Cookies disclaimer

I agree Our site saves small pieces of text information (cookies) on your device in order to deliver better content and for statistical purposes. You can disable the usage of cookies by changing the settings of your browser. By browsing our website without changing the browser settings you grant us permission to store that information on your device.

Current Filters

Recipients:
University of Oxford
Award Year:
2018
2016

Results

Delivering Care Through AI Systems 08 May 2018

For this project, I aim to examine 4 issues. First, I will consider whether introducing machine learning (ML) systems requires a revision of the ‘standard of care’ for clinicians, by understanding the moral permissibility of using second-hand information (from ‘black box’ systems) and whether practitioners’ medical expertise justifies judgments about such systems. Second, given the possibility of ML systems systematically underserving groups that are underrepresented in the training data, I will consider accounts of distributive justice to operationalize ‘equal access to care’. Third, to address the disagreements between clinicians on how to trade-off risks in clinical choices, I will catalogue the factual, rational, and moral sources of this disagreement to yield a principled method of evaluating these trade-offs. Finally, I will weigh the potential harms and gains from deploying AI systems in healthcare so that certain ethical and legal arguments don’t deprive society of the good such systems can provide. Key goals: To represent the ethical concerns in deploying AI systems over the appropriate standard of care, ensuring equal access to care, and representing reasoning about risk trade-offs. To balance these concerns against the benefits of such a deployment. To deliver practical ethical guidance to healthcare policy-makers and AI system-builders.

Amount: £140,538
Funder: The Wellcome Trust
Recipient: University of Oxford

The role of BMP signalling in diseases of the motor unit 06 Dec 2016

Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset, neuromuscular disease characterized by lower motor neuron degeneration as result of misfolding and accumulation of mutant Androgen Receptor (AR). In recent years this scenario of selective neuronal vulnerability has been challenged by the discovery that in SBMA, as in other diseases of the motor unit, skeletal muscle, rather than being a mere bystander of motor neuron degeneration, is primarily affected and therapies exclusively targeting muscle ameliorate the pathology in motor neuron while preventing the development of a neuromuscular phenotype in animal models. My goal is to elucidate the molecular mechanisms underlying the intrinsic contribution of skeletal muscle in SBMA pathogenesis. I will investigate the role of the Bone Morphogenetic Protein (BMP) signalling pathway in SBMA pathophysiology, testing the central hypothesis that failure to activate the protective BMP pathway in SBMA muscle in response to denervation causes primary muscle atrophy and affects motor neuron ability to cope with the stress posed by mutant AR. The rationale is to provide a molecular basis for the cell-autonomous and non-cell autonomous roles of muscle in the mechanisms of toxicity in SBMA and other diseases of the motor unit and to identify novel therapeutic targets.

Amount: £1,048,938
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural and functional dissection of the RH5:CyRPA:RIPR complex required for erythrocyte invasion by Plasmodium falciparum 05 Dec 2016

Invasion of human erythrocytes by Plasmodium falciparum is essential for parasite replication and occurs before the symptoms of malaria. It is a complex process involving many parasite surface proteins. Recently, one of these, RH5, emerged as the leading vaccine candidate to target the ‘blood stage’ of the parasite life cycle. RH5 interacts with erythrocyte basigin while monoclonal antibodies that prevent binding also prevent erythrocyte invasion. Immunization with RH5 protects animal models from parasite infection and RH5 enters human clinical trials in 2016. We already determined the structure of RH5 bound to basigin and inhibitory antibodies: a major goal of my investigator award. On the merozoite surface, RH5 forms part of a larger complex, interacting with CyRPA, RIPR and a fourth, GPI-anchored component. RH5, CyRPA and RIPR are each essential for erythrocyte invasion and are targets of antibodies that block invasion. Despite this, their functions are unknown, leaving a major gap in our understanding of erythrocyte invasion by Plasmodium falciparum. We will now undertake structure-function studies of the RH5:CyRPA:RIPR complex. Working with Simon Draper, we have developed eukaryotic expression systems to produce RH5, RIPR and CyRPA. We assembled them into a complex and showed that this is elongated, homogeneous and rigid by negative stain electron microscopy. Monoclonal antibodies targeting each component havebeen generated. We will now determine the structure of this recombinant RH5:CyRPA:RIPR complex using electron cryo-microscopy, and investigate where inhibitory monoclonal antibodies bind.

Amount: £150,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Defining the import mechanism of pyocin AP41 and klebicin G 30 Sep 2018

There is an urgent need to develop new antibiotics against multidrug resistant Gram-negative bacteria such as Pseudomonas aeruginosa and Klebsiella pneumoniae. These organisms are major causes of pneumonia and sepsis, with recent reports identifying hospital isolates of each resistant to all known antibiotics. The present research focuses on the mode of action of a family of antibiotic proteins known as nuclease bacteriocins that have not been developed as antimicrobials, but show promise in animal models of infection. Nuclease bacteriocins are species-specific toxins that are used by bacteria to compete with their neighbours. Although folded proteins these molecules are capable of penetrating the defences of Gram-negative bacteria to deliver an enzyme to the organism’s cytoplasm to degrade essential nucleic acids by an unknown mechanism. Two types of nuclease bacteriocin will be investigated, pyocin AP41 which targets Pseudomonas aeruginosa, and klebicin G which targets Klebsiella pneumoniae. Preliminary computational and experimental work on pyocin AP41 has identified potential candidate proteins involved in its import. This will be followed up with structure and function studies of AP41, a dissection of its import mechanism and new studies on klebicin G, a nuclease bacteriocin that has only recently been identified.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Institutional Translation Partnership Award (iTPA): Thailand Major Overseas Programme 30 Sep 2018

The team at MORU will focus on closing the gap between research and implementing interventions, building capacity and expertise to support early translation to improve the health of people in low-income countries.

Amount: £988,404
Funder: The Wellcome Trust
Recipient: University of Oxford

open access award 2017/18 30 Sep 2018

Not available

Amount: £100,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Flexible task representations for intelligent behavior 24 Apr 2018

A long research tradition in cognitive neuroscience has investigated the role of the prefrontal cortex (PFC) in flexible goal-directed behaviour. This work has yielded important insights, e.g., that the PFC’s coding properties flexibly adapt when task demands change to prioritise goal-relevant information. However, it relies primarily upon the use of familiar and explicitly instructed tasks that provide poor fit to human behaviour in naturalistic and open-ended environments, and likely miss essential aspects PFC function. I therefore propose to study the representations that form within PFC as humans learn to perform complex categorisation tasks with only minimal external instruction. I hypothesise that during learning the PFC will form abstract representations of the task’s latent structure, that support not only performance in the given task, but also provide provides a scaffold for learning in similar environments. Using representational similarity analyses, in combination with multiple brain recording techniques (fMRI, MEG, ECoG), I will measure how stimulus-evoked neural responses change adaptively during learning, and test if these changes generalise to novel task environments with similar structure. These findings will provide important new insights about the coding mechanisms by which PFC supports flexible behaviour in complex, naturalistic environments.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford
Amount: £11,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Investigating the GWAS-identified target NCX3 in nociception 30 Sep 2018

Evolutionary, pain is a protective sensation. However, it can persist beyond its usefulness and become debilitating for patients. Chronic pain affects up to one half of the population in the UK (Fayaz et al, 2016). Currently, the treatment options are limited and discovering new drug targets is of great importance. In a recent genetic study (genome-wide association study), we identified a gene (SLC8A3 encoding the protein NCX3), which was associated with higher pain sensitivity to experimental pain stimuli in healthy participants. My thesis will therefore focus on studying the function of NCX3 on a molecular, cellular and systems level. NCX3 is an important part of the machinery that moves ions in and out of cells. Its role in pain is poorly understood, but previous reports show that it is involved in regulating Ca2+ levels in pain-sensing neurones. Inhibition of NCX3 can cause increased Ca2+ in these cells leading to higher activation of the central nervous system and increasing pain sensation. To investigate the function of NCX3, I will use genetically modified mice lacking the gene as well as isolated pain-sensing neurones. Our genetic data, combined with published results, makes NCX3 an attractive target for future research and drug discovery.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Signal transduction of the GPCR Smoothened: a key protein in Hedgehog-regulated morphogenesis and oncogenesis 30 Sep 2018

In complex multicellular organisms, cell-to-cell communication is often managed by morphogen gradients. The secreted Hedgehog ligands fall within this class, as they act in this manner during embryonic development. The Hedgehog signalling pathway (stimulated by these morphogens) tightly regulates crucial developmental processes including body patterning and symmetry. Serious developmental disorders result from inactivation of this pathway during embryogenesis, including holoprosencephaly and cyclopia. Hedgehog signalling is also active through stem cell programs throughout adult life, and aberrant Hedgehog activation, either ligand dependent or mutations in pathway components, can lead to cancer including medulloblastoma and basal cell carcinoma. The G-protein coupled receptor (GPCR) Smoothened is a key protein of this pathway, as it initiates the intracellular cascade, and is already targeted by anti-cancer drugs including Vismodegib and Sonidegib. However, the mechanism of signal transduction has only been poorly characterised. This project aims to explore this using both structural and biophysical approaches. We will study the mechanism and interplay of the two identified ligand-binding sites and the dynamics of agonist association with Smoothened. The ultimate goal is to determine the structure of active-state Smoothened and hence describe the mechanism by which its signal is transmitted across the plasma membrane.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Oxford

Large-scale data integration to advance mechanistic inference and precision medicine in type 2 diabetes 17 Jul 2018

Advances in understanding the genetic and genomic basis of complex diseases have had limited impact on the delivery of translational goals, including those concerning personalised management. Recently, we have shown that, by integrating information on quantitative trait associations and tissue-specific regulatory annotation, genetic variants influencing type 2 diabetes (T2D) predisposition can be characterised in terms of the pathophysiological processes through which they operate. The central hypothesis of this proposal is that this allows a deconstruction of T2D pathophysiology that addresses phenotypic and clinical heterogeneity, promotes mechanistic insights, and reveals novel translational opportunities. The approach begins with generation of "process-based" genetic risk scores that better capture patterns of individual T2D-predisposition and phenotype. I will refine these risk scores, more precisely characterise the cellular, molecular and physiological events they reflect, and describe their relationships to clinical outcomes. For multifactorial diseases, there are limits to the clinical prediction achievable through genetics alone: I will combine genetic risk scores with measures of individual external and internal environment, and with clinical and biomarker data, to generate "integrated risk profiles".This approach aims to advance understanding of the pathophysiological basis of T2D and deliver precise, personalised information for key clinical outcomes including complication risk and therapeutic response.

Amount: £2,234,438
Funder: The Wellcome Trust
Recipient: University of Oxford

Plasmodium vivax Volunteer Infection Studies in Thailand 12 Mar 2018

Vivax malaria remains a major global health problem. Because of the existence of a hypnozoite stage and the clinical relapses this causes, elimination strategies are more difficult to design and implement successfully than for falciparum malaria. Vaccines and new well-tolerated anti-relapse drugs are badly needed. To accelerate vaccine development, we will develop and assess the feasibility of conducting Plasmodium vivax volunteer infection studies in Thailand, recruiting semi-immune volunteers from endemic areas representative of target populations for vaccine deployment. We will draw on the participating institutions' expertise in clinical malaria, immunology, entomology, parasitology, volunteer infection studies, and vaccine development. We plan to develop vivax controlled human vivax malaria infection models able to test protective efficacy of the pre-erythocytic and blood stage vivax malaria vaccines currently in development. During this programme we plan to conduct six volunteer infection studies, determine immunological correlates of protection, and test four vaccine candidates. The programme will lay the groundwork for developing models to test future transmission blocking vaccines and new anti-relapse drugs for radical cure. The volunteer infection studies will be accompanied by a programme of social science and empirical ethics research to assess their acceptability and the understanding of volunteers, patients, researchers and policy-makers.

Amount: £996,222
Funder: The Wellcome Trust
Recipient: University of Oxford

All-optical interrogation of neural circuits during behaviour 26 Oct 2016

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.

Amount: £1,320,200
Funder: The Wellcome Trust
Recipient: University of Oxford

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.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford

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.

Amount: £11,463,085
Funder: The Wellcome Trust
Recipient: University of Oxford

Wellcome Centre for Ethics and Humanities 30 Oct 2016

Building on the University of Oxford’s outstanding track record for research in ethics and the humanities, the Wellcome Centre for Ethics, Innovation, Globalisation and Medicine will conduct world-leading research on the ethical challenges presented by advances in medical science and technology. Much contemporary medical ethics, with its origins in 20th Century concerns, is no longer fit for purpose. New thinking is required. Through its research and engagement activities, the Centre will lead debate on the ethical requirements for 21st Century scientific research capable both of improving health and of commanding public trust and confidence. The Centre’s research will focus on four themes. The first will address challenges presented by the use of large-scale data-driven science. The second, will engage critically with ethical problems presented by developments in genomics. The third will investigate the ethical and social implications of neuroscience. The fourth will explore ethical questions arising out of greater global connectedness and interdependence. These activities will be complemented by a programme of cross-cutting research activities engaging with the issues presented by the convergence of these developments. The Centre will put in place a well-resourced, cutting-edge, and attractive programme of public engagement activities around the key issues addressed by its research.

Amount: £2,991,157
Funder: The Wellcome Trust
Recipient: University of Oxford

Core Support for the East African Major Overseas Programme 30 Jun 2016

Our application provides the platform for a uniquely inter-disciplinary scientific programme linking biomedical, social and health systems research to deliver scientific insights of global importance to human health. We will work based from Kenya (Kilifi and Nairobi) and Eastern Uganda (Mbale). The Kilifi Programme will tighten its focus on our integrated platform (i.e. linked hospital/demographic/molecular surveillance) and legacy of continuous epidemiological data and stored samples over 25 years. Work in Mbale will consolidate a leading centre of clinical investigation in an area of hyper-endemic malaria transmission, and the Nairobi Programme will increase its independence with a focus on international disease mapping and health systems. Our major scientific themes include vaccines (including pre and post-licensing studies with exploratory immunology and epidemiological components), genomics and infectious disease transmission, clinical research (focusing on multi-centre clinical trials and the pathophysiology of critical illness with a developing programme on neonatal and maternal health), public health (with an emphasis on spatio-temporal analyses) and health systems research. The Programme is delivered by 29 PIs (i.e. scientists with independent funding). Training is central to our vision, and additional awards support 18 post-doctoral scientists and a projected 50 PhD students during the next 5 years.

Amount: £26,595,243
Funder: The Wellcome Trust
Recipient: University of Oxford

Core award for the East African Major Overseas Programme - KES portion 30 Jun 2016

Our application provides the platform for a uniquely inter-disciplinary scientific programme linking biomedical, social and health systems research to deliver scientific insights of global importance to human health. We will work based from Kenya (Kilifi and Nairobi) and Eastern Uganda (Mbale). The Kilifi Programme will tighten its focus on our integrated platform (i.e. linked hospital/demographic/molecular surveillance) and legacy of continuous epidemiological data and stored samples over 25 years. Work in Mbale will consolidate a leading centre of clinical investigation in an area of hyper-endemic malaria transmission, and the Nairobi Programme will increase its independence with a focus on international disease mapping and health systems. Our major scientific themes include vaccines (including pre and post-licensing studies with exploratory immunology and epidemiological components), genomics and infectious disease transmission, clinical research (focusing on multi-centre clinical trials and the pathophysiology of critical illness with a developing programme on neonatal and maternal health), public health (with an emphasis on spatio-temporal analyses) and health systems research. The Programme is delivered by 29 PIs (i.e. scientists with independent funding). Training is central to our vision, and additional awards support 18 post-doctoral scientists and a projected 50 PhD students during the next 5 years.

Amount: £18,904,756
Funder: The Wellcome Trust
Recipient: University of Oxford

Capture NanoporeSeq: A novel technique for targeted full-length transcript sequencing and gene expression analysis 08 Apr 2016

The accurate characterization and quantification of expressed gene isoforms is essential to understanding how genetic variation affects gene expression and ultimately disease risk. However, the expressed isoforms identified by standard RNA sequencing methods are often incorrect due to the near ubiquitous presence of alternative gene isoforms in the human transcriptome. This project aims to address this problem by developing a novel technique (Capture NanoporeSeq) to perform full-length cDNA sequencing of target human genes and so unambiguously identify which isoforms are expressed. Capture NanoporeSeq will combine Oxford Nanopore long-read sequencing, which can sequence full-length cDNAs, with targeted RNA sequencing (CaptureSeq), which will provide high sensitivity for targeted gene isoforms. Once developed, Capture NanoporeSeq will be validated in post-mortem human brain tissue to identify and quantitate the expression of gene isoforms from genomic regions linked to neuropsychiatric disorders. Capture NanoporeSeq will significantly improve our ability to accurately characterize and quantify gene expression. This will be of immediate use in neuropsychiatric disease genetics where many risk genes have lowly expressed disease-linked isoforms and/or complex splicing patterns, helping to illuminate the impact that disease-associated genetic variation has on gene expression.

Amount: £86,822
Funder: The Wellcome Trust
Recipient: University of Oxford

Development of compounds that inhibit RAS-effector protein-protein interactions in cancer using a single antibody domain drug surrogate emulator approach 30 Jul 2016

Prof Rabbitts and colleagues from the Weatherall Institute of Molecular Biology have been awarded Seeding Drug Discovery funding to develop small molecules specifically targeting the RAS-effector protein-protein interactions. The RAS family of oncogenes is among the most frequently mutated in human cancers. Using minimal antibody fragments, the group has characterized an anti-RAS VH segment whose binding site covers the region of RAS where the signal transduction effector proteins bind, the “switch region.” In models of lung cancer this anti-RAS VH inhibits tumourigenesis, thus validating the mutant RAS-effector interaction as a therapeutic target. Using two different approaches small molecules have been identified that bind to RAS at the same point of contact as the anti-RAS VH. The Seeding Drug Discovery Award will be used to develop these hits through to leads and ultimately the identification of a preclinical development candidate.

Amount: £1,199,301
Funder: The Wellcome Trust
Recipient: University of Oxford