- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 30 Sep 2017
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
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.
Pain in infancy has negative long-term consequences and its prevention is a clinical priority, but adequate treatment requires mechanistic understanding of the structural and functional development of human nociceptive circuitry. Recent scientific and technological advances provide insights into how noxious information is transmitted to the infant brain, providing a platform to ask how intrinsic brain network connectivity and the environment affect noxious-evoked brain activity, behaviour and ultimately pain perception in the developing infant nervous system. The fellowship goal is to understand the mechanisms that drive and modulate pain perception in early human development. I will ask whether inherent differences in how the brain behaves at rest influence variability in noxious-evoked activity, and will determine how this relationship is altered by environmental factors and pathology. I will establish how the development of structural and functional network connectivity alters noxious-evoked brain activity, and influences the dynamic relationship between brain activity and behaviour. I will translate this mechanistic understanding into clinical practice by conducting a clinical trial of an analgesic (fentanyl) during a minor surgical procedure, and will establish whether our newly-developed measures of noxious-evoked brain activity are suitable for use in infant analgesic dose-finding studies.
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.
Bone Morphogenetic Protein signalling and stromal-epithelial interaction in intestinal inflammation and carcinogenesis. 05 Apr 2017
The intestinal mucosa is a complex ecosystem and the epithelium has a dynamic relationship with underlying stroma. Key aspects of intestinal homeostasis and disease states, including inflammatory bowel disease and cancer are characterized by the interdependence of the epithelial and stromal compartments. Inter-compartmental cell-signalling pathways regulate intestinal epithelial cell fate determination in homeostasis, and transient perturbation of these networks is required in the physiological response to inflammation and injury. This promotes epithelial stem cell behaviour, cell proliferation and migration as part of a wound healing response. However, failure of restoration of homeostatic control in chronic inflammation, or pathological disruption of signalling can result in neoplasia initiation and progression. In resultant tumours, optimally selected somatic mutation spectra differ and reflect these variable influences on lesion pathogenesis. This proposal will explore these concepts using disruption in Bone Morphogenetic Protein signalling and it's pleiotrophic antagonist Gremlin1, as exemplars of the paradigm. Specific goals include: 1. Identifying stromal cell populations expressing Grem1 in intestinal regeneration and tumour desmoplasia. 2. Assess the functional role of BMP disruption in these conditions. 3. Using mouse models to test therapeutic manipulation of BMP signalling. 4. Using somatic mutation analysis to generate molecular biomarkers of Grem1 initiated tumourigenesis.
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.
Mechanisms by which missense variants in myosin and myosin binding protein C alter cellular contractility in genetic cardiomyopathies. 19 Apr 2017
Summary: The cardiac sarcomere is a multi-protein complex essential to cardiac contractile function. Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are caused by pathogenic variants (PV) in sarcomere protein genes. Variants in genes directly involved in cellular contractility MYH7 (beta-myosin heavy chain), MYH6 (alpha-myosin heavy chain), and MYBPC3 (Myosin binding protein C) are either known or hypothesised to cause disease. Previous analyses of the mechanisms by which variants cause disease have relied on rodent models and extrapolation from clinical data. The introduction of clinically defined mutations into human iPSC-CMs using CRISPR/Cas-9 would allow the interrogation of these cellular phenotypes in a human background using molecular and mechanical strategies, adding clarity to the uncertainties of variant-phenotype relationships in these genes. Key goals: i) Interrogation of the molecular and biophysical (contraction and relaxation) mechanisms by which PVs in MYH7, MYH6, and MYBPC3 cause either HCM or DCM. ii) Define the contractile mechanism of MYH6 and MYH7 PVs to establish if they mirror one another. iii) Investigate if high throughput functional analyses of iPSC-CMs can be used to test individual variants of unknown clinical significance (VUS) to discriminate between those that are disease causing versus ‘benign’.
Utilising snake endogenous toxin inhibitors for the development of improved antivenom treatments 09 Nov 2016
Snake envenoming causes significant annual mortality, predominantly in the developing world. Currently the only effective treatment is antivenom, which is produced by hyperimmunising large animals with crude venom, and then extracting and purifying the antibodies raised against the snake proteins. This method requires keeping and maintaining large numbers of livestock, a key contributor to the high cost. Furthermore, the efficacy of antivenom is completely dependent on the venom sample(s) utilised for production, and the animal-derived antibodies can cause unwanted immunogenic effects in the patient, such as anaphylaxis. This project aims to make steps towards developing new antivenom treatments by utilising the endogenous toxin inhibitors used by snakes to protect themselves from their own venom. First, both the toxin and toxin inhibitor repertoire of 5 species of venomous snake will be elucidated using multi-'omic' technologies. Candidate inhibitors will be expressed in human cell lines, and subsequently tested experimentally to determine their efficacy in neutralising venom effects which cause the most life-threatening pathology. This method will revolutionise the antivenom field, and pave the way to developing treatments which are more cost effective, have fewer side effects, require no live animals, and have a greater and wider efficacy in treating snakebite.
Interactions of membrane proteins with lipids are important in their stability, regulation, and targeting. These interactions are of biomedical importance given the roles of membrane proteins in disease and as drug targets; with drugs often acting via lipid binding sites. We will develop a computational pipeline and database for molecular simulations to predict the structure, specificity, and affinity of membrane protein/lipid interactions. This will provide a unique 'computational biochemistry' resource for functional annotation of membrane protein structures, identifying potentially druggable sites. Building upon our MemProtMD methodology (http://sbcb.bioch.ox.ac.uk/memprotmd/), we will provide a server enabling simulation-based predictions of lipid binding sites to membrane protein structures, defining the structural basis of lipid interactions for each protein alongside predictions of lipid specificity and affinities. We have successfully established proof-of-principle methodologies which allow us to predict and explore free energy landscapes of membrane protein-lipid interactions. This technology needs methodological development to improve the accuracy, applicability, and robustness of predictions of lipid-protein interactions. We will develop a high-throughput software pipeline for lipid annotation of membrane proteins (LipID) for both known and new structures of two major groupings of membrane protein: (i) receptors, channels, and transporters from humans; and (ii) membrane proteins from pathogenic bacteria.
Mechanical testing of tendons and ligaments 27 Apr 2017
The mechanism for collagenous connective tissue damage is little understood. The micromechanics of collagenous tissues is important to understand as it may contribute to injury prevention and be useful in designing treatments for pre existing tissue damage. Bontempi et al in 2009 theorised a relationship between the the probability density function of the stretch value of individual fibrils and the 2nd derivative of stress with stretch. This relationship gained experimental backing in 2016. Recent research suggests that fibrils fail in the order they are first recruited. Combining this model with Bontempi's work suggests fibrillar level damage can be found by performing a stress - stretch test in vivo. However the relationship between order of recruitement and failure is yet to be experimentally proven. A collagen fibril is considered recruited once it is straight enough to bear load and be treated as a Hookean material. During my research I will be tracking fibrils from point of first recruitment to failure. A tensile loading rig will be used with a microscope to image the tendons at different stretch levels.
Assessing the effect of the Xrn1 exoribonuclease on global and specific rates of protein synthesis 27 Apr 2017
Gene expression is a complex process requiring the coordination of transcription, transcript turnover, translation and proteostasis. When coordinated, these processes can be adapted to allow cells to respond to changes in growth rate and during differentiation. How these processes are coordinated remains a long-standing question. The exoribonuclease Xrn1 is proposed to coordinate transcription and translation via control of steady-state RNA levels and may be part of the mechanism. In this proposal we intend to test one aspect of the proposed model: that Xrn1 regulates steady-state RNA levels and this in turn affects steady-state protein levels. We predict that rates of protein synthesis will change as steady-state RNA levels change and this relationship will be disrupted in cells lacking Xrn1. To assess rates of protein synthesis, we will pulse label cells with puromycin and use a specific antibody to assess the degree of global and specific protein puromycylation in the presence and absence of Xrn1. By assessing rates of protein synthesis for specific proteins we will be able to relate this to levels of protein, transcripts and transcription in the WT and xrn1Delta strains, obtain preliminary data to validate our hypothesis and if encouraging to support a larger scale analysis.
The project aims to utilise mutations identified in congenital myasthenic syndromes to study the interactions of the muscle acetylcholine receptor (AChR) and its anchoring protein, Rapsyn.Widely quoted publications suggest that Rapsyn interacts with the M3-M4 intracellular loop of the AChR alpha, beta and epsilon subunits, however we have identified several kinships in which mutations in the M3-M4 intracellular loop of the AChR delta subunit underlie a phenotype that mimics myasthenic syndromes caused by mutations in RAPSN. The project will use in vitro mutagenesis and cell culture experiments to investigate how mutations in CHRND impair agrin induced-AChR clustering in C2C12 myotubes. Variants identified in CMS patients, ie. p.(Glu381Lys) or p.(Arg376His) will be incorporated into expression constructs and transfected in chrnd-/- C2C12 cell that have been created using CRIPR/Cas9 techniques. Similar experiments will be performed following in vitro mutatagenesis that is designed to disrupt potential PKA, PKC and tyrosine kinase phosphorylation sites within the M3-M4 intracellular loop of the delta subunit. The effects of the mutations on agrin-induced AChR cluster formation will be assessed by using fluorecent-labelled alpha bungarotoxin and microscopy. This short project will provide novel data on how mutations within the AChR itself can impair the cluster formation.
In Their Own Voices: Vulnerabilities & Abilities of Women, Children, & Families in Health Research 26 Jan 2016
Efforts surrounding the Millennium Development and Sustainable Development Goals have brought much needed attention to lessening the burden of disease shouldered by women and children, which is most severe in low-income countries. Lasting advances in women’s and children’s health will require improvement of health systems, environment, education, improved access to effective health interventions, including better ways to deliver care in rural, low-income settings. Innovations in each of these areas will require clinical, social science and implementation research. However, many of these women and children are considered to be vulnerable to harms, coercion or exploitation, making inclusion in even potentially beneficial research ethically concerning. While significant strides have been made to develop research ethics guidance for those working with vulnerable populations, critical gaps remain in our understanding of specific vulnerabilities in context, accompanying abilities, the role of social support in mitigating vulnerability, and individuals’ own perceptions of vulnerabilities and abilities. To address these gaps and to improve support and guidance for responsible research with women, children and families, we propose an interdisciplinary collaborative study with investigators in maternal-child health, infectious disease, and social science research across three international sites in the Wellcome Trust Major Overseas Programmes: Kenya, South Africa and Thailand.
The motivation for a second instrument is that it has enhanced capabilities and will permit many critical experiments that are currently not possible. We have contributed to the design stage of this instrument which will be launched in September 2016. This second generation Orbitrap Q-Exactive is capable of performing tandem MS studies to identify lipids bound directly to membrane proteins. With current technology these lipids can be observed attached to the protein but their identification is not possible. Our research group is at the forefront of these developments worldwide and we believe it is important for us to retain this position. not just for UK Science and Technology, but also for start-up companies, UK Biotech and SMEs.
31P magnetic resonance spectroscopy (31P-MRS) has already contributed significantly to our understanding of cardiac metabolism. However, its great promise has so far gone largely untapped because technical limitations require comparatively long acquisitions which have relatively low spatial resolution. The ability to quantify metabolites in each of the 17 cardia segments in under 20 minutes, ideally from a single subject, would represent a step change in the clinical potential of 31P-MRS. To accomplish this, every stage in the protocol for 31P-MRS must be optimised because improvements at each stage are cumulative. Therefore, I propose to address the hardware used for cardiac 31P-MRS, the acquisition pulse sequence, the reconstruction of the acquired data and the post-processing of spectra to estimate metabolite concentrations. The most significant gains are likely to arise by increasing the magnetic field strength from 3T to 7T by employing the UK's first cardiac-capable 7T MRI sc anner, which has just been installed in Oxford, to collect the first cardiac 7T 31P spectra. My proposed visits to leading experts in the USA will build on my existing expertise in 31P-MRS and cardiac 7T magnetic resonance, positioning me well to be at the forefront of future developments in this field.
Assessing the safety of low dose primaquine in Plasmodium falciparum infected African children with glucose 6 phosphate dehydrogenase deficiency 02 May 2016
Malaria remains a major problem in tropical countries, especially in Africa. Insecticide treated bednets and new powerful antimalarial drugs have led to a reduction in the number of malaria deaths. However malaria control remains poor in many areas, and if we are to eliminate and eventually eradicate the disease from the world we will require the use of all the tools at our disposal.One potentially very valuable tool, currently underused, is the antimalarial drug primaquine, which is uniquely able to kill the mature male and female sexual forms of the malaria parasite. Research has shown that primaquine greatly reduces the malaria offspring in the mosquito and thus effectively reduces transmission of the disease. So, primaquine looks to be a good 'transmission blocker' and, if used widely in patients, may reduce malaria transmission and contribute to the elimination of malaria in a community.Unfortunately primaquine has one major disadvantage. It can damage the red blood cells and cause anaemia in individuals who carry a very common genetic abnormality deficiency of an enzyme called glucose-6-phosphate dehydrogenase, G6PD for short. This deficiency is much more common in men because of the way it is inherited. This is called haemolysis. This is a real downside of primaquine, though this problem has mainly been seen when primaquine is given in high doses for many days. However, for its 'transmission blocking' effects on the malaria parasite only a single, low dose of primaquine is thought to be required. This is considered by most experts to be too little primaquine to cause a major problem with haemolysis. Despite this many malaria control programmes are unwilling to use primaquine because they consider it too dangerous. You can test for G6PD deficiency but this requires test kits and staff to administer them. Many countries cannot afford to test millions of malaria patients before giving primaquine. In 2012 the World Health Organization (WHO) concluded on the basis of the available evidence and expert opinion that single low dose primaquine was safe to use even in malaria patients with G6PD deficiency. However the WHO also called for more research.Four years later virtually no one is using low dose primaquine because that research has not been done. If we can show beyond doubt that low dose primaquine is safe in G6PD deficient children with malaria, malaria programmes would feel much happier giving it and we could then go to the drug companies and ask them to make primaquine that is suitable for children.To see if single low dose primaquine is as safe as experts think we plan to study over 1,500 children with malaria attending outpatients in two hospitals in Uganda and one in the Democratic Republic of the Congo. Using a simple test for G6PD deficiency we will find 750 children with malaria who have G6PD deficiency, and 750 who have normal G6PD levels. Within these two groups we will, on a random basis, give half of the patients normal antimalarial treatment and the other half normal antimalarial treatment PLUS single low dose primaquine. We will then watch the children very carefully to see whether giving primaquine causes more anaemia than not giving primaquine, and whether this occurs particularly in the G6PD deficient group. We need to have comparison groups of children who do not receive primaquine and some children who do not have G6PD deficiency as malaria itself causes haemolysis, as can G6PD deficiency in some circumstances even without primaquine treat. Our aim is to unpick the effects of G6PD deficiency, malaria, and primaquine administration to really be sure whether in all circumstances giving low dose primaquine is safe.If this research shows that giving single low dose primaquine is safe, this will enable WHO and national governments to recommend safe treatment regimens that will both cure the patient and also prevent transmission of malaria to other children.
(Pilot) Parenteral interventions to support families of children with neurodisability in low resource settings 16 Nov 2015
I plan to conduct cross sectional surveys in five demographic surveillance sites across sub-Saharan Africa, to identify cases of active convulsive epilepsy (ACE). This cohort will be used to determine the prevalence of ACE and the extent of the number of people not receiving treatment (treatmetn gap) in these sites, identify the causes (particularly parasitic diseases that could be prevented) and establish cohorts of people with epilepsy, from which the magnitude and causes of excess mortality a ssociated with epilepsy can be determined. In addition, a community based intervention will be tested through a randomised cluster trial in one of the sites, to reduce the treatment gap and improve the quality of life of people with epilepsy in this area.
Recent evidence suggests that strictly regulated positioning of specific genetic loci respect to each chromosome territory, could be linked to their transcriptional status. With this study we therefore aim to investigate the relationship between gene positioning and transcriptional activation or repression. In detail, we are interested in following the relative positioningof specific sequences within the X-chromosome during its inactivation. X- Chromosome Inactivation (XCI) is, indeed, the mechanism through which all mammals compensate the different gene dosage between male (XY) and female individuals (XX), and a well-studied model of large-scale time-regulated gene repression. In detail, we will specifically assess the involvement of some candidate genes into this mechanism, such as SmchD1, which is known to be essential for maintaining gene repression on the Inactive-X in a Xist-independent fashion, as well as for a more general maintenance of chromosome structure. Indeed, preliminary data we got in the lab, suggest thatSmchD1 might have a major role in positioning the inactivated genes as soon asthey are silenced during XCI. For this purpose, we intend to take advantage ofsome recently developed techniques, such as 3D DNA-FISH, 4C sequencing and super-resolution microscopy.
Investigating the temporal and spatial dynamics of somatic transposition events in fruitflies and mice. 17 Jan 2014
Ever since the remarkable experiments of early neuro-anatomists such as Santiago Ramon y Cajal we have appreciated the unmatched diversity in shape and structure of neurons within an organism1. In addition, current efforts to study the brain structures of large cohorts of humans reveal a similar degree of diversity between the brains of individuals2. Transposons, mobile genetic elements, have been shown to actively "jump" within the neural genomes, makingthem diverse mosaics3-6. Somatic transposition events might be the source thatintroduces individuality and diversity into a pool of otherwise genetically identical cells7. The goal of this project is to further our understanding of somatic transposition in neurons of fruitflies and mice, and to unravel novel molecular principles that underlie behavioural diversity. I propose to first develop a novel method to detect somatic insertion site variants (SISV) between two different tissue samples (see appendix 1), second, to establish tools to study the temporal and spatial dynamics of SISVs in fruitflies and mice, and third to relate SISV patterns with distinct patterns in behaviour. The results will help identify key SISVs that might be responsible for the anatomical and behavioural diversity in insects and vertebrates.