- 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
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.
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.
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.
Computational phenotyping research uses big data methods to refine the diagnosis of rare genetic diseases. Photographs (and other biomedical data) of people with genetic syndromes are used to train machine-learning algorithms to identify the phenotypic features associated with different disorders. The data are obtained from consortia of clinicians and researchers involved in rare disease research, and directly from patients themselves through online direct participation initiatives. This research programme will identify ethical issues arising from the use of photographic images in computational phenotyping research. This grant will enable us to: a) undertake exploratory interviews with data–sharing consortium members and patient group representatives to determine their perceptions of ethical issues arising from the sharing and use of photographic data in phenotyping research b) undertake a scoping literature review concerning the use of photographs in (biomedical) research, and c) hold a meeting of Consortium members to disseminate and discuss findings of the pilot work. The expectation is that this will lead to a collaborative proposal that will develop an ethical position on the sharing of image data and explore research participants’ views of the use of their photographs and other data in phenotyping research.
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.
Exploiting whole genome tagging of trypanosomes to identify new ciliopathy candidate genes in humans 27 Apr 2017
Ciliopathies are a range of human genetic diseases in which the normal functions of cilia/flagella are disrupted or prevented entirely. Ranging from mild to embryonically lethal, these diseases are often difficult to investigate as many do not appear to have clear links with particular genes or molecular mechanisms. This project aims to identify potential ciliopathy protein candidates and their corresponding human ciliary/flagellar genes by identifying previously unrecognised ciliary proteins conserved across eukaryotic life using the human parasite Trypanosoma brucei as a model organism. To start with, I plan to use TrypTag, a major new data resource, to identify which proteins localise to the flagellum and cilium. I shall then use bioinformatics tools and human genetic disease databases to identify which are conserved in humans not yet linked to a ciliopathy. Having excluded known ciliopathy-related proteins, I will then screen T. brucei deletion mutants for defects in flagellum growth, motility or flagellar beat. Those with defective phenotypes have the potential to be involved in human ciliopathies when mutated. The intended goal is to create a list of these novel candidate genes for involvement in human ciliopathies, with evidence for localisation and function in the flagellum/cilium of T. brucei.
The input required to control a prosthetic device greatly defines the subsequent precision that can be achieved. Robust mechanisms that are low-cost often use musculoskeletal motion for control. However, this often limits the level of control and applicability issues can arise when the system that is augmented also generates the power and drives the control. A device that is powered and controlled by breathing could expand the product options for patients and address certain requirements that are difficult to meet with the currently available prosthetic solutions. Computational modelling has been applied to asses if a Tesla turbine can be used for power and control. Positive results from the model and subsequent conceptual testing has indicated this innovative concept could indeed provide precision control for prosthetic users. The aim of the project is to design and produce a working prototype and test out the functional capabilities of the system using several predetermined tasks.
Investigating the role of cyclin-dependent kinases in the regulation of DNA repair by non-homologous end-joining 27 Apr 2017
DNA double-strand breaks (DSBs) are highly toxic lesions that can drive genome instability and cancer. In human cells, most DSBs are repaired by the non-homologous end joining (NHEJ) pathway, except when they occur during DNA replication or mitosis when NHEJ is toxic and can generate chromosomal translocations. NHEJ must therefore be tightly regulated to maintain genome stability. However, little is understood about how the core NHEJ repair machinery is regulated. PAXX is the last core NHEJ factor to be identified, and may be a substrate for cyclin-dependent kinases (CDKs). A highly conserved residue in PAXX, S148, matches the consensus for phosphorylation by CDK1/2, and preliminary data indicate that it is indeed phosphorylated by these kinases. The aim of my project is to generate human cell lines expressing PAXX-S148 mutants that either prevent or mimic phosphorylation (Ser>Ala or Ser>Glu) on this site and investigate how expression of these PAXX variants impacts on DSB repair. Key goal 1: produce human cell lines expressing wild-type or mutant fluorescent PAXX variants and examine their DSB repair capacity and sensitivity to ionising radiation Key goal 2: investigate when CDK-dependent phosphorylation of PAXX occurs during the cell cycle
Human Genetics and Disease Biology: Core Renewal for the Wellcome Trust Centre for Human Genetics 30 Oct 2016
Human genetics provides a unique and powerful tool for understanding normal biology, disease pathophysiology, and infectious mechanisms. The "genetic revolution" of the last decade has witnessed an explosion in knowledge of associated variants for individual traits. Looking forward, large population resources will facilitate a new paradigm, going from variants (individually or collectively) to multiple phenotypes, and new functional tools will help unlock causal genes and mechanisms. In parallel, genome sequencing will become routine in parts of clinical medicine. The Wellcome Trust Centre for Human Genetics (WTCHG), a large interdisciplinary research centre comprising 400 scientists in ~45 research groups, is one of the leading institutes, globally, in human genetics. Since its founding 21 years ago, the WTCHG has played a pioneering role in the progress and success of human disease genetics and mechanism research. Our focus is the development and implementation of novel approaches to exploit human genetics and uncover disease biology so as to improve healthcare. Critical to the Centre’s success is its lively environment which fosters collaborations between research groups across disciplinary boundaries, with research supported by seven Core teams. This application seeks core support to enable the WTCHG to continue its leading role in the field.
Wellcome Centre for Integrative Neuroimaging 30 Oct 2016
Understanding how interactions between neurons generate human behaviour, why individual brains vary from one another, or whether a patient is likely to develop a particular disease, requires explanations that span vast differences in scale. Yet such explanations are essential if insights from neuroscience are to make a meaningful impact on human health. Precise mechanisms discovered in animal models must be related to clinical phenotypes discovered through population studies; both must be combined to improve diagnosis and treatment in individual patients. Neuroimaging offers a powerful route to connect these different scales, providing measurements that are sensitive to cellular phenomena and that can be acquired in living humans. The WT Centre for Integrative Neuroimaging will enable novel insights into brain function that span levels of description, and therefore bridge the gap between laboratory neuroscience and human health. This will require fundamental discoveries concerning relationships between species and between scales, and major technological developments for mapping big-data discoveries onto neurobiological mechanisms. We will bring together diverse investigators who can tackle different themes within this grand challenge. Within each theme, neuroimaging will be used alongside complementary methodologies, ensuring that it takes inspiration from, and has impact on, areas beyond its typical reach.
Key words: platinum, controlled release, cancer, ultrasound, drug delivery This research develops a powerful new methodology for treating cancer with a highly specific, potent action and markedly lower side-effects, compared with existing therapies. It combines the potency of platinum anti-cancer complexes – encapsulated to prevent unwanted side-reactions – with the selectivity of drug release at a tumour afforded by focused ultrasound. We will synthesise new PtIV prodrugs designed for encapsulation and delivery using ultrasound; a novel approach for platinum drug delivery. Groups will be attached to the PtIV centre to aid tracking both in cellulo and in vivo. Once inside cancer cells, the PtIV complexes will be rapidly converted to PtII by intracellular reducing agents. The resultant PtII fragment is anticipated to form DNA lesions, ultimately inducing cell death. The PtIV prodrugs will be liposomally encapsulated, and the liposomes attached to large gas-filled microbubbles, creating a drug delivery vehicle. Ultrasound – focused at the site of a tumour – will destroy the vehicle, releasing the prodrug and enhancing the penetration of the prodrug into the tumour. We will investigate PtIV prodrug characterisation, release from the delivery vehicle, cellular uptake, reduction to PtII species, cellular distribution and cytotoxicity.
Contraction of heart and skeletal muscles relies on the highly regular assembly of two main contractile protein filaments, actin and myosin, into sarcomeres. Actin and myosin are cross-linked in transverse planes in parallel arrays of interdigitating filaments, enabling their sliding motion to generate force. Antiparallel actin filaments are cross-linked at the Z-disk, requiring the coordinated action of the cross-linker alpha-actinin and the sarcomeric blueprint titin. Z-disks are stable yet flexible tensegrity networks acting possibly not only as mechanical integrators, but also as mechanosignalling platforms via protein kinases, phosphatases and adaptor proteins, sensing and relaying information on biomechanical stress. The Z-disk is extremely hard to analyse by conventional top-down ultrastructural methods, and we will hence pursue a bottom-up molecular approach. Mutations in Z-disk protein genes and those controlling its turnover are emerging as major causes of dilated and hypertrophic cardiomyopathy (DCM, HCM), left-ventricular non-compaction (LVNC), myofibrillar myopathy (MFM) and others. Our work will unravel how Z-disk mechanical, architectural and signalling functions operate from the atomic to the cellular and physiological level and how it is disrupted by cardiomyopathy mutations. This insight will allow better understanding of novel disease-causing mutations in Z-disk genes and reiteratively drive the fidelity of variant interpretation.
In the last two years a convergence of a new generation of cryo-electron microscopes, with the first generation of direct electron detectors, and new algorithms for image analysis have enabled the routine determination of the structure of macromolecular complexes by EM. It is now possible to look directly at molecules as small as 150-200 kDa with an electron microscope and determine their atomic resolution structure; even more revolutionary, tomographic methods allow direct imaging of the internal machinery of cells at the level of single molecules. These advances are bridging the resolution gap between light microscopy and molecular structures. The goal of this proposal is to make our own research part of this revolution. We request funds to purchase two cryo-EM that will allow the collaborative group immediately to accelerate their own research and to nucleate an advanced cryo-EM facility in the South Parks Road science campus of Oxford University. This facility is also part of an Oxford-wide strategic plan, further integrating structural biology, and ensuring that the co-PIs, and others, can effectively generate the preliminary data needed to justify access to the Titan KRIOS microscopes that are now installed at Harwell as a national facility.
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.
Reducing risk of recurrent stroke and cognitive decline after TIA and stroke through characterisation and treatment of novel physiological markers 25 May 2017
Despite optimal medical management, there is significant post-stroke residual risk of recurrent cardiovascular events and cognitive decline. This fellowship aims to reduce this risk through characterisation and modification of novel physiological factors, including BP variability and cerebrovascular pulsatility, whose relative prognostic significance is currently unclear but which represent potential therapeutic targets to further reduce cardiovascular risk. I will develop and lead the Cardiovascular Laboratory in the new Centre for Prevention of Stroke and Dementia, measuring BP variability, arterial stiffness, autonomic, cerebrovascular and endothelial function and chronic cerebrovascular injury on MRI to: l. Detemine these physiological indices' relative prognostic significance for cerebrovascular events and vascular-type cognitive decline in 1000 Oxford Vascular Study patients, creating the largest fully-phenotyped cohort after TIA and stroke with clinical, cognitive and physiological follow-up; 2. Test potential treatments in exploratory randomised trials, including antihypertensives (amlodipine/losartan/atenolol) and vasodilators (sildenafil/hydralazine); 3. Assess drug tolerability and novel intermediate endpoints for future potential phase 3 trials ; 4. Develop the skills and facilities to manage large, physiologically-guided clinical trials, testing novel interventions to treat well characterised physiological effects; leading to phase 3 trials assessing effects of novel treatments on cardiovascular risk and chronic cerebrovascular injury in stage 2 of the fellowship.
This five-year collaborative programme will develop approaches for understanding laboratory animal research as a nexus, asking how reconceptualising connections and generating communication across different perspectives can contribute to improving the future of animal research. New research will draw attention to historical independencies between science, health and welfare; identify challenges emerging at the interfaces of animal research and create opportunities for informing policy and public engagement. We suggest collaborative approaches are essential for understanding how rapid transformations across science and society are changing the patterns of responsibility, trust and care which hold together, or constitute, this nexus. We will deliver new: integrated research across the social sciences and humanities, using historical research to inform understanding of present challenges and create new engagement opportunities for the future; interactive research projects, co-produced with researchers, animal suppliers, veterinarians, publics and patients, to investigate the contemporary dynamics of animal research; interfaces for generating cultures of communication with publics, policy-makers and practitioners across the animal research nexus. This programme brings together five leading researchers on the social and historical dimensions of animal research, uniting the strengths of five institutions, engaging creative practitioners, and advancing the work of five early career researchers and three PhD students.
Linking human genotype and immunological phenotype to understand pathogenesis and improve treatment in tuberculosis 19 Jun 2017
TB kills more people worldwide than any other infectious disease, yet its pathogenesis is still poorly understood which hinders therapeutic advances. The heterogeneity of immunological responses and clinical presentations make the investigation of the major determinants of outcome challenging. Host genetic variants regulate the immune response during infection, drive immunological pathogenesis of the disease, and can lead to poor outcomes. My aim is to link human genotype and immunological phenotype to better understand TB pathogenesis and thus improve TB treatment. The fellowship has three key goals: Investigate the impact of dexamethasone on transcriptional profiling of the immune response, bacterial clearance and survival/death in TB meningitis Determine whether LTA4H genotype can be used to predict inflammatory transcriptome and to identify additional genes associated with inflammatory transcriptome variation in TB meningitis Link human genotype and transcriptional immune responses associated with treatment failure or relapse in pulmonary TB To pursue these goals, I will use RNA-Seq to provide data on both human variants and whole-genome gene expression. These results will reveal the pathogenesis of different forms of TB, including pulmonary TB, meningeal and multi-drug resistant TB. Pathways associated with inflammasome and neutrophil-driven immunopathogenesis will be a particular focus.