NIHRDataInsights/HRCSData huggingface dataset:
Title: Capital award for UK DRI at University of Edinburgh
Funder: Medical Research Council

Abstract: The aim of this award is to support the University of Edinburgh with capital investment for setting-up of one of six UK Dementia Research Institute (UK DRI) centres; in particular, the capital required for building, refurbishment and the procurement of equipment. At present, 5 programmes have been selected planned for the UK DRI at the University of Edinburgh and with scientific and operational leadership provided by its associate director, Professor Giles Hardingham. The project at the University of Edinburgh will involve expansion of facilities on 1st floor of the Chancellor Building at the Edinburgh Bioquarter Campus, to house a larger centre. Full occupancy is expected by October 2018. The approach of the institute as a whole, of which the UK DRI at the University of Edinburgh forms a core part, is to amplify and enhance, not replace, current dementia research efforts in the UK. The UK DRI will help to cement the UK’s world-leading position by supplying vital new funding for research, coupled to promoting innovate approaches and forging much closer collaboration and integration of on-going UK research efforts. There is a gap in our knowledge of how the healthy brain functions and what leads to its degeneration. The UK DRI will fill this crucial gap that exists at the start of the dementia research journey. It will study the healthy brain and neurodegeneration in order to build new knowledge and understanding that will lead to new treatments. It will also proactively connect to existing clinical and population-level dementia initiatives – for example as being undertaken by the MRC Dementias Platform UK and through the NIHR TRC-D – to catalyse a unique national and strategic approach to confronting the dementia challenge. In particular, the present research at the UK DRI at the University of Edinburgh plans to look at the interplay between immune, vascular and metabolic factors – the ‘neurogliovascular’ unit. Funding to these science programmes is provided separately.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: NEUROLOGICAL
Title: Capital award for UK DRI at Imperial College London
Funder: Medical Research Council

Abstract: The aim of this award is to support Imperial College London with capital investment for setting-up of one of six UK Dementia Research Institute (UK DRI) centres; in particular, the capital required for building, refurbishment and the procurement of equipment. At present, 5 programmes have been selected planned for the UK DRI at Imperial College London and with scientific and operational leadership provided by its associate director, Professor Paul Matthews. The project at Imperial College London will involve refurbishment of a floor in the new Michael Uren with space for 64+ researchers. An interim solution at the Burlington Danes facility at Hammersmith campus is being used before completion of the final location at the Michael Uren, ready for eventual occupancy by September 2019. The approach of the institute as a whole, of which the UK DRI at Imperial College London forms a core part, is to amplify and enhance, not replace, current dementia research efforts in the UK. The UK DRI will help to cement the UK’s world-leading position by supplying vital new funding for research, coupled to promoting innovate approaches and forging much closer collaboration and integration of on-going UK research efforts. There is a gap in our knowledge of how the healthy brain functions and what leads to its degeneration. The UK DRI will fill this crucial gap that exists at the start of the dementia research journey. It will study the healthy brain and neurodegeneration in order to build new knowledge and understanding that will lead to new treatments. It will also proactively connect to existing clinical and population-level dementia initiatives – for example as being undertaken by the MRC Dementias Platform UK and through the NIHR TRC-D – to catalyse a unique national and strategic approach to confronting the dementia challenge. In particular, the present research at the UK DRI at Imperial College London plans to look at the innovation theme, including: Individual variation in dementia within populations; Metabolic factors, microbiome and role of sleep; Glial-neuronal interactions; Novel bioelectronics technologies to modulate neurons and glia in sleep, neuroprotection and cognition Funding to these science programmes is provided separately.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: NEUROLOGICAL
Title: Capital award for UK DRI at King's College London
Funder: Medical Research Council

Abstract: The aim of this award is to support King's College London with capital investment for setting-up of one of six UK Dementia Research Institute (UK DRI) centres; in particular, the procurement of equipment. At present, 3 programmes have been selected planned for the UK DRI at King's College London and with scientific and operational leadership provided by its associate director, Professor Chris Shaw. The project at King's College London will involve purchasing equipment to scale up and fill the UK DRI at King’s College London, to be located at new Maurice Whol Clinical Neuroscience building which could house up to 250 researchers. The location is ready to be occupied. The approach of the institute as a whole, of which the UK DRI at King's College London forms a core part, is to amplify and enhance, not replace, current dementia research efforts in the UK. The UK DRI will help to cement the UK’s world-leading position by supplying vital new funding for research, coupled to promoting innovate approaches and forging much closer collaboration and integration of on-going UK research efforts. There is a gap in our knowledge of how the healthy brain functions and what leads to its degeneration. The UK DRI will fill this crucial gap that exists at the start of the dementia research journey. It will study the healthy brain and neurodegeneration in order to build new knowledge and understanding that will lead to new treatments. It will also proactively connect to existing clinical and population-level dementia initiatives – for example as being undertaken by the MRC Dementias Platform UK and through the NIHR TRC-D – to catalyse a unique national and strategic approach to confronting the dementia challenge. In particular, the present research at the UK DRI at King's College London plans to look at the earliest stages of fronto-temporal dementia and ALS, looking for common mechanisms across neurodegenerative diseases, including: misfolding and aggregation of TDP-43; RNA binding activity; nuclear pore protein transport Funding to these science programmes is provided separately.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: NEUROLOGICAL
Title: Capital award for UK DRI at University College London
Funder: Medical Research Council

Abstract: The aim of this award is to support University College London with capital investment for setting-up of the interim hub of the UK Dementia Research Institute (UK DRI) centres; in particular, the capital required for building, refurbishment and the procurement of equipment. At present, 8 programmes have been selected, planned for the UK DRI at University College London and with scientific and operational leadership provided by its director, Professor Bart De Strooper. The project at University College London will involve refurbishment of three wings in UCL’s Cruciform building to establish an Interim Hub of the UK DRI with capacity for 100 researchers and full occupancy expected by March 2018. This is separate to the final hub location of the UK DRI at UCL, at Queen Square House, but will act as the hub location until 2022 (when those works would be complete). The approach of the institute as a whole, of which the UK DRI at University College London forms a core part as the central hub, is to amplify and enhance, not replace, current dementia research efforts in the UK. The UK DRI will help to cement the UK’s world-leading position by supplying vital new funding for research, coupled to promoting innovate approaches and forging much closer collaboration and integration of on-going UK research efforts. There is a gap in our knowledge of how the healthy brain functions and what leads to its degeneration. The UK DRI will fill this crucial gap that exists at the start of the dementia research journey. It will study the healthy brain and neurodegeneration in order to build new knowledge and understanding that will lead to new treatments. It will also proactively connect to existing clinical and population-level dementia initiatives – for example as being undertaken by the MRC Dementias Platform UK and through the NIHR TRC-D – to catalyse a unique national and strategic approach to confronting the dementia challenge. In particular, the present research at the UK DRI at University College London plans to look at the linking molecular pathway dysfunction with genetic and lifecourse factors; Axonal transport; Single cell analyses of gene expression & biological pathways in AD; New biomarkers to monitor disease progression.. Funding to these science programmes is provided separately.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: NEUROLOGICAL
Title: Imaging Centre (Bristol)
Funder: Medical Research Council

Abstract: The award is in support of a fourth Imaging Centre to complement the three centres already in existence and is designed to accelerate the imaging of the 100,000 UK Biobank participants. Including the repeat imaging of 10,000 participants funded by Dementias Platform UK. Along with the existing centres, the Bristol imaging centre will further provide data to help identify the earliest (pre-clinical) manifestations of dementia, supporting the development and testing of dementia interventions. The standard suite of brain and body measures (using the same protocols), as used for the 100,000 imaging project, will be used for the repeat imaging of 10,000 participants.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: NEUROLOGICAL
Title: Early-life origins of brain resilience to mental illness and cognitive impairment across the life-course
Funder: Medical Research Council

Abstract: Cortical surface area on Magnetic Resonance Imaging (MRI) from the Paediatric Imaging and NeuroGenetic dataset in North America varies with family income and this relationship is steepest at poorest incomes. This result was not found in Norway, where there is greater equality of socioeconomic circumstance (SEC). Our own research has shown that poorer childhood SEC predicts smaller hippocampi and more brain lesions in late life, which are linked to depressive symptoms and poorer cognition. Here we will extend research to cohorts in Mysore, India, with different SEC and culture, in whom rich life-course and risk factor data exist. We propose pilot work, public engagement and workshops to inform a large-scale future application to investigate hypotheses that early life factors influence risk of subsequent mental illness and cognitive decline. Concentrating on the Mysore groups here, we plan four activities that will inform design of a future project to include cohorts in Mysore and Mumbai. These are deliberately designed around data science, to enable work to be scaledup and to create a resource for future research: Imaging - we will invite subsamples of young and older Mysore cohorts for brain MRI to assess feasibility, acceptability and to measure effect size to inform future power calculation. Health informatics - using public engagement with participants we will determine their views on data linkage of pre-existing data, data to be collected and creation of a bio-resource. Bioinformatics - we will collect new cognitive data, using a game that tests navigational ability, repeat previous cognitive and depression data, blood samples and buccal smears to obtain DNA and RNA for future analysis. Computing science - we will host a workshop at the University of Aberdeen to which Indian and UK co-investigators will be invited to brainstorm "big data' management, analysis and machine learning methods to test in pilot data and apply to future large-scale work.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: NEUROLOGICAL
Title: AMPA receptor biogenesis and allosteric control
Funder: Medical Research Council

Abstract: AMPA receptors (AMPARs), glutamate-gated cation channels, are main mediators of excitatory neurotransmission and are central to synaptic plasticity, a process underlying learning. AMPARs are also essential for brain development and their dysfunction contributes to various neurological diseases, rendering them a potential drug target. AMPARs are composed of four pore-forming (core) subunits and various types of auxilliay subunits, in various combinations. The composition of the AMPAR comlex is essential for post-synaptic signal processing as it determines: signalling properties, trafficking to/from synapses and synaptic positioning of the receptor. Our research aims to unravel mechanisms underlying AMPAR biogenesis, receptor organisation, and principles of allosteric regulation. We built on this information to investigate rules of receptor operation at synapses in the brain to ultimately understand its central role in information storage and learning. The bulk (~80%) of the receptor’s mass is extracellular (facing the synaptic cleft) and is composed of two domains - the ligand-binding domain (LBD) and N-terminal domain (NTD), which are connected by a flexible linker. We showed that the sequence-diverse NTD is essential for receptor assembly and for anchoring at postsynaptic sites and that deletion of the NTD impedes synaptic potentiation. We hypothesise that the NTD provides a (subunit-selective) synaptic anchor that positions the receptor opposite presynaptic glutamate release sites and that this process is essential for efficient signal transmission and synaptic potentiation. Inherent to this model is the unique conformational freedom of the modular AMPAR extracellular region, permitting NTD interactions with (to be identified) synaptic cleft proteins. We have observed conformational dynamics in coarse-grained simulations, by cryo-electron microscopy (cryo EM), and by peptide mapping (where we detect interactions between the membrane-distal NTD with the membrane proximal TARP). We aim to characterise structural dynamics of AMPAR/auxiliary subunit combinations predominating at hippocampal CA1 synapses (a well characterised, plastic model synapse) by single particle cryo-EM and are aiming to isolate NTD interactors in biochemical screens. Results from these efforts will be studied in an intact CA1 neuronal circuitry, where we utilize our in vitro data to selectively manipulate both receptor conformations and expression profiles of NTD-interacting proteins using CRISPR. We are also implementing 3D-stochastic optical reconstruction microscopy (3D-STORM) in brain tissue, which will allow us to follow AMPAR dynamics (and NTD-mediated positioning) at synapses undergoing potentiation with high precision.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Genes, circuits and behaviour
Funder: Medical Research Council

Abstract: We seek to understand how nervous systems generate behavior. The current model is that inputs from the environment, and from internal sensors, are interpreted in the light of previous experience to reconfigure dynamic networks of neural circuits to generate adaptive behaviours. What are the molecular and neural mechanisms mediating these changes? Understanding even simple human actions in these terms is difficult, because of our complex brain and elastic behaviour. We therefore initiate our studies in the worm C. elegans. In C. elegans an array of tools enable us to link the activity of identified neural circuits to molecular mechanisms and to behaviour. Hunts for behavioural mutants lead us to molecular mechanisms that we can dissect using transgenic engineering of single identified neurons, neural imaging, and optical manipulation of neural activity. Importantly, and uniquely, we can recognize each of this animal’s 302 neurons, and have a map of their connectivity. Our goal is to discover molecular mechanisms and circuitry principles conserved from worm to man. We are concentrating our efforts in two directions. One takes a reductionist approach, guided by forward genetics, to study a complex behaviour, group foraging. C. elegans integrates information from food, other animals, gases and internal nutritional state to decide whether to forage alone or in groups. Two regulators of foraging are oxygen and carbon dioxide levels. C. elegans has tonically signaling circuits whose activity continuously report levels of these gases. These circuits then tune the behavioural state of the animal. Similarly acting circuits are thought to control mammalian physiology and mood. Our work on these circuits is identifying many molecules conserved in humans but previously unstudied in any nervous system. A recent discovery is that the pro-inflammatory cytokine interleukin 17 can act like a neuromodulator. In a second approach we use C. elegans to study neuropeptide biology. Neuropeptides are ancient, potent and widespread regulators of behaviour. They control a wide array of our behavior e.g. sleep, pain and appetite. Their biology is poorly understood. C. elegans offers special opportunities to study the cell biology of neuropeptides because its neurons can be visualized by light microscopy in vivo, and forward genetic screens can be designed to identify molecules involved in neuropeptide synthesis, traffic and release. Our work is guided by the principle, now well established, that because the molecular mechanisms found in a worm are usually found in humans, one of the fastest, cheapest and most effective way of understanding our biology is to study these more experimentally tractable organisms.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: Molecular mechanisms of neurodegeneration
Funder: Medical Research Council

Abstract: Considerable progress has been made in characterizing the molecular neuropathology of dementias and movement disorders, including Alzheimer’s and Parkinson’s diseases. Most cases of disease associated with pathological filament formation are now accounted for by either tau or alpha-synuclein deposits. The discoveries of mutations in MAPT, the tau gene, in inherited forms of frontotemporal dementia, and SNCA, the alpha-synuclein gene, in inherited forms of Parkinson’s disease, have established that the pathways leading from soluble to insoluble, filamentous proteins are central to the aetiology and pathogenesis of these familial cases of disease. The same is probably true of the much more common cases of sporadic disease. A detailed understanding of the mechanisms underlying the assembly of tau and alpha-synuclein into abnormal filaments could provide novel therapeutic options. We are in the process of investigating the relevance of individual phosphorylation sites in tau by producing lines of transgenic mice with mutations in these sites. This work is based on the hypothesis that the abnormal hyperphosphorylation of tau contributes directly to neurodegeneration. We are also studying the importance of tau aggregation for the neurodegenerative process by producing mouse lines transgenic for human mutant tau that is unable to aggregate. In 2009, we showed that experimental tauopathy can be transmitted and that it spreads between adjacent brain regions in a tau-dependent manner. We are using cell assays to define the mechanisms of tau aggregate uptake and seeding. Like aggregated tau, aggregated alpha-synuclein also behaves in a “prion-like” manner. We are using transgenic mice and cell models, in conjunction with brain extracts from patients with Parkinson’s disease and multiple system atrophy, to define spreading pathways and molecular conformers. We are also using the cell models to define mechanisms of aggregate uptake and seeding. Current evidence indicates that in human tauopathies and synucleinopathies, nucleation-dependent aggregation may happen in a localised fashion, followed by seed-dependent propagation. In 2013, we showed that different molecular conformers of aggregated tau (or strains) might account for different human tauopathies. The definition of a strain of aggregated tau needs to be structural. In recent collaborative work with the group of S. Scheres at the LMB, we have determined the high-resolution structures of tau filaments from Alzheimer’s disease brain by cryo-electron microscopy (cryo-EM). We showed that paired helical and straight filaments are ultrastructural polymorphs that are made of a common protofilament. This work has shown that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and paves the way to study a range of neurodegenerative diseases.


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