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

Results

Regulatory T cell-neutrophil interaction in the development and maintenance of secondary pneumonia 06 Dec 2016

Secondary pneumonia following influenza infection is common, with considerable associated morbidity and mortality. Strikingly, secondary infections tend to arise from bacteria which live otherwise asymptomatically in the oropharynx. Based on existing data, I hypothesise that the development of secondary streptococcal pneumonia is dependent on a key immune-cell molecular pathway, namely Phosphoinsitol-3-Kinase delta (PI3Kdelta), and that inhibition PI3Kdelta will be protective via the following mechanisms. 1) Influenza-induced expansion of immunosuppressive regulatory T-cells (Treg) which depend on PI3Kdelta for suppressive functioning 2) Viral and Treg mediated suppression of neutrophil function 3) A change in the lung microbiome as a result of the effects 1 and 2, leading to established infection by Streptococcus pneumoniae. The goals are: 1) To determin whether PI3Kdelta-null animals are resistant to secondary streptococcal pneumonia. 2) To use tools including Treg depleted animals, conditional knockout animals and small molecule PI3Kdelta inhibitors to explore mechanisms of resistance. 3) To develop a more clinically relevant murine model secondary pneumonia, using a streptococcal colonisation model which when exposed to influenza will develop secondary pneumonia. 4) To characterise the respiratory microbiome of animals at various stages will be characterised, looking for factors that may facilitate or militate against development of secondary pneumonia.

Amount: £516,560
Funder: The Wellcome Trust
Recipient: University of Cambridge

Obesity: Exploiting Genomes for Novel Insights 06 Dec 2016

What are the mechanisms by which genes influence an individuals propensity to obesity. I study animal models to find answers to that question. I will study the link between genes and obesity in two complementary research streams. Firstly, I will build on my recent discovery of an obesity-associated POMC mutation in animal models which disrupts hypothalamic leptin-melanocortin signalling. Deep phenotyping of eating behaviour and physiology in the absence and presence of a synthetic MC4R agonist with the goal of defining the contribution of POMC-derived peptides to energy homeostasis. Secondly, I will use genome-wide association studies in animals to find further genetic determinants of obesity. Their relevance to humans will be tested in large patient cohorts with both rare, severe obesity and common obesity, and putative obesity loci studied in relevant cell models. Preliminary data has shown this approach is successful.

Amount: £415,141
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

Using parasite population genomics to improve understanding of malaria epidemiology 30 Nov 2016

This collaborative project will use genomic approaches to characterise demographic flux and evolutionary trends in the malaria parasite population. Using novel methods for parasite genome sequencing that are suitable for large-scale field applications, we will perform longitudinal studies of parasite population genomics at multiple locations with different transmission intensities in Africa and Southeast Asia, and we will examine the clinical and epidemiological correlates of population genomic variables under a range of ecological settings. We will develop statistical and computational approaches to use longitudinally sampled genome sequencing data to construct spatial maps of parasite demography and examine how this changes over time. We will promote collaboration between experts on population genomics, geospatial mapping and mathematical modelling to use these data to inform and improve epidemiological models of malaria transmission. Our overarching goal is to establish the practical and analytical foundations to use parasite genome sequencing to investigate the causes of epidemiological events such as resurgence and emerging drug resistance, and thus to assist in planning effective interventions.

Amount: £3,989,275
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

Understanding the functional role of GABA across the human motor network 05 Dec 2016

Understanding the functional role of GABA across the human motor network

Amount: £214,011
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

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 translational potential of mass spectrometry and next-generation sequencing in patients with central nervous system infections in Vietnam 22 Nov 2016

Central nervous system (CNS) infections are devastating conditions worldwide, especially in low- and middle-income counties (LMIC). Clinical outcomes are dependent upon the rapid identification of the causative agent and instituting effective antimicrobial therapy, although the causative agent is only identified in This Fellowship will focus on the translational potential of mass spectrometry and next-generation sequencing (NGS) in clinical diagnostics of CNS infections in Vietnam, and has three key goals: To determine whether Mass spectrometry of cerebrospinal fluid (CSF) will identify protein/peptide signatures associated with different infectious aetiologies. To determine whether NGS-based metagenomic analysis will identify a broad range of known/unknown pathogens in the CSF and improve upon current standard laboratory assays. To determine whether NGS can provide rapid, whole genome sequence-based prediction of antimicrobial susceptibility for Mycobacterium tuberculosis and Streptococcus pneumoniae. I aim to provide proof-of-principle that CSF proteomics- and NGS-based methods can improve upon the diagnostic assays currently available in hospital settings, especially in LMIC, and thereby potentially improve patient outcomes.

Amount: £685,086
Funder: The Wellcome Trust
Recipient: University of Oxford

Adaptive decision templates in the human brain 30 Nov 2016

Interacting with the surrounding environment depends on our ability to extract meaningful patterns from incoming streams of sensory information. Learning and experience are known to facilitate this skill; yet, we know little about how the brain extracts structure and generalises this knowledge to novel settings. Here, I propose to test the brain mechanisms underlying structure learning using contrasting tasks that involve learning structure in space vs. time at different levels of complexity (simple vs. complex feature contingencies). I will use computational modelling to interrogate the processes involved in learning behaviourally-relevant structures (i.e. decision templates). I will relate this system-level insight to multimodal neuroimaging to provide converging evidence for brain mechanisms that mediate learning specialisation and generalisation. I will exploit high-field imaging to test fine-scale decision templates in the visual cortex. I will combine 7T imaging with human electrophysiology (MEG/EEG) and interventions (TMS) to test for local and larger-scale brain circuits that retune decision templates through feedback and inhibitory interactions. Finally, I will test whether these mechanisms support our ability to generalise previous experience to novel contexts and tasks. This integrated approach will advance our understanding of the brain’s capacity for adaptive and resilient behaviour with implications for promoting lifelong learning.

Amount: £1,344,200
Funder: The Wellcome Trust
Recipient: University of Cambridge

Circuit principles of memory-based behavioral choice 30 Nov 2016

We aim to elucidate the circuit mechanisms underlying three key computations essential for memory-based behavioral choice: 1) updating valences attached to sensory cues, when actual and expected outcomes differ; 2) computing the “value” for each action, based on multiple, conflicting cues; and 3) selecting one action and suppressing other physically incompatible competing actions. One obstacle to progress in this field has been the problem of identifying underlying circuits with synaptic resolution, and causally relating structural motifs to their proposed function. Both insects and vertebrates have evolved cerebellar-like higher-order parallel-fiber systems specialized in forming large numbers of associative memories and in guiding memory-behavioral choice. However, no synapse-resolution wiring diagram of any such system has been available to guide analysis and inspire understanding.    We have recently mapped the synaptic-resolution wiring diagram of one such system, the insect mushroom body, in Drosophila larva, which reveals multiple novel circuit motifs and provides clues about learning and decision-making models and their neuronal implementation. An exquisite genetic toolkit available in this model system allows selective manipulation of individual neuron types to establish causal relationships between their activity and behavior. We are now in a unique position to causally relate the identified structural motifs to their function.

Amount: £1,737,376
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

Characterising extreme innate immune response phenotypes informative for disease using a functional genomics approach 30 Nov 2016

The overall aim is to define and characterise extreme innate immune response phenotypes in order to gain insights into the functional alleles driving such differences between individuals; biological consequences in terms of gene regulation, cellular function and disease; and opportunities for therapeutic intervention. Key goals are (1) to analyse existing transcriptomic and expression quantitative trait mapping datasets for primary monocytes activated by lipopolysaccharide (endotoxin) or interferon-gamma from a large cohort of healthy volunteers to identify extreme responders (aggregated and gene level), using genetics to resolve functional alleles then validate and establish functional consequences including through chemical probes; (2) to use genome editing to conduct high-throughput screens in human induced pluripotent stem cell derived monocytes complementing the genetic data; (3) to define key nodal genes and networks for drug target discovery and prioritisation; and (4) to characterise prioritised genes and functional alleles modulating gene transcription and epigenetic regulation relevant to disease. Anticipated outcomes are improved understanding of pathophysiology in immune-mediated disease notably sepsis; exemplars to the field of how to establish mechanism for functional alleles involving regulatory genetic variants; improved interpretation of genome-wide association studies; novel nodal points involving TLR and related pathways as drug targets; and better drug target prioritisation.

Amount: £1,575,666
Funder: The Wellcome Trust
Recipient: University of Oxford

Targeting malaria hotspots in Myanmar: An individual-based modeling approach 22 Nov 2016

The epidemiology of malaria in Myanmar has been changing with its decreasing incidence in Myanmar, while there is also an urgent need to address emerging resistance to artemisinin. Current malaria control strategies are no longer enough to achieve elimination. New strategies, like targeting of malaria hotspots where transmission intensity exceeds the average, have been suggested both by studies and the WHO. Such targeted strategies has been implemented in Kayin, Myanmar. However, detection of hotspots using qPCR has been limited to randomly selected villages because of the financial and operational constraints. This could be optimized by a simulation model. The proposed project will develop an individual-based mathematical model to: - Understand/model the changing epidemiology of malaria as its incidence declines in Myanmar - Derive cost-effective strategy to identify and treat malaria hotspots in Kayin, Myanmar As inputs, the model will have census data, population movement, and malaria data from relevant sources to create a dynamic, synthetic population. Simulated individuals will have their own risk of infection, health behaviour and response to treatment which will influence the overall disease transmission dynamics. A corresponding mosquito model will drive the force of infection for humans. Several detection methods and treatment strategies will be simulated.

Amount: £128,087
Funder: The Wellcome Trust
Recipient: University of Oxford

Future of Animal-sourced Foods (FOAF) 06 Oct 2016

Changes in the amount and type of animal-sourced food (ASF) we consume, and in the way they are produced, are critical drivers of global human health and environmental quality. The project will develop novel policy tools and interventions to allow more informed and effective action to be taken to maximise the health and environmental co-benefits of changes in ASF consumption. We shall build a quantitative food system model incorporating economic, health and environmental modules that will allow the effects of existing drivers and novel policy interventions to be assessed. We shall exploit unique epidemiological resources to provide new evidence about how different types of ASF affect health, and conduct experiments to develop new interventions to influence the consumption of ASFs and ASF substitutes. A social-science component will research how social norms and political economic factors affect the practicality and acceptability of interventions, and how this may be changed. The effects of different types of ASF production on climate change, water use and quality, and ecosystem functions will be measured and brought together for the first time. The project will develop a distinct work stream in China and engagement with multiple audiences will be integral to all its activities.

Amount: £4,391,572
Funder: The Wellcome Trust
Recipient: University of Oxford

Future of Animal-sourced Foods (FOAF) 06 Oct 2016

Changes in the amount and type of animal-sourced food (ASF) we consume, and in the way they are produced, are critical drivers of global human health and environmental quality. The project will develop novel policy tools and interventions to allow more informed and effective action to be taken to maximise the health and environmental co-benefits of changes in ASF consumption. We shall build a quantitative food system model incorporating economic, health and environmental modules that will allow the effects of existing drivers and novel policy interventions to be assessed. We shall exploit unique epidemiological resources to provide new evidence about how different types of ASF affect health, and conduct experiments to develop new interventions to influence the consumption of ASFs and ASF substitutes. A social-science component will research how social norms and political economic factors affect the practicality and acceptability of interventions, and how this may be changed. The effects of different types of ASF production on climate change, water use and quality, and ecosystem functions will be measured and brought together for the first time. The project will develop a distinct work stream in China and engagement with multiple audiences will be integral to all its activities.

Amount: £947,700
Funder: The Wellcome Trust
Recipient: University of Oxford

University of Cambridge PhD Programme for Clinicians 30 Nov 2016

This programme recruits clinicians of outstanding calibre nationwide. With the largest concentration of biomedical science in Europe in laboratories on the Campus or wider Cambridge, we offer research training of highest quality that spans the spectrum from basic science through experimental medicine to epidemiology and public health. Strong, ongoing, mentorship is central to our programme; this, coupled with carefully chosen placements in laboratories empowers fellows to make better-informed choices of research and supervisor, including interdisciplinary projects. During PhD training, we aim to maximise their potential to acquire research skills and achieve a doctorate linked to significant discoveries and publications. With continued, intensive, guidance postdoctorally via established mechanisms, we guide fellows into pathways (e.g. higher research fellowships, clinical lecturer posts) that are tailored to individual progress, balancing re-entry into clinical training with maintaining research momentum. Our vision is to strengthen and broaden this model to include fellowships at veterinary and MBPhD level; and, in partnership with the University of East Anglia, extend opportunities to trainees throughout the region and add research diversity with a new theme in Gastroenterology, Nutrition and Microbiology. The longterm aim of the programme is to produce the next generation of clinical academics.

Amount: £6,397,500
Funder: The Wellcome Trust
Recipient: University of Cambridge

Neuronal reward mechanisms 30 Nov 2016

We investigate neuronal reward and economic decision signals in behavioural tasks with designs from learning and economic decision theories, supplemented by selected, closely related neuroimaging experiments. We study the main components of the brain's reward system, including dopamine neurons (reward prediction error), orbitofrontal cortex (economic decision variables), striatum (so far insufficiently characterised reward signals) and amygdala (short- and long-term rewards). We search for reward and decision signals that provide explanations and hardware implementations for the constructs of reward and economic theories. We need to know these fundamental neuronal signals before focussing on cellular and molecular mechanisms, which differs from work on sensory and motor systems whose signals are better characterised.  We state three aims:  Aim 1: We characterise neuronal processing of skewness-risk, arguably the most frequent risk form.  Aim 2: We identify neuronal signals for utility and test formal axioms for utility maximisation, which is supposedly the goal of 'rational' agents. Utility is THE basic economic decision variable that explains most economic choices.  Aim 3: We assess neuronal representations of preferences, and bridge the gap between biologically necessary rewards and tradable economic goods, by testing basic assumptions of revealed preference theory.

Amount: £4,413,529
Funder: The Wellcome Trust
Recipient: University of Cambridge