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Recipients:
University College London

Results

Primate lentiviral Vpx: insights into DNA sensing and zoonotic potential 30 Sep 2016

Innate detection of cytoplasmic DNA is central to human health and disease. DNA sensor cGAS and adaptor protein STING represent a key pathway. On recognition of viral cytoplasmic DNA, cGAS produces a secondary messenger that activates STING. This initiates signalling that stimulates transcription factors IRF3 and NF-kB and an inflammatory response. I have discovered that lentiviral accessory protein Vpx, expressed by zoonotic HIV-2 and related lentiviruses, is a DNA sensing antagonist. I have shown that Vpx selectively inhibits NF-kB, but not IRF3, activation downstream of cGAS/STING. I propose that Vpx is a tractable tool to interrogate the molecular mechanisms of DNA sensing that underpin diverse infectious and immune pathologies. Furthermore, Vpx allows examination of the central role for DNA sensing as a barrier to zoonosis. My specific objectives are: 1. To characterise the mechanism of Vpx inhibition of NF-kB activation. 2. To use SILAC to identify novel Vpx-host factor interactions occurring specifically after cGAS activation. 3. To characterise Vpx proteins from zoonotic and non-zoonotic simian lentiviruses, and epidemic and non-epidemic HIV-2, with a view to understanding the role of DNA sensing antagonism in cross-species lentiviral transmission. This fellowship will produce critical insight into central biological pathways of emerging medical importance.

Amount: £241,313
Funder: The Wellcome Trust
Recipient: University College London

Control of receptor trafficking as a therapeutic target in the inherited neuropathies. 19 Nov 2015

In this fellowship I plan to investigate whether mutations in hereditary neuropathy genes affect endosomal sorting of proteins and receptors to the plasma membrane of motor neurons and whether this leads to aberrant activation or inhibition of specific cellular pathways that can be targeted as potential therapies. In order to answer this question I will investigate a model of hereditary neuropathy due to mutations in BICD2. This fellowship has the following five aims. 1. To generate and charact erise a mouse embryonic stem cell-derived motor neuron model of neuropathy due to mutations in BICD2. 2. To analyse changes in the cell surface receptor landscape induced by mutations in BICD2. This will be performed using Stable Isotope Labelling of Amino-acids in Culture (SILAC) and mass spectrometry. 3. To validate in vitro the signalling pathways revealed in aim 2. 4. To validate in vivo alterations in the cell surface proteins identified and validated in aims 2 and 3. 5. To validate the changes in cell surface protein expression in human tissue. As almost all hereditary neuropathy mutations can impact on endosomal sorting and recycling to the cell surface, the techniques learnt during the fellowship may be applied to other forms of hereditary neuropathy.

Amount: £412,604
Funder: The Wellcome Trust
Recipient: University College London

Dissecting the neural components of the hippocampal cognitive map 05 Jul 2016

The existence of place, directional, boundary and grid cells in the rat hippocampal formation provides strong evidence that this part of the brain functions as a cognitive map. This theory suggests that the hippocampal formation contains map -like representations of familiar environments which enable the animal to identify its current location together with desirable and undesirable locations and to generate the vectors to move towards or away from these. I propose to use novel behavioural tasks, high-density extracellular recording probes, 2-photon imaging, and pharmacological and optogenetic manipulation of cell activity to explore in-depth the properties of these spatial cells and the role of different components of the hippocampal formation in spatial memory and navigation. Specifically I will address the following questions: How well does the activity of place, head direction and grid cells correlate with the animal’s perception of the different aspects of space and which cells are important in supporting navigation to an unmarked goal? What are the relative roles of external landmarks versus internal path integration signals in determining the firing of place cells? Do the l grid cells signal distance travelled in a particular direction or something else such as the shape of the environment?

Amount: £2,837,189
Funder: The Wellcome Trust
Recipient: University College London

Illuminating the brain: engineering light to monitor brain activity. 31 Dec 2015

Perinatal brain injury remains a significant cause of neonatal mortality and is associated with long-term neurological disabilities including cognitive impairment, mental retardation and accounts for 15 to 28% of children with cerebral palsy. There is an urgent clinical need to detect as early as possible those neonates at most risk and who may benefit from adjunct therapies and/or redirection of clinical care for effective rehabilitation. Early detection and assessment of brain neurological sta tus and outcome requires sensitive, robust and easy to measure biomarkers. The aims of my fellowship are to: (1) develop new methods for assessing neonatal brain injury and deliver early bedside biomarkers of atypical cognitive and neurological development; (2) inform and access efficacy of targeted interventions and clinical management for long-term neurological outcome in brain injured neonates through a clinical evaluation program. For several years now I have been developing instrumentati on and methodology that can non-invasively measure brain tissue oxygenation, haemodynamics and uniquely assess mitochondrial oxygenation through measurement of the oxidation status of cytochrome-c-oxidase (oxCCO). We have shown recently that, utilising our novel multimodal measurements that combine optics and magnetic resonance spectroscopy, in the neonatal animal model, the oxCCO measurement is a good indicator of the biochemical status of the brain and is directly related to recovery and outco me following brain hypoxic-ischaemia. This Fellowship will enable me to build upon my previous achievements and embark on an ambitious program of research to clinical evaluate and establish the brain optical measurement of oxCCO as a neuromonitoring biomarker.

Amount: £158,818
Funder: The Wellcome Trust
Recipient: University College London

Loneliness in severe mental illness: impact on relapse 29 Jun 2016

Loneliness is the distressing subjective feeling one’s social relationships do not meet one’s social needs. Its adverse impact in physical health and mortality is established. I will investigate its impact on relapse in acute psychiatric crises, and its potential mediating role between neighbourhood social deprivation and relapse. Objectives 1) Test hypothesis that loneliness is associated with: a. increased relapse rate at twelve months follow-up (primary hypothesis) b. reduced time to relapse c.increased service use and cost 2) Test if loneliness is associated with neighbourhood-level deprivation and social isolation Test if loneliness mediates any association between neighbourhood-level deprivation and relapse 3) Discovery replication: second acute psychiatric care cohort Methods Analyse data from multicentre cohort (UCL ‘CORE’) study of acute psychiatric patients with serious mental illness. Validate results in different cohort. I will use logistic regression, with adjustment for relevant confounders/modifiers, to test the hypotheses. I will use survival analysis, (Kaplan-Meier curves and Cox hazard ratios) for ‘time-to-relapse,’ and structural equation modeling to investigate whether loneliness mediates any relationship between deprivation and relapse. Key goals Establishing how loneliness affects outcomes should inform the development of future loneliness interventions. These may reduce relapse, and incorporate both individual and area-level elements.

Amount: £236,225
Funder: The Wellcome Trust
Recipient: University College London

Do Amniotic Fluid Cells Represent a Viable Cell Source for Regeneration of the Neonatal Upper Airway? 02 Mar 2016

Aim To evaluate human Amniotic Fluid Cells (AFCs) for fetal and neonatal tracheobronchial tissue engineering. Objectives & Methodology I will isolate hAFC subpopulations already displaying primitive airway basal cell surface markers and quantify co-expression of nuclear respiratory lineage markers (NKx2.1, FOXA2 and SOX2). I will ascertain if this subpopulation can be enriched using ‘proximal airway’ culture conditions, and whether these enriched hAFCs can be rapidly expanded via our novel in-house epithelial expansion protocol. I will investigate whether my enriched ‘respiratory’ hAFC population can differentiate to form cell types present in mature tracheobronchial epithelium by manipulation of Wnt, Notch and TGF-beta signalling. I will assess their ability to generate a ciliated pseudostratified epithelium in vitro in ALI and 3D spheroid cultures. I will use an immunosuppressed rabbit airway surgical model to assess the in vivo suitability of these airway-differentiated hAFCs. I will implant seeded decellularised rabbit donor tracheae in lateral thoracic musculofascial flaps and, following orthotopic transfer of grafts, I will analyse the grafts weekly (by bronchoscopic biopsy) and at post-mortem using histology and immunofluorescence. Keywords Tissue Engineering - Regenerative Medicine – Fetal and Neonatal Therapies - Amniotic Fluid Cells – Autologous Cell Source - Proximal Airway Epithelium - Epithelial Expansion

Amount: £197,003
Funder: The Wellcome Trust
Recipient: University College London

Autophagy-inflammasome interplay in Wiskott-Aldrich syndrome 02 Mar 2016

Background: Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disorder associated with haemorrhage and malignant potential. 70-80% also suffer severe inflammatory complications. Despite excellent survival post stem cell transplant, 30% of children have ongoing autoinflammation. Emerging evidence indicates that the actin cytoskeleton has an important role in autophagy, and inflammasome activity is intricately linked. Aims: Define the molecular role of Wiskott-Aldrich syndrome protein (WASp) in autophagy and inflammasome activation and investigate the impact of potential therapies. Methods: WASp knockout macrophage cell lines will be generated using CRISPR technology and GFP-tagged WASp introduced using lentiviral transduction. ATP, starvation and infection will be used to stimulate autophagy/ inflammasome activation. Cellular events will be followed by qPCR, western blotting and flow cytometry. Cellular localisation will be investigated by high resolution microscopy (epifluorescent, confocal, super resolution). Transcriptomics will be used to identify the impact of WASp deficiency on cellular gene expression. Implications: Inflammasome dysregulation has been implicated in a wide range of disease processes. Investigation of inflammasome dysfunction mechanisms in WAS will facilitate better understanding of the actin cytoskeleton role in the autophagy-inflammasome axis, providing therapeutic implications far beyond WAS.

Amount: £237,672
Funder: The Wellcome Trust
Recipient: University College London

The consequences of, and relationship between, amyloid deposition, grey matter microstructural change and atrophy in the MRC NSHD 1946 birth cohort 19 Nov 2015

The development of disease modifying therapies to delay the clinical onset of Alzheimer’s disease (AD) is of the highest public health importance. Robust biomarkers of the long pre-symptomatic period between the first appearance of the histopathological hallmarks of AD and the onset of clinical symptoms will be crucial for recruitment and monitoring in drug trials and clinical practice. I will analyse the multi modal MRI and amyloid PET imaging data of 500 individuals from the MRC National Survey for Health and Development (NSHD; the British 1946 birth cohort) to address the following key objectives: 1. Investigate whether amyloid deposition leads to microstructural grey matter change utilising diffusion based MRI and a new and novel multi-shell acquisition technique (NODDI).2. Investigate the extent and pattern of grey matter atrophy associated with amyloid deposition and compare sensitivity of diffusion based/NODDI metrics with measures of grey matter atrophy.3. Evaluate the sensitivity of tests of cognition, audition and olfaction in assessing early impairment of cortical function and the relationship with the the neuroimaging data.4. Investigate the relationship between neuroimaging metrics and cognitive trajectory throughout life.

Amount: £174,791
Funder: The Wellcome Trust
Recipient: University College London

In-hospital resuscitation under the microscope: Analyzing inter-professional communication using video 10 Mar 2016

The aim of this proposal is to explore the possibilities and challenges of video-recording inter-professional teams working to resuscitate patients on hospital wards following a cardiac arrest. Video recordings provide an essential data source for an approach to communication research which is now commonly used in the social sciences yet currently not widely applied in health research. This approach draws on recent theoretical and methodological advances in discourse analysis, which allow for the development of a much more fine grained and inclusive set of categories for describing communication. With this approach, currently largely tacit, unverified understandings of what counts as ‘good’ communication, teamwork and leadership can be made explicit, tested empirically, and refined accordingly. The Seed Award will bring together a strong, multi-disciplinary research team to jointly develop a methodological, ethical and legal framework for the envisioned research. This will be achieved through a simulation-based pilot study and engagement with stakeholders. The main outcomes of the Award will be an application for a large research grant, an ethics application and a methodological paper.

Amount: £49,582
Funder: The Wellcome Trust
Recipient: University College London

Epstein Barr Virus: Paving the way for a vaccine using epidemiological and mathematical modelling approaches 15 Aug 2016

Epstein Barr Virus (EBV), a Lymphocryptovirus, permanently infects >90% of humans. EBV causes >90% of glandular fever, and is linked to 1% of global cancers. Why only a small fraction of infected individuals get cancer is poorly understood. No anti-EBV vaccines are currently licensed, although several candidates are in pre-clinical development. Lymphocryptoviruses have evolved with humans for many millennia. Our immune systems are likely to be well-adapted to EBV and vice versa. The impact of EBV infection through the human life-course is not known, nor is that of remaining permanently EBV-negative. As vaccines become available such questions will become increasingly important. Information derived from large cohorts and mathematical models of transmission will be critical before vaccines can be adopted. Prior to extensive vaccine investment a feasibility and scoping exercise of currently available data and resources is required. Our goals are: 1) Using pre-existing datasets, pilot assembly of a cohort of EBV-seronegative individuals for a life-course study; 2) Undertake systematic reviews to determine the strength of available evidence for different risk factors for EBV infection and EBV-associated cancers in different settings; 3) Develop a preliminary transmission dynamic model for vaccination, and identify knowledge gaps for a full model.

Amount: £88,097
Funder: The Wellcome Trust
Recipient: University College London

Neural Circuits for Selective Auditory Filtering 05 Apr 2016

To facilitate sensory processing in complex environments, the brain can selectively filter auditory input to enhance neural responses to relevant sounds and suppress responses to background distractors. Neural correlates of selective filtering have been observed in auditory cortex (AC), but the underlying neural circuitry has not yet been identified. A synthesis of existing results and our preliminary data suggests that selective auditory filtering arises through interactions between AC and two thalamic structures: the medial geniculate body (MGB), which sends direct excitatory input to AC and receives direct excitatory feedback from AC, and the thalamic reticular nucleus (TRN), which relays indirect inhibitory feedback from AC to MGB. In this proposal, we outline a plan to answer three key questions related to selective filtering: Q1: Are selective spectral and temporal filtering evident in the auditory thalamus? Q2: How do thalamocortical interactions contribute to spectral and temporal filtering? Q3: How does attention modulate spectral and temporal filtering? The proposed experiments will lead to significant advances in our knowledge of the general mechanisms that underlie active sensory processing in all mammals, while also helping build toward a detailed understanding of the neural circuitry that allows humans to understand speech in noisy environments.

Amount: £1,442,282
Funder: The Wellcome Trust
Recipient: University College London

Heterogeneities in stem cell mechanics during division and exit from pluripotency 19 Apr 2016

Embryonic stem cells are pluripotent cells that can give rise to the three germ layers. Evidence indicates they can maintain pluripotency whilst giving rise to progenitor cells for all the embryo cells, suggesting that they are capable of asymmetric division. However, the cell biology of embryonic stem cell division is poorly understood. Interestingly, embryonic stem cells have mechanical properties very different from their differentiated counterparts, and their fate is strongly influenced by the mechanical properties of the substrate, suggesting that stem cell division might be asymmetric with respect to daughter cell mechanics. We propose to explore the geometry, mechanics and physical control by the environment of stem cell division using mouse embryonic stem cells as a model. We will follow cell division and the fate of the daughter cells at the single cell level and in colonies. Altogether, this project will broaden our understanding of the molecular and biophysical control of embryonic stem cell division, a process key to stem cell homeostasis and embryonic development, and will clarify how cell shape and mechanics influence embryonic stem cell fate.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

Improving the long-term impact of child soldiering 31 Jan 2016

Little is known about the longitudinal effects of child soldiering onto the lives of these participants in wars, particularly in the children’s transition to adulthood. A culturally-grounded understanding of the multiple levels in which this experience shapes their subsequent lives in highly politicised communities is needed. My aim is to conduct a pilot assessing the feasibility of a future study on the long-term effects of early age involvement in political violence in the context of Nepal. This pilot will lay the foundation for a future application of funding for a larger research project. Knowledge of these effects will inform policy-makers and the rehabilitation services’ ability to support this population into adulthood. The funding will enable the facilitating of: i) A pilot in Nepal where I will reengage with my former PhD cohort of informants; ii) Workshops in Nepal and the UK to discuss the results of the pilots with scholars, informants, and stakeholders; iii) Time to prepare an academic paper. The key outputs will be: i) an assessment of the feasibility of the study; ii) the development of a network of collaborators; iii) an academic paper drafted for an academic journal. Key words: child soldiers, ethnopsychology, longitudinal research, war.

Amount: £10,000
Funder: The Wellcome Trust
Recipient: University College London

A phase I clinical trial of DARC 30 Sep 2016

Preclinical development of a novel diagnostic for glaucoma. Glaucoma is the major cause (15 per cent) of irreversible blindness worldwide. A recent UK report suggested 10 per cent earlier detection of glaucoma would save £1billion/year in treatment costs alone.Professor Francesca Cordeiro and colleagues from the Institute of Ophthalmology at University College London, have been given Translation Award support to fund the preclinical development of their Detection of Apoptosing Retinal Cells (DARC) Technology. DARC is a novel technique that utilises the unique optical properties of the eye to allow direct visualisation of dying nerve cells. If successful, early diagnosis and treatment would mean that DARC will increase patient benefit and decrease burden of care costs.

Amount: £271,521
Funder: The Wellcome Trust
Recipient: University College London

Investigating the development of visual object perception from noisy images 01 Apr 2016

As we perceive the world, our brain continuously makes educated guesses about what we will see next. These inferences allow us to distinguish objects in our field of vision without having to examine every detail. This is known as the Bayesian model of visual perception. Recent evidence suggests that object recognition tasks for which such inferences are likely to be crucial may develop well into adolescence. There is anecdotal evidence that children find tasks such as identifying objects in poor lighting conditions or when borders are unclear (Bova, 2007) very difficult, even when they know exactly what the object they are looking for looks like (Yoon, 2007). This suggests that the robust object perception described in Bayesian models of the adult system takes surprisingly long to develop. This piece of research will test this hypothesis by (a) measuring children’s ability to recognize objects in a distorted ("noisy") image, and (b) testing how expectations about the objects (e.g. what it will look like) can improve perception. This aims to further our understanding of how the brain learns to use existing knowledge to interpret new sensory information, and make better inferences about the world.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University College London

Investigating the neural odometer function of entorhinal grid cells in rats navigating a multi-planar environment. 01 Apr 2016

It has been proposed that the grid cell system in the medial entorhinal cortex acts as a ‘neural odometer’, encoding both distance travelled and an animal's position in space. These features may be necessary for spatial computations such as path integration, but the relationship of grid cell firing patterns to behaviour remains speculative. In not-yet-published work, it has been shown that for a rat climbing a wall with its body plane aligned vertically the grid fields are expanded, as if the cells underestimate distance travelled. If grid cells support spatial computations then rats should also underestimate distances in this plane. To test this hypothesis rats will learn a distance match-to-sample task leading to triangle completion while both sample and choice phases are in the same plane (both horizontal or both vertical). In probe trials, the sample will be horizontal but the choice vertical. Distance underestimation in the probe trials (walking too far on the vertical wall to achieve a match to the horizontal sample) will link grid cells to behaviour, while the basic distance-matching task will serve as a springboard for neurobiological studies investigating the role of grid cells in odometry generally.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University College London

Cloning of a galactosyl transferase gene promoter to understand the mechanism linking genetic variation to the altered enzyme activity found in IgA nephropathy 01 Apr 2016

IgA nephropathy (IgAN) is the most common glomerulonephritis and is a major cause of kidney failure worldwide. IgAN is characterised by abnormal deposition of galactose-deficient IgA (Gd-IgA) in the kidney, and levels of Gd-IgA are raised in the serum of patients, with levels correlating with clinical outcomes [1, 2]. Why some people have elevated Gd-IgA is unknown, but we have shown that Gd-IgA levels are highly heritable [3, 4] and recently performed a genome wide association study (GWAS) that showed that the presence of a haplotype across a particular galactosyl transferase gene is strongly correlated with Gd-IgA level (p-10), implying that common genetic variation across the locus modulates enzyme activity in the population. Fine mapping of the locus using imputed genotypes, and consultation of available expression quantitative trait loci (eQTL) maps disclosed the set of common variants across the region that might explain the effect, and we now wish to understand the mechanism linking the known genetic variation with altered enzyme activity. The aim of this project is to clone the promoter region of the gene from individuals with and without the associated haplotype for studies using a reporter gene to assess promoter activity of different allotypes.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University College London

Public health data science to investigate and improve migrant health. 25 May 2017

Migration is a defining political challenge of our time and a global health priority. Internationally there is a lack of epidemiological data on new migrants including the prevalence of high morbidity conditions and estimates of risk factors for disease. The overarching aim of this research is to generate evidence that will improve the health of migrants moving from low and middle-income to high-income countries. Key goals: Million migrant study: Create an electronic cohort that will establish the first national rates of age-specific morbidity and risk factors for disease in migrants. Migrant eCohort: Investigate the migrant exposome and how this changes over time since migration, using digital technologies (smart phones and apps) for data collection. Personalised public health intervention: Develop and test the feasibility of a tailored health advice website to improve migrant health. Outcomes: These studies will transform how we conduct digital cohorts in mobile populations and have wide application for efficient study design. The detailed epidemiological and health service data produced will provide the first national evidence of the health effects of rapid epidemiological transition as a result of UK migration, and a platform from which to carry out digitally enabled personalised public health interventions.

Amount: £1,164,786
Funder: The Wellcome Trust
Recipient: University College London

Effective public policy for improving sexual health of migrants/refugees 30 Sep 2017

Summary: Identifying and implementing appropriate and effective public policy responses for improving the sexual health of migrants and refugees Global challenges are complex, interwoven "wicked problems" whose solutions require systemic thinking, cross-disciplinary collaboration, and engagement with a range of stakeholder opinions and positions. In this proposal we will address the interlinked problems of inequalities, migration/refugees and global health. Using the tracer example of sexual health (sexually transmitted infections including HIV) we will explore rigorous evidence for interventions to address upstream determinants driving poor health outcomes for refugees/migrants from West Asia/Middle East North Africa (WA/MENA). Results from systematic reviews, realist reviews and mathematical modelling will be synthesised to identify effective interventions which can be translated into policy (in a range of sectors). These policy options will be assessed and refined to enhance their ‘palatability’ – i.e. their legitimacy, feasibility and acceptability with a range of key stakeholders in countries in the WA/MENA region as well as in pan-EU and national level (UK) health institutions.

Amount: £673,516
Funder: The Wellcome Trust
Recipient: University College London

Overcoming constraints on T cells in the HBV-infected liver 05 Dec 2016

My request for enhancement funding arises from the component of my existing award focused on developing T cell immunotherapy of hepatitis B and hepatocellular carcinoma using patient samples. We recently made important contributions to the testing of genetically redirected T cells for a first-in-man treatment of HBV-related hepatocellular carcinoma1. We are also collaborating with academic and pharmaceutical partners to develop immunotherapeutic vaccines aiming to boost antiviral T cells for hepatitis B control. However, these approaches remain limited by the profound exhaustion and other immune constraints imposed on T cells by high-level antigenic stimulation in the tolerogenic liver. Front-line candidates to revive T cells are checkpoint inhibitors such as PD-1 blockade. However, we have found that genetic knockdown of PD-1 can initiate detrimental effects in virus-specific T cells (Fig.1). The emerging concept that PD- 1 may actually be required to support long-term maintenance of T cells in the setting of persistent antigenic stimulation is underscored by recent work in murine models2, 3 and by our finding that liver-resident PD-1+T cells can remain highly functional (Pallett, in preparation). These discoveries underscore the need to investigate more fundamental drivers and mediators of T cell failure as alternatives or additions to checkpoint inhibition.

Amount: £175,008
Funder: The Wellcome Trust
Recipient: University College London