-179 (NMDA), [11C]ABP688 and [18F]FPEB (mGlur5), [11C]MMTP (mGlur1), [11C]CMGDE (mGlur2/3), [11C]Zolpidem (GABAA) and [11C]BU99008 (GABAB). These tracers are planned to be used in the investigation of CNS disorders such as psychosis, autism, addiction and epilepsy by the collaborating clinical partners. These parallel pre-clinical/clinical streams will give the opportunity to the trainees to develop independent projects of great value and impact.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: NEUROLOGICAL
Title: Gene Therapy for Tay-Sachs and Sandhoff diseases
Funder: Medical Research Council

Abstract: The overarching research objective is completion of a clinical trial of gene therapy for Tay-Sachs and Sandhoff diseases (GM2 gangliosidosis) - relentless neurodegenerative conditions due to inborn defects in lysosomal beta-hexosaminidases that degrade GM2 ganglioside. Definitive correction by gene transfer is warranted since there is no effective treatment: lysosomal diseases, of which Tay-Sachs is emblematic, account for 45% of progressive neurodegeneration diagnosed in UK children. Investigational Medicinal Products for first-into-human gene transfer will be developed by extending preclinical research to generate safe and effective GMP-grade clinical vectors for use in an open-label phase I/II single-centre clinical trial in infants and young patients with GM2 gangliosidosis. Therapeutic vectors expressing human hexosaminidase subunits will be surgically delivered to intracranial structures on a single occasion using convection-enhanced delivery. The research stratagem is based on proof-of-concept studies showing long-term restoration of lysosomal function by recombinant adeno-associated viral (rAAV) vectors expressing wild type enzyme subunits in GM2 gangliosidosis modelled authentically in mice and cats. Once-only intracranial inoculation of monocistronic vectors preserves neurological function and induces >2 year survival in animals that would otherwise be moribund by 4 months.Outcomes are optimal when gene therapy is given early. We justify translation to patients because enzymatic augmentation is sustained throughout brain and spinal cord with rescue of disease hallmarks and neuronal loss. We will study rAAV vector serotypes (eg 2/1 and 2/rh.10) for optimally safe and effective expression; preclinical research will be dovetailed with patient evaluation for study enrollment. Individual patient outcomes will be assessed longitudinally using neurological, neuropsychiatric and MR studies with life-quality scoring and compared with the natural disease course.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES;6.2 CELLULAR AND GENE THERAPIES
Health categories: NEUROLOGICAL