NIHRDataInsights/HRCSData huggingface dataset:
Title: UKDP: Integrated DEmentiA research environment (IDEA)
Funder: Medical Research Council

Abstract: Our objective is to achieve a step-change in UK dementia research capacity through establishing national networks of existing and emerging centres of excellence in imaging, informatics and cell-biology. The UK Dementias Platform (UKDP) is a radically new approach to dementias research, providing a highly efficient and cost-effective translational pipeline from discovery through to early phase trials. UKDP will create closer synergy between epidemiology and experimental medicine with the re-purposing of epidemiologic cohorts for trials readiness. The size and depth of phenotyping available to UKDP will deliver a step-change in the complexity and granularity of dementia related hypothesis testing and accelerate compound development. Proposed here is an infrastructure of investment and collaboration. Underpinning UKDP is a critical mass of researchers and resources that will work together to encourage, facilitate, and develop a fully integrated dementia dedicated UK research environment. This will raise standards, reduce costs, and deliver innovative and coordinated research, to make the UK an internationally unique research environment. Through its partnership with major academic centres and industry, UKDP is well positioned to achieve this goal. Building on the recent MRC investment in UKDP, we propose here to renew and extend the UKDP integrative research environment with an advanced molecular imaging network strategically located to exploit UKDP cohorts. Also proposed is an integrated informatics environment to facilitate the location of and access to both data and bio-samples. The third proposal is for a stem-cells network to promote the use of this important and emerging technology. Each of these elements adds value to existing infrastructure investments and fills significant gaps in the UK research landscape.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: NEUROLOGICAL
Title: Mito-ND: Mitochondrial Neurodegeneration
Funder: Medical Research Council

Abstract: The Mito-ND program is based on the use of unique tools, in terms of infrastructures (mass spectrometry, equipment for animal behaviour and metabolism, laser capture microdissection). To pursue Mito-ND objectives, we will implement three distinct Workpackages (WP) articulated in Action Lines (AL), further divided in specific Tasks (T). 4.1. WP1. Screening of patient cohorts AL 4.1.1 Sequence analysis T 4.1.1.1 Patient selection. T 4.1.1.2 NGS and Sanger sequencing. AL 4.1.2 Characterisation of mutant protein variants T 4.1.2.1 mRNA and protein levels. T 4.1.2.2 Functional assays. T 4.1.2.3 Genotype-phenotype correlations. 4.2 WP2. Generation of iPSCs as a human neuronal model of PITRM1-associated neurodegeneration AL 4.2.1 Generation of integration-free human iPSC lines. AL 4.2.2 Generation of isogenic gene corrected and PITRM1 knockout iPSC lines. AL 4.2.2 Neuronal differentiation of iPSCs. T 4.2.2.1 2D-neuronal differentiation of hiPCSs into cortical neutrons. T 4.2.2.2 Generation of a 3D-culture of differentiated iPSCs. AL 4.2.3 Investigating mitochondrial function in iPSC-derived PITRM1 mutant and knockout neutrons. T 4.2.3.1 Mitochondrial functionality. T 4.2.3.2 Morphology. T 4.2.3.3 Mitochondrial dynamics. T 4.2.3.4 A-beta and MTS metabolism. 4.3 WP3. Characterization of Pitrm-mut mouse models AL 4.3.2 Conditional mouse models. T 4.3.2.1 Brain-specific Pitrm1-/- mice. T 4.3.2.3 Crosses of a brain-specific Pitrm1-/- model with an AD mouse model. T 4.3.2.4 Behavioral and neurological characterisation. T 4.3.2.6 Metabolic characterisation. AL 4.3.3 In vitro and Mass Spectrometry analysis. T 4.3.3.1 Morphological analysis. T 4.3.3.3 Molecular analysis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Imaging neural activity in freely-behaving rodents at the single cell level
Funder: Medical Research Council

Abstract: A transformative technology -imaging the activity of single neural cells deep in the mammalian brain during behaviour via GRIN-optics in vivo microscopy (GIVM) -has recently become available. GIVM gives a step-change in the analysis of how neurons and other cells, such as glial cells, control behaviour and has imposed a new evidential standard for understanding the neural basis of behaviour in mammals. We propose to become early adopters of GIVM in the UK and apply it to three core projects where we have made leading contributions that shape the international research agenda. These projects –central control of feeding, chemosensory control of breathing, and functional connectivity within the master circadian clock –are areas of untapped potential at Warwick. Application of GIVM will give major advances by refuting or validating untested assumptions, and new ways to examine neural control in each of these projects. We shall extend the use of GIVM by: imaging activity of non-neuronal cells in the brain; combining it with real-time measurement of neurochemicals; and simultaneously performing fluorescent and bioluminescent detection. After establishing GIVM in the core projects, we shall extend its application to next-phase projects that engage other Warwick neuroscience researchers. Potential projects include: longitudinal monitoring of how environmental enrichment alters hippocampal synaptic connectivity and network activity; studying development of pathological patterns such as seizure activity. Our proposal fits fully with the MRC strategy for discovery research in neuroscience (linking genome data and cognitive processes with behaviour and neuronal systems). By adopting GIVM, we will be able to attain the highest standards of rigour in mammalian neuroscience. This achievement will underpin a range of future grant applications that will build on, and sustain, the aims of the Discovery Award, and allow wider dissemination of these methods in the UK.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: NEUROLOGICAL
Title: University of Bristol Momentum Award – Dementias
Funder: Medical Research Council

Abstract: Developing effective treatment for dementia critically depends on characterising the development and progression of cognitive decline many years prior to current dementia diagnosis. ContinUous behavioUral Biomarkers Of cognitive Impairment (CUBOId) leverages a £12M investment in the EPSRC Sensor Platform for HEalthcare in a Residential Environment (SPHERE) Interdisciplinary Research Collaboration, which aims to advance the state of the art in sensing for many different health-related behaviours at home. The objective of this proposal is to develop novel computational behavioural analysis algorithms that derive signatures relevant to dementia from SPHERE’s sensor network. Using these new algorithms, CUBOId aims to demonstrate that it is possible to reveal previously unseen behavioural biomarkers of early Alzheimer’s disease (AD) pathology, derived from autonomous, continuous, long-term, behavioural measurement. As proof of principle, enhancing diagnosis will be explored through testing the hypothesis that in Mild Cognitive Impairment (MCI), where subtle cognitive deficits can be difficult to interpret, there is a behavioural AD signature identifiable using SPHERE technology. Second, we explore the hypothesis that behavioural markers of AD observable with this technology will be more sensitive to treatment effects than standard cognitive measures used in clinical trials. In so doing, the CUBOId team will have developed, tested and de-risked a unique new asset for the community of researchers in the UK Dementias Research Institute, which can also be applied to cohorts in the Dementias Platform UK as well as internationally. Importantly, the proposed proleptic appointment of a “rising star” at Bristol is intended to develop the potential of SPHERE-type sensors and algorithms specifically for use in dementia; to nurture the important interface between computer science and dementia research at the University and to personally lead engagement between Bristol and the DRI.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: Cardiff University Momentum Award – Dementias
Funder: Medical Research Council

Abstract: The MRC Momentum Award will catalyse recruitment of two Cardiff University (CU) Dementia Rising Stars working in ‘immune pathways’ and ‘polygenic iPS cell disease modelling’ linked to dementia genetics. This approach aligns to our strategic priority to build capacity in dementia research (see Section 2), and complements our internationally-leading genetics and neuroinflammation research groups, who have identified new targets with the potential to deliver novel drug therapies. We will recruit in microglial cell biology, given that microglial activation and function is potentially critical in Alzheimer’s disease (AD) pathology. For example, SPI1, a central transcription factor in microglial function, has a significant association with AD and shows AD-associated variants altering gene network expression in monocytes. A second Rising Star, with induced pluripotent stem cell (iPSC) expertise, will develop a pipeline for human polygenic disease risk modelling. This individual will create both rare variant isogenic and extreme polygenic risk iPSC models, plus in vitro models of neuroinflammation for target validation and drug discovery. Current expertise in iPSCs (Allen) and macrophage biology (Taylor) is not dedicated to dementia. Rising Star recruitment will, therefore, generate new critical mass, catalyse new research avenues and facilitate collaborative research with current PIs in our genetics, neurobiology and immunology groups. Rising Stars will be hosted in Biosciences or Medicine, where there are excellent facilities and research support available. In future (see Section 2), we plan to co-locate all our dementia researchers in a new state-of-the-art interdisciplinary research building. As discussed with the MRC, we request MRC funding for 3-years of Rising Star salaries and two 2-year postdoctoral salaries, with the Institution covering research consumables, PhD Studentships and permanent employment for the Rising Stars as a matched contribution. Projects included Principle Investigator: Dr Gaynor Ann Smith MC_PC_16030/1 The Pathological Role of Risk Genes and Ageing in Drosophila. Principle Investigator: Dr Owen M. Peters – MC_PC_16030/2 Understanding the role of neurodegenerative disease risk genes in the ageing nervous system


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL
Title: University of Edinburgh Momentum Award – Dementias
Funder: Medical Research Council

Abstract: Microglia, the resident macrophages of the central nervous system (CNS), and monocyte-derived cells are critical effectors and sculptors of changes in the CNS environment (1). In recent years, it has become clear that microglia and myeloid cells such as monocytes, macrophages, or dendritic cells are ontogenetically and also functionally distinct innate immune cell populations in the CNS. The goal of my research is to characterize the heterogeneity of CNS myeloid cells and to determine their differential functions in neurodegenerative diseases. Using multiplexed single-cell mass cytometry (CyTOF), we have characterized the phenotypic signature of human microglia, which is distinct from myeloid cells in the cerebrospinal fluid and peripheral blood (2). Notably, we detected significant regional heterogeneity of human microglia. We are currently combining CyTOF with another high-dimensional technique (scRNA-seq) to investigate the context-specific adaptive responses of microglia during pathology. This approach will enable us to identify and characterize previously unknown microglia subsets in the human brain, their spatial distribution, and their changes with aging and neurodegeneration. In a second line of research, we are establishing a novel CNS-conditioned in vitro model of human microglia using patient-derived induced pluripotent stem cells (iPSCs) in collaboration with Siddharthan Chandran’s group at the DRI. This approach will enable us to study the dynamic changes of microglia that occur in neurodegenerative diseases as a result of genetic mutations and environmental changes. It will also provide us with the opportunity to model the context-specific adaptive responses of microglia that we detect in the human brain, and to explore their potential pathogenetic relevance in neurodegenerative diseases. We hope that the characterization of disease-associated microglia subtypes in the human CNS will open new avenues for subset-specific therapeutic interventions in neuropsychiatric disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: University of Oxford Momentum Award – Dementias
Funder: Medical Research Council

Abstract: Research and drug discovery for Alzheimer’s disease (AD) is undergoing a minor crisis with a paucity of novel therapeutic approaches that is human evidence-based. Whilst, human genetic studies have identified AD associated variants important for CNS glial function, there is uncertainty over whether inflammation plays a beneficial or deleterious role. As a result, many pharma companies are hesitant before committing significant resources to this novel therapeutic opportunity. Our proposal is therefore focused on the scientific theme “Microglial interactions in Alzheimer’s Disease”. The indicative projects will leverage four key capabilities within the University of Oxford that represent untapped potential and are ripe for development for dementia research, (1) access to human primary CNS cell types from human tissue coupled with single cell analysis, (2) Human iPSC derived microglia, (3) High order imaging analysis of cellular phenotypes driven by machine learning, (4) Protein-protein interaction disruption to probe signalling pathways. The proposed projects approaches neuro-inflammation in AD through these technical capabilities and are supported by world-leading bioinformatics and unrivalled structural genomics consortium (SGC) pharmacological tools. These tools enable pharmacological pilot studies within the projects, which if successful, will more rapidly lead to drug discovery projects because of the enabling structural knowledge and chemical starting points held within the SGC. Momentum funds will support the recruitment of a new research leader from outside the UK, as well as supporting early career high flyers within Oxford. Our pharma partners and institution leverages the MRC funds with significant institutional funds, platforms, space and expertise totalling ~£2million (~£850K from the institution and $1.5million industry in-kind). We have developed strong partnerships with Oxford University Hospital NHS Trust and industry including world-leaders in single cell biology and dementia drug discovery. The Award will support the diversification of target identification and develop human in vitro models that are more likely to be predictive of clinical outcomes compared to current dominant murine models. Our approach will facilitate synergy between disciplines and maximise the contribution of the grant towards the acceleration of new dementia research in Oxford.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Cortical microcircuiltry after traumatic brain injury: molecules to networks
Funder: Medical Research Council

Abstract: Traumatic brain and spinal cord injury lead to severe motor, sensory and cognitive dysfunctions, which are then followed by a variable recovery in performance. The acute functional deficits depend on the injury severity and extent of neuronal and connectivity loss (deLanerolle et al., 2015). Direct severing of neuronal processes by the mechanical forces set forth detrimental consequences of pathogenic cascades, such as signaling cascades and inflammation. On the other hand, the recovery phase depends on the compensatory and repair responses attributed to the spontaneous circuit connectivity rearrangements that take place after neurotrauma. In a partial spinal cord injury model, sprouting of existing supraspinal and propriospinal connectivity, as well as the formation of new detour connections to input-deprived neurons are fundamental in triggering the recovery of effective locomotor function. Notably, this remodeling of local and long-range connectivity is critically dependent on a specific somatosensory input, namely, from muscle spindle afferents. Moreover, synaptic input and activity properties also shape vulnerability and neuronal survival, suggesting that the connectivity of a neuronal network also affects the activation of signaling cascades at the level of a single neuron. As functional and structural connectivity are key targets of acute pathogenic cascades and are significant modulators of recovery, it is essential to understand both acute and chronic effects of TBI in the context of neural circuitry. The proposed collaborative project, therefore, aims to understand changes within the cortical microcircuitry in the acute and recovery phases and to identify factors, both in intracellular and extracellular context, which shape this restructuring. The ultimate aim of the project is to derive new targets for translational applications.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL
Title: Capital award for UK DRI at University of Cambridge
Funder: Medical Research Council

Abstract: The aim of this award is to support the University of Cambridge 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, 3 programmes have been selected planned for the UK DRI at the University of Cambridge and with scientific and operational leadership provided by its associate director, Professor Giovanna Malluci. The project at the University of Cambridge will involve refurbishment of labs located on level 2 at the Island Research Building on levels 2 and finishing touch refurbishment to Level 4 needed. Ultimately to accommodate around 30 researchers with full occupancy expected by May 2018. The approach of the institute as a whole, of which the UK DRI at the University of Cambridge 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 Cambridge plans to look at the early stages of neurodegeneration; understand tau misfolding, synapse repair, autophagy as a protective cellular response. 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 Cardiff University
Funder: Medical Research Council

Abstract: The aim of this award is to support Cardiff University 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, 3 programmes have been selected planned for the UK DRI at Cardiff University and with scientific and operational leadership provided by its associate director, Professor Julie Williams. The project at Cardiff University will involve refurbishment of unoccupied office space in the Haydn Ellis Building building. Ground floor and 1st floor spaces have been set aside. The proposed layout is for approximately 60 researchers with short-term flexibility for further space and significant long-term capacity. For occupancy by end of May 2018. The approach of the institute as a whole, of which the UK DRI at Cardiff University 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 Cardiff University plans to look at the synapse loss and cell death in AD; How AD risk genes affect microglial production & activation ; Cross-DRI programmes: novel mathematical and statistical approaches and models to stratify dementia risk and identify patterns in large ‘omics’ datasets.. 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