- Total grants
- Total funders
- Total recipients
- Earliest award date
- 10 Apr 2001
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Future of Animal-sourced Foods (FOAF) 06 Oct 2016
Changes in the amount and type of animal-sourced food (ASF) we consume, and in the way they are produced, are critical drivers of global human health and environmental quality. The project will develop novel policy tools and interventions to allow more informed and effective action to be taken to maximise the health and environmental co-benefits of changes in ASF consumption. We shall build a quantitative food system model incorporating economic, health and environmental modules that will allow the effects of existing drivers and novel policy interventions to be assessed. We shall exploit unique epidemiological resources to provide new evidence about how different types of ASF affect health, and conduct experiments to develop new interventions to influence the consumption of ASFs and ASF substitutes. A social-science component will research how social norms and political economic factors affect the practicality and acceptability of interventions, and how this may be changed. The effects of different types of ASF production on climate change, water use and quality, and ecosystem functions will be measured and brought together for the first time. The project will develop a distinct work stream in China and engagement with multiple audiences will be integral to all its activities.
Investigating the role of Kv1.6 in pain pathways 31 Jan 2017
Kv1.6 is a member of the Shaker-like Kv1 potassium channel protein family. Widely expressed in the nervous system, these channels have delayed outward rectifier properties and evidence indicates that they act to suppress action potential firing. In the field of neuropathic pain, of which neuronal hyperexcitabilty is a common hallmark, these channels are of interest as their malfunction or downregulation may contribute to the disease pathophysiology. While less is known of Kv1.6 than other subunits of the same family, it has recently been reported that this channel is upregulated following nerve injury, signifying some role for Kv1.6 during the time after injury. Pharmacological inhibition at this stage indicates a functional role for Kv1.6 in restoring hypersensitive pain thresholds somewhat towards more normal values. Having already conducted some preliminary research on the Kv1.6 knock-out mouse, I will employ various in vivo, ex vivo and in vitro techniques from behavioural chronic pain models to electrophysiology, calcium signalling and gene/protein expression analysis in order to further probe the importance of this channel in health and disease, and to determine its sites of action amongst the various neuronal populations along somatosensory/pain pathways in the peripheral and/or central nervous system.
Chemogenetic silencing of nociceptor populations 31 Jan 2017
Nociceptors are heterogeneous sensory neurons and due to single cell sequencing, our understanding of their diversity is expanding. To understand which nociceptor populations are responsible for different pain-related behavioural phenotypes, we aim to employ a chemogenetic silencing tool to allow reversible inhibition of selected cells in vivo. Our chemogenetic tool of choice is the mutated glutamate-gated chloride channel (GluCl). Initially, we expressed the channel in cultured DRG neurons and using patch-clamp recordings observed dose dependent silencing upon application of the agonist ivermectin (IVM). We have optimised the channel and assessed channel functionality in vitro and in vivo following AAV-mediated delivery. Behavioural assays suggest IVM treated animals had significantly elevated pain thresholds compared to vehicle treated mice. Using rodent pain models (SNI, CCI) in conjunction with conditioned place preference tasks, we aim to further establish this method of nociceptor silencing as a potential therapeutic. Furthermore, to understand nociceptor heterogeneity our first target population will be the A-delta nociceptors. Using transgenic strategies we hope to selectively express GluCl in A-delta nociceptors and perform electrophysiological and sensitive behavioural assays pre and post IVM treatment. Ultimately this project aims to facilitate the discovery of novel nociceptor populations, their roles and their therapeutic potential.
This PhD focuses on developing statistical methods to discover gene – environment (G-E) interactions. To date there has been some interest in testing for G-E interactions in animal models, but limited success in uncovering examples of G-E interactions in humans. This is in part due to the problem of exposure assessment, or rather, because representative data on the environment of a number of individuals over a lifetime has been hard to acquire. However the data recently made available by the UK BioBank, on over 500000 individuals and a wide array of environmental covariates, may now make it possible to detect these interactions. We aim to use a Bayesian methodology to first test a number of known models, such as a random effects model, against the dataset. We will then attempt to use a Gaussian Process Regression model to identify covariates involved in G-E interactions. This approach is advantageous as GPR is non-parametric, thus avoiding the curse of dimensionality, and places no assumptions on the order of interactions. However as this method currently scales in a cubic manner following the number of samples, significant computational challenges remain.
Diversification of mesoderm and endoderm subtypes occurs at the outset of mouse gastrulation as epiblast cells migrate through the primitive streak (PS). The underlying inductive signals, gene-regulatory networks, and epigenetic modifications that direct lineage diversification at this early stage remains ill-defined. The aim of this project is to dissect the molecular mechanisms that underpin cell fate diversification, as cells egress the PS, by investigating the function of T-box transcription factors (TF), Eomesodermin (Eomes) and Brachyury (T). Eomes and T are expressed in the PS and Eomes is required for specification of cardiac mesoderm (CM) and definitive endoderm (DE). Single cell lineage tracing and RNA-seq experiments will be completed to define the potency and heterogeneity of Eomes and T expressing progenitors. The functional role Eomes plays in haematopoiesis will also be investigated using multiple gain and loss of function experiments. Finally, we will investigate context dependent Eomes binding sites and interacting partners. Eomes tagged mouse embryonic stem cells (mESC) will be differentiated into CM or DE progenitors and with them we will perform ChIP-Seq, RNA-Seq and immunoprecipitation-mass spectrometry(IP-MS). The experiments proposed will help resolve the functional and molecular roles T and Eomes play during early stages of lineage diversification.
The role of intra-area and inter-area neuronal interactions in the formation of perceptual decisions 31 Jan 2017
Humans and animals have to make decisions based on the integration of sensory information in order to thrive. In primates, neuronal activity in sensori-motor parietal area LIP has been proposed to reflect the accumulation of sensory information from a range of areas to make a perceptual decision. The change in firing rates has been described as an integration process with a diffusion-to-bound model or alternatively as step-like changes. This project aims to gain a better understanding of the neuronal processes underpinning perceptual decision-making and to test the universality of the proposed models. Simultaneous recordings with multiple probes from cortical areas LIP and V5/MT while animals solve a stereo-motion task will measure neuronal interactions (i) within LIP and (ii) with V5/MT. Extrastriate visual area V5/MT is important for the perception of motion as well as stereovision and has anatomical connections with LIP. Combined electrical stimulation and recording will establish the interaction of signals between these areas. I will also incorporate contextual effects into task and model to develop a realistic network model of how decision signals arise and shape cognitive function. This model can be applied to and tested with other brain areas and cognitive tasks.
Defining how different types of midbrain dopamine neuron mediate behaviour in the contexts of reward and aversion 31 Jan 2017
Learning the value of actions based on prior experience is critical for adaptive behaviour. Rewarding and aversive stimuli have opposite motivational valence, with evidence suggesting that the phasic firing of distinct groups of midbrain dopamine neurons differentially encodes reward and aversion as a function of their projection target. My first research aim is to elucidate the molecular signatures of subpopulations of dopamine neurons innervating the nucleus accumbens or prefrontal cortex. To achieve this, I will combine injections of retrograde tracers with immunofluorescence revelation of molecular markers in mice. My second aim is to determine how distinct types of dopamine neuron, as defined by their specialised molecular profiles and projection targets, encode behaviour. To achieve this, I will carry out recordings of individual molecularly-identified neurons in head-fixed mice as they perform a classical conditioning task incorporating rewarding and aversive events. My third aim it to elucidate a causative role for a specific subpopulation of dopamine neurons in behaviour. To achieve this, I will use an optogenetics-based approach to inhibit these neurons in behaving mice. Overall, this research project is predicted to advance understanding of how different subpopulations of midbrain dopamine neuron subserve behaviour in the context of reward and aversion.
Mucosal-associated invariant T (MAIT) cells are innate-like T cells that express a semi-invariant, MR1-restricted, T cell receptor (TCR). In humans, they comprise 1-10% of peripheral blood T cells and are enriched at mucosal sites. MAIT cells display characteristic expression of several surface molecules and transcription factors, and a typical cytokine response to stimulation. Therefore, they have been regarded as relatively homogeneous. However recent evidence indicates diversity in TCR expression and function that varies between tissues and individuals. Further investigation is required to understand the extent of MAIT cell heterogeneity and tissue-specific functionality. In several human autoimmune and inflammatory diseases, MAIT cells are activated or show phenotypic changes. How the altered cytokine environment in such diseases can modulate MAIT cell function remains to be determined. The key goals of my research are to provide a comprehensive assessment of diversity and plasticity in MAIT cell function, and to understand the factors that regulate this. To achieve this, I will use a combination of approaches including single-cell mRNA sequencing and epigenetic analysis, and will explore MAIT cells from varied settings encompassing resting and activated, tissue-localised, and disease-associated MAIT cells. This will provide important insights into their physiological role both in health and disease.
The evaluation of effective healthcare delivery in China using electronic medical records for 10 years in 0.5M participants in the China Kadoorie Biobank 02 May 2017
This DPhil project will assess the social determinants and equality in hospital care delivery and use, in 0.5 million participants who have been followed up for 10 years in the China Kadoorie Biobank. The first goal of this research is to evaluate differences in the annual rates of people hospitalised, the annual rates of hospital admissions per person, and the average length of stay (ALOS) overall and for 10 of the most frequent causes of hospitalisation (5 mostly unavoidable and 5 mostly avoidable causes) over the last 10 years and by region, hospital-tier, type of health insurance (HI) package and socioeconomic characteristics. Another goal is to study the variation in hospital care costs in China, considering LOS, and use of specialised procedures and major treatments, overall and for the 10 most frequent causes of hospitalisation over the last 10 years, by region, hospital-tier, HI package, and socioeconomic characteristics. Finally, the inequalities behind the variation in use and costs of hospital care will be investigated across regions, HI package and socioeconomic characteristics. This will provide the reliable quantitative evidence to evaluate operational defects and plan initiatives to improve healthcare delivery by individual hospitals, HI organisations and the wider community in China.
Epidemiology and health burdens of antimicrobial resistant bacterial infection in Southeast Asia and impact of antibiotic use on patient survival 19 Jun 2017
Epidemiology of drug-resistant infection (DRI) and impact of antibiotic use on patient mortality remain largely unknown in Southeast Asia. Correction factors are crucial to estimate the total deaths attributable to DRI when only mortality of patients with bacteraemia is known. The correction factors are available for developed country and not for developing country. I aim to establish correction factors for developing country. I also aim to study the epidemiology of drug-resistance and estimate the number of excess deaths attributable to DRI in Southeast Asia. Most studies on the impact of inappropriate antibiotic use on mortality were conducted in high-income countries, and methods used were vulnerable to biases. Neglecting both the time-varying nature of contributing factors; including risk of DRI over time, and the effect of antibiotic overuse on risk of DRI in other patients could misestimate the impact of antibiotic use on patient mortality. I aim to use advanced statistical models to overcome the potential biases, and to estimate and compare the impact of appropriate and inappropriate antibiotic use in Thailand and Vietnam against that in the United Kingdom where antibiotic stewardship is well established. These are important to assist designing and assessing of antibiotic stewardship programme in developing countries.
The MYRIAD Project: Exploring Mindfulness and Resilience in Adolescence
In 2015 the WT Major Overseas Programme Vietnam was awarded a renewal of its Core funding. The MOP has a history of successful public engagement, funded through International Engagement awards and from industry sponsorship. However, with the introduction of the Provisions for Public Engagement funding scheme, we applied for funding for engagement at an institutional level, enabling us to create a 5-year strategic plan for developing engagement capacity within the MOP and in the region. Now, 20 months into the award, we reflect on activities to date, and plan strategically for the second part of the programme. The 5-year public engagement programme includes a schools engagement programme (SEP) and a capacity building programme (CBP), both of which have proved to be very successful and highly valued by our local government and school partners. The third focus has been to develop researcher capacity for engagement – through small grants and offering training and mentoring. We have had a good uptake of these ‘seed awards’ from MOP researchers and increasing interest in engagement from researchers at local institutes in Vietnam. Schools Engagement: The SEP has been very successful (http://www.mediafire.com/file/td3kaomtu9t7ia7/Application.7z), in particular: afterschool science clubs; weekly science articles in a children’s magazine; science theatre; and lab visits enabling young people to interact with scientists. The SEP has also included ‘I’m a scientist, Get me out of here’ - a competition linking children and scientists, run with Gallomanor UK (https://imascientist.org.uk) (https://www.youtube.com/watch?v=n--SJOtFm1w). Capacity building: The CBP was developed in recognition that much of the ‘front-line’ contact with patients and communities enrolled in clinical trials or cohort studies is from hospital or government study staff. In response we have started a CBP to train and support hospital health care workers (HCMC), community-based data collectors (Nepal) and local vets (in provinces where we conduct research on zoonosis). As the funding for the IAS project and other awards come to an end, we need additional funding to support the current PE team. This application is for additional staff salary costs and to run PE workshops to develop engagement capacity across the region.
T cells orchestrate immune responses crucial for the elimination of infections and cancers. They do this by initiating a diverse set of effector responses when their T cell surface receptors (TCRs) recognise these threats. It is now appreciated that a large number of other, "accessory", receptors shape these responses. Indeed, the remarkable clinical success of checkpoint inhibitors and chimeric antigen receptors is based on perturbing accessory receptor signalling. Despite extensive research into the underlying biochemistry, we have yet to formulate canonical models of signalling that can predict how accessory receptors shape T cell responses. Here, we propose to use a mathematical method known as adaptive inference to identify signalling models directly from T cell response data, without prior biochemical assumptions. The method produces what we term phenotypic models because it coarse-grains over molecular information. These models provide effective pathway architectures showing how accessory receptors integrate (or not) with TCR signalling to shape response phenotypes. This will move the field beyond the current stimulatory/inhibitory binary paradigm of accessory receptors. The work offers a different way to study receptor regulated signalling pathways and the predictive power of the phenotypic model will be exploited for T cell-based therapies.
Decision-making by lymphocytes 11 Jul 2017
It was recognized sixty years ago that a "trigger mechanism" must initiate immune responses. Today, however, not even the broad features of the mechanism are fully agreed, despite its intrinsic scientific interest and the remarkable clinical utility of modulating lymphocyte behaviour. We do know, however, that it encompasses two separate events: receptor triggering per se, and the integration of multiple triggering outputs. Breakthrough developments in fluorescence imaging mean that we can now study molecular behaviour at cell-cell interfaces at single-molecule resolution, in real time. This means that we can directly test whether TCR triggering is explained by a theory relying on the local, physical exclusion of phosphatases from sites of receptor engagement and phosphorylation, called the kinetic-segregation model. We will explore how 'close-contact' formation affects the interplay of local signaling molecules, and test our theory using quantitative models of receptor signaling. We will also study the emergent properties of the types of modular networks known to mediate downstream signaling in T cells and, building on these findings, test a new, simple theory of signal integration. This programme of work will produce a fuller understanding of decision-making by lymphocytes, and a richer framework for thinking about immunotherapy.
Studying the molecular mechanisms of mutagenesis is crucial to understanding genome evolution and the emergence of drug resistance in pathogens. It is known that cellular stress responses increase mutation rates after DNA damage and antimicrobial treatment. Recent evidence suggests that stochastic effects play key roles in these responses, causing cell-to-cell variation in mutation rates and diversifying cell phenotypes to evade drug treatment. However, existing cell biology, biochemistry, and genetics assays fail to resolve mutation rate dynamics and cellular heterogeneity. By combining live-cell single-molecule microscopy, single-cell manipulation, and DNA sequencing techniques, I will bridge the divide between molecular-level and genome-level approaches. I will visualise mutagenic molecular processes in real-time and link them to genome sequence changes in individual bacterial cells. Ultimately, I will discover how individual mutation events are related to single-cell phenotypes such as DNA repair activities, stress responses, and growth characteristics. My focus will be on the conserved SOS response that globally regulates genome maintenance and has been implicated in the bacterial response to antibiotics. Using a novel method to quantify post-translational modifications of the master SOS regulator, I will uncover the molecular choreography of the SOS response and establish how it contributes to the evolution of antibiotic resistance.
Neural circuits display complex spatiotemporal patterns of activity on the millisecond timescale. Understanding how these activity patterns drive behaviour is a fundamental problem in neuroscience. To address this challenge, I have recently introduced a novel approach that combines simultaneous two-photon calcium imaging and two-photon targeted optogenetic photostimulation with the use of a spatial light modulator (SLM) to provide 'all-optical' readout and manipulation of the same neurons in vivo. I propose to probe the neural code in mouse barrel cortex during sensory-guided behavioural tasks by using this approach to uncover the underlying mechanisms of decoding and encoding of information by ensembles of neurons. I will train mice to make perceptual decisions based on quantitative control of cortical activity, as well as perturb neural activity in somatosensory cortex while animals are performing discrimination tasks using their whiskers. I can perform decisive tests of theoretical models describing the neural code by assessing the spatiotemporal pattern of activation required in somatosensory cortex to drive a behavioral response. These experiments will shed light on how many neurons with which functional signature are minimally sufficient to subserve a percept.
Real-time genetic cartography of viral epidemics 26 Oct 2016
Predicting the course of an epidemic following its emergence remains one of the greatest challenges in infectious disease control. Although rapidly evolving viruses frequently threaten global public health, uneven surveillance efforts can obfuscate predictions of virus dynamics across local, regional and global scales. Genomic epidemiology is currently being revolutionized by the "real-time" sequencing of whole virus genomes in the field within days. Yet empirical datasets are often biased or hampered by limited analytical tools, potentially biasing inferences of viral dynamics and hindering predictions useful for outbreak control. To address these problems, I propose to develop a framework, termed ‘genetic cartography’, aimed at unifying the evolutionary analysis of viral genomes with medical surveillance data, high-resolution geographic measurements, and real-time human mobility data. The proposed research will deliver a statistical framework that unifies genetic, epidemiological and cartographic data in order to: 1) determine the impact of ecological and epidemiological drivers on the historical spread of RNA viruses across spatial scales, mobility networks and social groups; 2) incorporate metrics of human movement to infer present patterns of virus diversity and transmission; and 3) combine real-time genetic and mobility measures to deliver accurate future predictions of virus movement and disease burden.
The antibody response against Plasmodium falciparum-infected erythrocytes (IEs) has been associated with protection against malaria, but the characteristics of this response at the monoclonal antibody level remain an open question. We have recently developed a high-throughput platform to isolate monoclonal antibodies against IEs that allowed us to identify novel LAIR1-containing antibodies that target RIFINs on the IE surface (Tan et al. 2016, Nature). Here, we propose to use this technology to interrogate the immune response of well-characterized malaria-exposed Malian individuals against IEs at the monoclonal antibody level. We plan to: a) compare the responses of naturally protected and non-protected individuals to identify potential signatures of protection, b) isolate antibodies that broadly target late-stage IEs and identify novel conserved antigens as malaria vaccine candidates, and c) study the repertoire of LAIR1-containing antibodies in Malian individuals. We believe that this plan is feasible, as we have obtained preliminary data suggesting that several Malian plasma recognize the majority of late-stage IEs and that a sizable proportion (5-10%) of these individuals possess LAIR1-containing antibodies. From this work, we hope to identify aspects of the antibody response that protect malaria-exposed individuals, potentially including broadly reactive antibodies against conserved IE antigens.
Human sensitivity to short-wavelength light in non-image-forming vision: Toward a mechanistic understanding of the impact of blue light on sleep and circadian rhythms 09 Nov 2016
Short-wavelength (blue) light takes priority in many functions associated with the non-image-forming (NIF) visual system, including pupil size and regulation of melatonin secretion. The human retina contains two short-wavelength sensitive photoreceptors: the blue-sensitive (S) cones (~440 nm) and the recently discovered photopigment melanopsin (~480 nm) expressed in a subset of retinal ganglion cells. Previous research has focused on the melanopsin contributions to NIF responses, but very little is known about how S cones contribute to and interact with melanopsin in these functions. Using the method of silent substitution which allows for the selective isolation of photoreceptor classes and by studying patient groups with S-cone anomalies, we will study the S cone and melanopsin inputs into pupil control and circadian mechanisms. In Aim 1, S cone and melanopsin inputs into the pupil will be characterised in controls and S-cone patients and related to sleep-wake actigraphy. In Aim 2, the spatial topography of S cone and melanopsin pupil inputs will be characterised using a novel spectral-spatial modulator. In Aim 3, S cone and melanopsin inputs into melatonin suppression will be characterised. In short, we will systematically characterise the receptor mechanisms that mediate the effect of short-wavelength light on circadian regulation in humans.