- Total grants
- Total funders
- Total recipients
- Earliest award date
- 11 Jan 2016
- Latest award date
- 06 Dec 2016
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
The CTLA-4 pathway is a key immune regulator whose absence or mutation leads to profound autoimmunity. CTLA-4 and its relative CD28 have opposing inhibitory and stimulatory functions respectively and interact with two ligands CD80 and CD86. Despite the key role of this pathway in immune regulation and high profile therapies in tumour immunology, our understanding of how CTLA-4 functionally interacts with its two natural ligands is remarkably incomplete. The aim of this proposal is to generate a robust molecular, cellular and functional framework for CTLA-4 biology which can be used to understand the impact of disease mutations, which are being identified as a result of next generation sequencing programmes, and generate knowledge which can underpin new approaches to manipulation of this key immune axis. We will address three key aims: 1). What is the cellular machinery used by CTLA-4 to capture and transfer ligands between cells? 2). How do CTLA-4 interactions with its natural ligands influence its function? 3). How do clinically identified mutations inform our understanding of the CTLA-4 pathway?
The CUSSH programme will deliver strategically vital global research on the complex systemic connections between urban development and health. Based on transdisciplinary methods, it will develop critical evidence on how to achieve the far-reaching transformation of cities needed to address vital environmental imperatives for population and planetary health in the 21st century. Its core components include: a systematic review of evidence on potential solutions; the development and application of methods for tracking the progress of cities to towards sustainability and health goals; the development and application of models to assess the impact on population health, health inequalities, socio-economic development and environmental parameters of alternative urban development strategies to support policy decisions; iterative in-depth engagements with stakeholders in partner cities in low-, middle- and high-income settings, based on participatory methods, to test and deliver the implementation of the transformative changes needed to meet local and global health and sustainability objectives. Through these steps, the project will provide transferable evidence on how to accelerate actions essential to achieving population-level changes in such areas as energy provision, transport infrastructure, green infrastructure, water and sanitation, and housing. Associated public engagement and training, based on principles of co-generation of research, will be embedded throughout.
Cellular and network mechanisms of hippocampal -prefrontal coordination during memory consolidation 09 Nov 2016
Consolidation of newly acquired memories takes place during sleep and involves the interaction of hippocampus and prefrontal cortex. The cellular mechanisms and synaptic pathways underlying this process are not fully understood but it has been hypothesized that synchronous hippocampal ripples and prefrontal cortex spindles mediate it. The present project proposes a multimodal approach to investigate these mechanisms in rodents. The first goal will be to dissect the fine-scale dynamics of memory reactivation in hippocampus and cortex during sleep after learning of a spatial memory task. This aim will be achieved with simultaneous large-scale recordings in both structures and advanced analysis of population activity. The second goal will be to unveil which anatomical regions and synaptic pathways are mediating this inter-regional synchronization. Simultaneous electrophysiological and functional magnetic resonance recordings will be performed in sleeping rats before and after the task and wide-brain activity will be assessed at times of high hippocampal-prefrontal synchrony. The last goal will be to causally verify the participation in inter-areal coordination and memory consolidation of the key synaptic pathway(s) pointed out in the previous stage. To achieve this, closed-loop optogenetic silencing of specific cellular populations would be performed at times of hippocampal-prefrontal synchrony during sleep memory consolidation.
The regulation of social behaviour in bacteria is key to several phenomena of medical relevance, including biofilm formation and the expression of virulence in pathogens. Specifically, quorum sensing is the chemical communication process bacteria use to coordinate changes in their collective behaviour in response to population density. A current challenge in the field is to understand how quorum-sensing works in scenarios that mimic real host environments, where spatial patchiness is omnipresent. In a recent Nature Communications article, I demonstrated that patchiness makes an active matter system – a system of self-propelled elements, such as motile bacteria – switch between gathering and dispersal of individuals. Using a novel combination of methods from microfabrication, advanced microscopy and molecular biology, the aim of this proof-of-principle project is to unambiguously demonstrate for the first time that bacterial quorum sensing can be triggered by similar dynamics of gathering and dispersal induced by spatial features in the environment. The validation of such a hypothesis will enable me to bridge my current expertise with a new long-term research programme on the effects of the environment on different, exciting quorum-sensing related phenomena. Examples include biofilm formation and development, antimicrobial resistance, host-pathogens interactions, and the expression of virulence.
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.
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.
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.
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.
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.
The research project represents an initial investigation into the role of the diverse components of the ventral hippocampal circuitry in the context of social interaction. The aim is to explore a potential correlation between complex behavioural patterns observed during social interaction tasks and degree of activation of ventral hippocampal neurons. Behavioural assessment will only be carried out on single housed male mice to avoid sex-specific differences. During my experiments I will compare two contexts. First, as a control, mice will be placed in a test chamber with a novel object. Second, social interaction will be tested by introducing a juvenile male. The behavioural patterns generated will be scored and compared both qualitatively and quantitatively. After 90 minutes, the degree of activation of distinct ventral hippocampal areas (CA1, CA2, CA3, Dentate Gyrus and Subiculum) will be tested in each of these groups of mice using expression of the immediate-early gene c-fos (which is correlated to neuronal activation), by optimising immunohistochemical detection in the lab. I will then aim to establish the involvement of the ventral hippocampus in social interaction by using fluorescent microscopy analysis, followed by appropriate statistical testing between the control and social groups.
Structural Basis of Gabapentinoid Drug Action 01 Apr 2016
Gabapentinoids are blockbuster drugs used to treat conditions including neuropathic pain and epilepsy. They act by binding alpha2delta voltage-gated Ca2+ channel subunits. The focus of this summer project is to investigate the structure of alpha2delta to help understand its role in presynaptic Ca2+ entry and reveal the molecular basis of gabapentinoid binding. We have developed constructs for alpha2delta expression in High5 insect cells and HEK293T eukaryotic cells. We will express and purify different regions of alpha2delta, taking advantage of enzymes at our disposal for modifying glycosylation and pre-protein cleavage. Co-crystallisation screens will be set up with natural and synthetic small molecules including pregabalin and gabapentin. Successful crystal hits will be tested for x-ray diffraction using an in-house x-ray source. In the final fortnight of reserach, the student will perform crosslinking coupled to mass spectrometry experiments to determine the interaction sites of different subunits within the calcium channel complex, depending on the progress of crystallisation experiments.
Background The mechanisms driving ketamine’s efficacy in treatment-resistant depression are unknown, but this treatment has been shown to elicit changes in the brain’s reward system. Together with the observation that anhedonia is specifically alleviated by ketamine, this finding has prompted the hypothesis that changes in brain and behavioural processes related to motivational processing may be important in the antidepressant action of ketamine. Main hypotheses Changes in motivational processes underlie the anti-anhedonic effect of ketamine in depression. Depressed patients experiencing a greater antidepressant response should exhibit greater neurocognitive changes in motivational processes following treatment. Research and educational goals - Method: Simultaneous fMRI+EEG imaging pre-, during, post- repeated ketamine administration and at 4 week follow-up. - Educational outcomes: Multimodal scanning, computational modelling, establishing task psychometrics. - Method: Behavioural testing in healthy and depressed individuals pre- and post- ketamine infusion combined with high-resolution fMRI. - Educational outcomes: fMRI data collection and connectivity analyses. Potential time line of proposed research Year 1 UCL: Develop behavioural tasks and neuroimaging methods; initiate tasks at the NIMH. Year 2 NIMH: Run tasks in healthy and depressed individuals during ketamine infusion and concurrent fMRI+EEG imaging. Year 3 NIMH : Retest patients at phase 3 and 4. Year 4 UCL: Neuroimaging analyses and writing thesis. Year 4 UCL: Neuroimaging analyses and writing thesis.
Our research has made major contributions to understanding the natural history and pathogenesis of human cytomegalovirus (HCMV) in allograft recipients. Critically, we have demonstrated that biomarkers can be applied to stratify patients most at risk of HCMV disease and thus inform clinical practice to reduce HCMV end-organ disease. This clinical approach of administration of antivirals to individuals with elevated viraemia above designated levels provides a unique opportunity to gain fundamental insight into disease processes in a human challenge model of HCMV infection. A multi-disciplinary consortium has been recruited to apply next generation DNA sequencing, molecular virology and functional immunological assays to identify virus and host cell determinants of disease susceptibility. Whole genome sequencing of virus in organ donors (live and cadaveric) and recipients will be used to track the source, replication kinetics and evolution of HCMV strains in seronegative and seropositive recipients. We will then define in vitro humoral, cell-mediated immunity and natural killer responses against HCMV that correlate with protective immunity against primary infection, reinfection and reactivation in these patient groups. This approach has the potential to provide unique insights into the natural history and pathogenesis of HCMV and identify innovative therapeutic approaches against it.
My current and previous Wellcome Trust Fellowships (Henry Wellcome, 2009-13; Henry Dale 2014- present) focus on important aetiological questions about psychotic disorders, using epidemiological data. Psychotic disorders are a debilitating set of mental health disorders, characterised by hallucinations, delusions and cognitive deficits. My research demonstrates that these disorders have a robust, replicable social aetiology, with higher incidence rates observed in young people,1–3 men,1–3 ethnic minorities2–7 and people exposed to greater social disadvantage.8–11 In my previous fellowship, I established the largest epidemiological study of first episode psychosis [FEP] in England since 1999, to demonstrate that these substantial mental health inequalities also exist in more rural populations (East Anglia)3,12; rates are over twice as high as expected,3,13 with deprived rural communities experiencing the highest psychosis incidence. This study has generated new Page 5 of 18 aetiological clues, for example by showing that people at "ultra-high risk" of psychosis are exposed to similar social and spatial markers of social disadvantage as FEP patients,14 implicating an aetiological role for social adversities prior to onset. I have also demonstrated that migrants face greatest FEP risk when immigrating in childhood,15 an important period of sociocognitive development. I am attempting to replicate this in my current Fellowship, in a larger longitudinal cohort using Swedish national register data. Using this data, I have already shown that refugees are at elevated psychosis risk compared with other migrants from the same region of origin,7 providing further insights into the possible social determinants of psychosis. Epidemiological data can also inform mental health service planning. In England, Early Intervention in Psychosis [EIP] services assess and treat people with suspected FEP, offering evidence-based multidisciplinary care to improve downstream clinical and social outcomes, shown to be highly costeffective.16 Unfortunately, original policy implementation guidance17 made no provision for the heterogeneity in incidence described above, with services commissioned on a uniform expectation of 15 new cases per 100,000 people-per-year. This was at least half the true incidence,1,3 and over three times lower than the overall referral rate for all suspected FEP, including "false positive" (nonFEP) referrals,3 who still require appropriate psychiatric triage and signposting, and consume additional EIP resources not factored into original guidance. In response, I demonstrated that epidemiological estimates of psychosis risk could be used to better predict the expected FEP incidence in the population at-risk in England,13 nationally and regionally. The tool, known as PsyMaptic, has had substantial impact on policy and commissioning since it was freely-released in 2012 (www.psymaptic.org).16,18–22 Most recently, it has been used to inform national EIP workforce calculations23 following the introduction of Access and Waiting time standards,19 as part of the Department of Health’s commitment to achieving parity of esteem between mental and physical health by 2020.24 Whilst I have demonstrated, via PsyMaptic, that it is possible to translate epidemiological data into effective public mental health,25 some vital methodological limitations require empirical attention. I therefore seek Wellcome Trust enhancement funding to answer four empirical questions to develop and apply novel statistical prediction methodologies to generate sustainable, dynamic populationbased models of future mental health need.
Life history of an organizer: what determins transient orgnaizer function in Hensen's node? 30 Sep 2016
The "primary organizer" of the vertebrate embryo is a group of cells at the gastrula stage which is able to induce a complete patterned nervous system when transplanted to another site. However, the position in the embryo where the organizer is located only has these properties for a short time. This time corresponds to when two particular populations of cells ("central epiblast" and "posterior deep") come together. After this, as cells leave to form the prechordal mesendoderm, organizer ability is lost again. The aim of this project is to find out whether the organizer function of Hensen's node is the sum of properties that exist in separate cell populations or whether new properties are generated by interactions between them, and thus determine how dynamics of these cells contribute to the transient nature of organizer function. Cell dynamics will be studied using carbocyanine dye (Dil and DiO) labelling of the 'central' and 'posterior' populations to identify their contributions and roles in the organizer. These populations, individually and combined, will be assessed by studying their transcriptomes by RNA sequencing. Their organizer function will then be assessed, in time-course, by the gene expression profiles in cells receiving signals from these populations
Coordinated neural tube closure: The role of biomechanical properties in directing neuropore 30 Sep 2016
Neural tube (NT) closure is a morphogenetic event of vertebrate development that results in severe birth defects (e.g. spina bifida) when disturbed. The key genes/pathways of neurulation have been studied extensively, but many aspects of the developmental mechanisms remain unclear. This project addresses two questions: (i) how is neurulation linked mechanistically with the process of axial elongation, which accompanies spinal closure in higher vertebrates, and (ii) how/where do tissue-level biomechanical forces arise that drive NT morphogenesis? Neuro-mesodermal progenitors (NMPs) generate both neuroepithelium and mesoderm during axial elongation, and will be fate-mapped in the NT of cultured mouse embryos. Single-cell labelling by photo-conversion of cells expressing the Dendra2 construct will reveal the timing of neural commitment in NMPs. Requirement for NMPs in NT closure will be assessed in embryos mutant for Grhl3, a gene expressed in NMPs and where loss- or gain-of-function causes spina bifida. Biomechanical forces in the closing NT will be detected by electroporating a FRET-based mechanosensor that reports stress in cytoskeleton-linked proteins (e.g. alpha-actinin). Embryo manipulations (e.g. closed NT incision) will be tested for effects on FRET-reporter activity to identify the origin of closure forces, while mutant embryos developing spina bifida will be assessed for altered force distribution.
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.
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