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Recipients:
University of Oxford
University of Cambridge
Award Year:
2016

Results

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

An advanced cryoEM instrument for the University of Cambridge 07 Dec 2016

We seek support to consolidate an advanced electron cryo-microscopy (cryo-EM) facility dedicated to structural studies of biological macromolecular assemblies. The facility would provide a revolutionary new tool to the large structural biology community in the University that would enable acquisition of critical data in support of a wide and diverse range of projects tackling fundamental problems in molecular biology relevant to human health. Currently, the named applicants primarily use X-ray crystallography to study large assemblies, but many of these samples cannot be readily crystallised. The recent development of a new generation of direct electron detectors, together with sophisticated data-processing software, has dramatically improved cryo-EM analysis, which now achieves routinely sub-nanometer resolution. Until recently, researchers in the university did not have access to cryoEM, but this has changed with the recent Wellcome Trust award to purchase a cryo-EM instrument for sample screening and intermediate resolution structure determination. We are building on this support, to develop the second phase of our strategy and seek funding for an advanced microscope capable of high resolution structure determination to complement and extend our existing instrumentations.

Amount: £3,000,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Transgenerational Epigenetic Inheritance - Cichlid as the New Model 05 Dec 2016

I aim to take advantage of the cichlid fish of Malawi to study the interaction between transposable elements, non-coding RNAs, epigenetics and heritability. This is in line with the overall goal of my Investigator Award. I believe this system to be superior to equivalent experiments we might conduct in mice. This is due largely to the high phenotypic diversity and low genomic diversity of these fishes. At the time of writing of my Wellcome Trust Investigator Award the cichlid model was too immature to proceed with an experimental plan. Now we have the required genomics, RNomics and epigenetics (DNA methylation) are all in place

Amount: £218,440
Funder: The Wellcome Trust
Recipient: University of Cambridge

The metabolic regulation of hypoxia inducible transcription factors. 05 Dec 2016

We have recently identified a novel pathway for metabolic regulation of HIF1 alpha by the OGDHC1. To continue this new area of research, it is essential that we have the necessary funds to maintian our competitive edge within the field, without diverting resources from our successful ubiquitin studies. The initial research on HIFs has been conducted by a talented graduate student, Stephen Burr. The timing of this funding request is particularly important, as it will allow Stephen to transfer his skills with a sufficient overlap for a new postdoctoral researcher to pursue this project.

Amount: £127,447
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

Computational tools for analysing developmental morphogenesis at the tissue-scale 05 Dec 2016

Computational tools for analysing developmental morphogenesis at the tissue-scale

Amount: £47,159
Funder: The Wellcome Trust
Recipient: University of Cambridge

The complete synaptic-level connectome of a nervous system and experimental connectomics 30 Nov 2016

Animals sense the local environment, learn and remember past events, predict future ones, and combine current and past information to choose appropriate motor responses. Underlying these capabilities is the nervous system, which continuously integrates multiple sources of information and chooses one response in exclusion to all others. Our vision is to study neural circuit function on the basis of known synaptic-level wiring diagrams. In Aim #1, we propose to map the complete wiring diagram of an insect, the Drosophila larval central nervous system, using serial electron microscopy. With the knowledge of the circuits formed by the identified and genetically accessible larval neurons we can study how circuits change either by experience or in disease. In Aim #2 we propose to read out the engrams, the persistent yet reversible structural circuit patterns that form in response to learning and that underlie long-term memories, using associative memory in the larval mushroom bodies as the model system. For circuits to assemble correctly while remaining plastic, hundreds of genes need to work in concert. In Aim #3, we will study the effects of mutations in select genes associated with neural diseases on the synaptic-level circuit structure, causing the disease phenotype.

Amount: £1,763,361
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

Characterization of the human extra-embryonic macrophage population, Hofbauer cells, phenotype and function 26 Oct 2016

Macrophages are among the first immune cells to seed embryonic tissues. They play important roles in early fetal development including tissue modeling and maintaining healthy tissue homeostasis. In humans, macrophages are present in the villous core of the placenta before a vascular connection with the embryo and these extra-embryonic macrophages, termed Hofbauer cells (HBC) are readily available for study. Developing our understanding of HBC and the role they play throughout gestation is important as they lie at the interface between the mother and fetus. HBC are likely to regulate placenta development, in particular the trophoblast cells that are the ultimate barrier between mother and fetus. HBC are also an important fetal defense against transplacental infections and in utero fetal infections are associated with pathogens that can survive in macrophages. However, the functions of HBC are poorly understood. Through this proposal, using some of the most advanced tools available today including multi-parameter flow cytometry, mass cytometry, RNA sequencing and organoid cultures, I will provide the first in-depth characterization of the human placenta extra-embryonic macrophages, HBC. I aim to describe the phenotype of HBC, their transcriptomic profile and functional properties. Keywords: Human extra-embryonic macrophages, Hofbauer cells, placenta, vertical-transmission, fetus, immunity.

Amount: £1,066,164
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

Control of limb movements by motor cortical circuit dynamics 08 Apr 2016

The control of limb movements has been richly investigated both at the level of behaviour and in cortical electrophysiology. However, a unified theoretical understanding of how limbs are controlled by collective neuronal dynamics is lacking. The core of this proposal is an analysis-by-synthesis approach to relate the dynamics of the motor cortex to the computational objective of limb control. In this pilot project, we will make use of recent developments in the fields of stochastic optimal control and optimization to build model cortical networks that robustly control reaching movements, in the presence of noise at all processing stages and under key physiological constraints inherent to brain circuits. We will then 1) dissect the dynamical strategies used by the model networks to achieve robust control of limb trajectories, 2) relate the model's activity to cortical electrophysiology, and 3) use the models to guide future experiments (involving optogenetic perturbations during movement planning an execution) in collaboration with Karel Svoboda's lab at Janelia Research Campus. In the long term, such models will provide unique insights into the dynamical regime of the motor cortex and suggest optimal ways of interacting with neuronal populations to restore lost function via closed-loop neuroprosthetics.

Amount: £99,500
Funder: The Wellcome Trust
Recipient: University of Cambridge

Regulation of HSV-1 infection by the non-homologous end joining machinery 08 Apr 2016

DNA viruses, such as Herpes Simplex Virus 1 (HSV-1), exploit specific host DNA repair mechanisms to assist their replication. More recently, the DNA repair machinery that senses damaged self-DNA was shown to function in the innate immune sensing of viral DNA during infection. We aim to understand how a specific DNA repair pathway, non-homologous end joining, affects HSV-1 infection and how this virus exploits or evades these host responses. This work will further our knowledge of cell-intrisic immunity and DNA repair as well as leading to the rational design of improved vaccines and oncolytic viruses. Our preliminary data indicate that two NHEJ proteins, DNA-PKcs and PAXX act to restrict HSV-1 in different ways, via activation of innate immune responses or by directly affecting virus replication. This study will provide the mechanistic basis of these observations and compare these data with the other components of the NHEJ machinery and how they regulate HSV-1 infection. This work will therefore explore two hypotheses: NHEJ proteins regulate innate immune sensing of HSV-1 DNA NHEJ proteins restrict HSV-1 replication in the nucleus

Amount: £99,981
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

Preventing violent crime and suicide in mental illness 05 Jul 2016

Risks of violent crime and suicide are increased in mental illness, but the most effective approaches to assess and manage these risks are uncertain. This proposal will focus on the prevention of violent crime and suicide in individuals with schizophrenia-spectrum disorders, bipolar disorder, and depression. I will use population-based datasets to investigate how risk assessment for violent crime and suicide can be improved, and using validated pharmaco-epidemiological approaches, examine whether these risks can be modified with medication. For risk assessment, the focus will be on deriving and validating scalable approaches that use web-based calculators (similar to the Framingham score) that are novel in psychiatry. This work will be mainly conducted using high quality population registers in Sweden with further validations in Denmark, Scotland, British Columbia, Queensland, and Pelotas, Brazil. For risk modification, I will use Swedish linked registers to examine specific psychotropic and common non-psychotropic medications for associations with violent crime and suicide using within-individual designs. Further, in a high-risk population under community supervision, I will use within-individual approaches to study psychological and behavioural interventions. Finally, I will examine how to link effective interventions to these novel risk assessment tools, and study the feasibility of a trial of risk assessment.

Amount: £1,549,670
Funder: The Wellcome Trust
Recipient: University of Oxford

Improving the treatment of Plasmodium vivax 05 Apr 2016

My current Fellowship has documented the public health importance of P. vivax and the comparative efficacy of alternative treatment regimens that will be needed for its elimination. In my next Fellowship I will determine the key translational elements required to implement these treatments safely and effectively. I will build upon an established collaborative clinical trials network, to conduct complementary studies with three integrated themes: 1) Studies to quantify the risks of P. vivax recurrence and the associated haemolysis attributable to the infection versus its treatment. These data will define the risk benefit of primaquine use in different endemic settings. 2) Investigation of the spectrum of G6PD deficiency and how this relates to genetic variants and the risk of drug induced haemolysis. These studies will improve population based surveillance and bedside diagnosis. 3) Laboratory studies to identify the molecular determinants of chloroquine resistance, to enable better surveillance of drug-resistant P. vivax. Identifying patients at greatest risk of recurrence and primaquine-induced haemolysis will ensure management strategies can be revised accordingly. My objective is that these tools will be endorsed by the WHO, adopted by National Malaria Control Programmes and become integral to current global malaria elimination efforts.

Amount: £1,406,829
Funder: The Wellcome Trust
Recipient: University of Oxford