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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

Characterisation of innate immune DNA sensing and viral evasion strategies 15 Sep 2016

We have identified an entirely new mechanism by which retroviruses regulate the process of DNA synthesis. We have discovered that, contrary to textbooks, the process of HIV-1 DNA synthesis occurs inside intact capsids and that the nucleotide fuel for DNA synthesis is sucked through regulated electrostatic channels formed by the hexmaeric capsid lattice making up the viral core. We have also discovered that the channels can open and close through a molecular iris formed by the capsid beta hairpin sequences at the 6-fold access of symmetry. This work is in press in Nature. Preliminary data suggest that non-pandemic forms of HIV do not properly regulate their capsid pores and that this causes these viruses to be less able to evade intracellular innate sensing mechanisms. This may explain their failure to reach pandemic levels of human-to-human transmission. Our current work aims to understand the molecular details of how pandemic HIV-1 regulates DNA synthesis through cofactor recruitment and regulation of the capsid channels. We also aim to understand whether the non-pandemic viruses also do this and to understand what features they lack. We also aim to understand when the process of channel regulation evolved, ie in the parental chimpanzee viruses or in humans as HIV-1.

Amount: £24,874
Funder: The Wellcome Trust
Recipient: University College London

Material Anxieties: The Perceived Health of Materials in Medical Products 11 Jan 2016

This project will study the dynamic trajectories of materials like stainless steel, silicone rubber and PVC that make up clinical and direct-to-consumer healthcare products. I will follow materials as they move from manufacturing to the marketplace and beyond, exploring their perceived risks and rewards, and examining how the choices of materials scientists and designers influence users’ experiences of health and wellbeing. The project’s innovative tripartite method will afford a uniquely holistic understanding of human experiences of materials, combining ethnography, design research and psychophysics to allow for a simultaneous focus on the physical, sensory, aesthetic and cultural affordances of materials. My key goals are to firmly establish this new interdisciplinary approach, thereby providing a bridge between the laboratory, design studio, care environment and society, with the potential to influence design practice, research directions in materials science and practices and experiences of healthcare. In bringing together materials producers, designers, clinicians and users this project encourages dialogue and enables translation between isolated disciplinary and professional communities. It therefore takes crucial first steps towards the identification and development of materials that accord with clinical and societal needs.

Amount: £200,556
Funder: The Wellcome Trust
Recipient: University College London

Understanding within-patient Mycobacterium tuberculosis genetic diversity to prevent drug-resistance 29 Jun 2016

Tuberculosis, caused by Mycobacterium tuberculosis (M.tb), is a major public health problem. Drug-resistant tuberculosis (DR-TB) cases are increasing, creating a significant barrier to disease control. DR-TB is difficult to diagnose and treatment often takes years. M.tb was traditionally thought to be genetically homogenous within the human host, but deep whole genome sequencing (WGS) data have revealed evidence of within-host genetic heterogeneity (GH), particularly in drug-resistance genes. Changing GH patterns over time can cause acquired drug-resistance (ADR). However, how and where in the host GH arises, or how important it is for ADR is not known. I hypothesise that GH represents isolated M.tb subpopulations in separate lung lesions within a patient, and that development of GH is related to local pathology or drug penetration. I will investigate this by WGS of M.tb extracted from resected human lung tissue, and comparing GH to pathology type and local drug concentrations. To evaluate whether GH causes ADR, I will follow patients with newly diagnosed MDR-TB and perform WGS of sequential sputum samples over 6 months for WGS. I will evaluate if ADR is related to baseline GH. Understanding the role of GH in ADR could help develop prevention strategies.

Amount: £380,125
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

Cross-Cultural Health Humanities in a Digital World 10 Mar 2016

This award will build a robust research collaboration between two global universities (Peking University [PKU]-UCL) which are both institutionally committed to support the Medical and Health Humanities. We aim to stimulate debate in three domains where we share complementary research strengths, namely Philosophy, Justice and Health; Transcultural History of Medicine; Culture and Health. We will use film and digital humanities as a resource to draw out challenges in six high-priority health issues: diabetes; antimicrobial resistance; privacy and health information; medical philanthropy in China; cross-cultural psychotherapy; healthy ageing. The use of film as a method to identify cross-cultural challenges and break down barriers to communication has been piloted as a regular part of the Medical Humanities programmes of both universities. During 2016-17 we will create a platform to showcase research and development and elicit online discussion engaging our student community and the wider public in shaping research directions and creating digital solutions to our questions. A series of networking events (open seminar, film screenings, social media video, video-conferencing) and the first Medical and Digital Humanities Film Exhibition (November 2017) will enable the identification, development and writing up of the three strongest collaborative research funding proposals to be generated by the exercise.

Amount: £49,708
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

Single cell decision making in development and dedifferentiation 05 Jul 2016

Our goal is to understand how cells make stochastic cell fate decisions in development and dedifferentiation. Understanding how individual cells make decisions has until recently been intractable, because gene expression has been measured from population averages. These averages mask the dynamics and differences between cells that define development or dedifferentiation in complex cell populations. Recently, we have pioneered approaches to visualize the transcription of individual genes in single, living cells. This means we can continually monitor the expression of cell fate regulators in single cells as they commit to fate decisions. We will now combine our imaging methods with molecular genetics, to test the hypothesis that stochastic cell fate choices in development are derived from heterogeneity in the expression of cell fate regulators. To determine how cells overcome the rate-limiting steps in dedifferentiation, we will use our technologies to dissect the gene expression dynamics required for successful reversal of the differentiated state. Overall our work will define the fundamental characteristics of the gene expression underlying stochastic fate choices in development, and provide new directions for developing safe, effective regenerative medicine.

Amount: £1,565,642
Funder: The Wellcome Trust
Recipient: University College London

Homeostatic monitoring and control of regional brain blood flow 05 Apr 2016

This research programme is designed to explore cellular and molecular mechanisms underlying homeostatic metabolic control of regional brain blood flow by addressing the following fundamental questions: (Q1) How are the changes in brain parenchymal PCO2/[H+] detected and what are the mechanisms underlying the effect of CO2/H+ on cerebral vasculature? (Q2) What are the mechanisms responsible for hypoxia-induced dilation of cerebral vasculature and what is their role in the redistribution of regional brain blood flow in accord with parenchymal O2 content? (Q3) What is the role of CO2/H+-sensitive mechanisms of astroglial/vascular interface in neuronal activity-dependent control of cerebral vasculature and in generation of the blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signals? (Q4) What are the cellular identity, sensory transduction mechanism and physiological role of an intracranial baroreceptor capable of sensing decreases in brain perfusion pressure? These questions are addressed by genetic targeting and blockade of hypothesized signalling pathways, in vivo two-photon excitation imaging of neurovascular interface ([Ca2+]i in astrocytes/neurones and parenchymal vasculature) and assessment of regional cerebral blood flow and cerebrovascular reactivity using BOLD and arterial spin labelling fMRI in experimental animals (rats and mice).

Amount: £1,295,793
Funder: The Wellcome Trust
Recipient: University College London

The neural circuits of social preference 01 Jun 2016

Social preference requires the ability to recognize and approach individuals of the same species (conspecifics). In humans, these behaviours are present from birth and are thought to be impaired in developmental disorders, such as autism, that are characterized by aberrant sociality. The innate brain circuitry that underlies human social preference is conserved in other social vertebrates, including the genetically accessible zebrafish. I have recently shown that larval zebrafish exhibit social preference from just two weeks post fertilization. At this developmental stage, larvae are transparent and thus amenable to the full range of modern optical techniques for single cell resolution circuit analysis. I will first use reporters that integrate neural activity to highlight the anatomical correlates of the social preference circuit. Two-photon calcium imaging during the presentation of virtual social stimuli will then be used to characterize the functional properties of the identified circuit elements. Finally, given that fish development occurs ex utero, I will monitor the development of this essential circuit and precisely document the impact of environmental and genetic manipulations that have been implicated in models of human disease.

Amount: £1,181,701
Funder: The Wellcome Trust
Recipient: University College London

Psychophysics of predictive motor control: a novel model of post-stroke fatigue 01 Jun 2016

Fatigue in neurological conditions, unlike exercise induced fatigue, is chronic, irreversible and does not arise from altered sensory afferent input from peripheral musculature. A distinctive feature of such fatigue is requirement of high effort for everyday activity. Normally, everyday activity feels relatively effortless. This is due to re-afferent sensory feedback from voluntary movement being attenuated under normal circumstances (sensory attenuation). I propose that neurological perceptual fatigue is a result of poor attenuation of re-afferent sensory feedback making even the simplest of movements feel effortful. Using a combination of behavioural and electroencephalography techniques, in a series of systematic experiments, I will study the interaction between self-reported fatigue, effort, behavioural and neural correlates of sensory attenuation. Furthermore, using brain stimulation techniques I will modulate sensory attenuation to determine the direction of causality between fatigue and neural processing. I will study chronic stroke survivors where post-stroke fatigue is a major problem. Fatigue is commonly seen as a neuropsychiatric symptom in neurological conditions and what I propose is a significant shift away from fatigue as a psychiatric problem and towards neurological fatigue being a sensorimotor disorder. The proposed project is also likely to identify a potential therapeutic target to develop interventions for neurological fatigue.

Amount: £905,754
Funder: The Wellcome Trust
Recipient: University College London

The impact of virus genetics on transmissibility of HIV-1 19 Apr 2016

Genome-wide association studies (GWAS) have greatly improved our understanding of human disease genetics, and are beginning to be applied to pathogens. Current pathogen GWAS have largely focused on the identification of variants behind bacteria and parasite drug resistance. A neglected application is identifying variants determining infectiousness for viruses such as HIV-1. HIV transmission is influenced in large part by an individual’s set point viral load (spVL), which itself is determined by variation in the viral genome. Given HIV’s short genome and large amount of common genetic diversity, spVL provides a tractable target in terms of potential pathogen GWAS with large global health implications. During this fellowship I will first adapt GWAS to HIV whole genome sequences by focusing on drug resistance, a phenotype where many variants are already well understood. Once the methods are perfected, I will analyse spVL in the PANGEA_HIV sample of 20,000 whole genome sequences. Identified variants will be combined with demographic data to understand how they influence transmission on a population level. They will also be tested for interactions with host genetic variants, to understand the biology of immune escape. This will allow for a better understanding of transmission risk.

Amount: £250,000
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

A Symposium on Enhancing Engagement, Co-production, and Collaborative Meaning-Making in Qualitative Health Research 30 Jun 2016

Traditional "lone researcher" models of qualitative research have shifted to include more collaborative ways of researching, with research participants and other stakeholders viewed as partners in the co-production of knowledge. As well as working alongside "lay researchers", qualitative researchers increasingly work in teams with colleagues unfamiliar with qualitative methods. This is largely driven by calls to engage the public in the production of knowledge and penetrate borders between disciplines. As a result, research is assumed to become more relevant to users’ needs, ethical, and broadly applicable, and is key to requirements of funding bodies and the Research Excellence Framework. However, such collaboration is complex and creates challenges for qualitative researchers. We will explore these issues in a one-day symposium hosted by University College London (UCL), and attended by 150 UK and international delegates. The symposium will provide a platform to develop critical perspectives on: How collaborative relationships are established and embedded, and particularly how qualitative researchers are positioned in multidisciplinary teams; How research designs, data interpretation and reporting are negotiated and enacted; The extent to which "lay researchers" offer the views and experiences of groups they represent and how marginalised groups are accommodated. Keywords: qualitative research, health, collaboration, engagement, symposium

Amount: £5,000
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

Development of a novel bioartificial liver device for the treatment of patients with liver failure 30 Sep 2016

In the UK, over 16,000 patients a year die of liver failure. Their livers have the capacity to repair and regenerate, but do not have time to do so. A device temporarily replacing liver function would save lives and reduce the necessity for liver transplantation worldwide. Dr Clare Selden and her team at UCL have developed a prototype 'bio-artificial liver' (BAL) to address this unmet need. Its key element comprises functioning liver cells in an external bioreactor. Plasma from a patient with liver failure will be passed through the bioreactor, contacting the alginate encapsulated liver cells, so that the cells replace those functions that the sick liver cannot perform. The machine will buy time for a patient's liver to improve or, if damage to the liver is irreversible, may buy time until liver transplantation can be arranged. The technology combines alginate encapsulation of a human liver cell line and subsequent culture of the encapsulated cells in a fluidised bed bioreactor - providing a convenient, manipulatable biomass in a form which maximises mass transfer between cells and perfusing plasma. The team have Translation Award funding to complete the design, specification, performance characterisation and manufacture of this fully biocompatible BAL.

Amount: £66,434
Funder: The Wellcome Trust
Recipient: University College London

Improved High Frequency Calibration for Dosimetry in Focussed Ultrasound Surgery 01 Apr 2016

Ultrasound at high intensities can cause tissue damage, therefore knowing the intensities used in clinical application is paramount. Ultrasound source outputs are calibrated using hydrophones, following a primary standard calibration at the National Physical Laboratory (NPL) in the UK. Yet uncertainty in the primary calibrations is surprisingly high: around 10% and growing with frequency (NPL 2014). The primary calibration uses optical interferometry for the measurements. This project will investigate one source of uncertainty in this procedure: the effect of the tension in the optically-reflecting membrane. The rig for these experiments will be designed and built following the design shown in Figure (1). There are three key goals: a) Create a measurement rig that can measure the normal incidence acoustic pressure transmission coefficient of a stretched mylar membrane as a function of frequency, membrane tension, and membrane thickness. b) Based on previous work in the literature (Thomas 1976; Romilly 1969; Lamb 1957; Ingard 1954; Chen et al. 2014), construct a mathematical and/or numerical model of the motion of a membrane under tension when a sound wave is incident, and make for comparison with the measurements. c) Formulate advice to the National Physical Laboratory on how to minimize this uncertainty.

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

Intracellular sodium and its effect on neuronal Gene Expression 01 Apr 2016

This project will involve investigating the effects of intracellular sodium on the gene expression in Dorsal root ganglion neurons. The key aims of the project will be to determine the role of sodium mediated signalling in neuronal gene expression. To determine this, high affinity sodium binding protein will be investigated; a cloned DNA construct of the protein will be transfected in to HEK (Human Embryonic Kidney) cells and then DRG neurons with a Nav1.7 knock out. The effect of low intracellular sodium concentration on expression of Penk will be assesed by analysis of the DRG neurons.

Amount: £1,750
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