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The MYRIAD Project: Exploring Mindfulness and Resilience in Adolescence 30 Jun 2017

The MYRIAD Project: Exploring Mindfulness and Resilience in Adolescence

Amount: £250,800
Funder: The Wellcome Trust
Recipient: University of Oxford

Healing Heathen Lands: Protestant Missions and Public Health in British India, 1855-1956 17 Jul 2017

This project will explore the role of Protestant missions in the making of British Indian public health by tracing the interactions between evangelical, colonial and vernacular sources. It will argue that Protestant missionaries in South Asia did not merely play a complementary role to imperial biomedicine. It will examine the ways in which missions contributed towards shaping colonial health policies as well as knowledge of colonial disease and treatment. The project would also explore the extent to which Indians and their knowledge was involved in medical missions. This work will add on to histories of imperial medicine, international health, global history, colonial Christianity and postcolonial studies. The key goal of the project is to produce a monograph explaining the distinctiveness and significance of Protestant missionary medicine in South Asia. The project will be contributing to the emerging literature on British voluntary religious organisations in the making of imperial public health. It will also contribute to the broader literature on the relationship of modern science and medicine with Christianity.

Amount: £174,774
Funder: The Wellcome Trust
Recipient: University of Oxford

The Opie archive: exploring play in Britain from the 1950s to the 1980s 25 Nov 2016

This project focuses on the archive of internationally renowned folklorists Iona (b. 1923) and Peter Opie (1918-1982). The Opies' landmark publications were based on information contributed by some 20,000 children from schools all over Britain, in response to three surveys (c.1950–80), supplemented by the Opies’ own in-depth observation and sound recording, of a wide variety of games and forms of play. The Opie archive at the Bodleian includes the survey responses, correspondence, and the Opies’ loose-leaf research files. At present, this collection can only be searched by physically looking through the papers. It is consequently little used, even by specialists. At the same time, even limited use results in wear and tear of a collection which is vulnerable to the possibility of damage through mishandling or misfiling. Our goal is threefold: One, to unlock this archive's full potential by creating a catalogue, and physically preparing the archive for a future digitisation project, which will permit creative uses of the content without endangering the original materials. Two, to publicise the archive in its usable form to a wide range of audiences and encourage increased and diverse use. Three, detailed scoping of digitisation possibilities in collaboration with intrerested academic partners.

Amount: £102,382
Funder: The Wellcome Trust
Recipient: University of Oxford

All-optical interrogation of neural circuits during behaviour 30 Sep 2017

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: £25,000
Funder: The Wellcome Trust
Recipient: University of Oxford

The role of diurnal intracellular chloride changes in cortical network activity and plasticity. 19 Apr 2017

Cyclical changes between sleeping and waking states are a fundamental feature of mammalian physiology. During these different states, our brains exhibit distinct patterns of network activity and different capacities to learn. An understanding of the cellular mechanisms that underlie these processes is important to fully appreciate how daily changes in brain function contribute in health and disease. Here I propose to explore how dynamic changes in synaptic inhibition influence the mammalian cortex across the sleep-wake cycle. This will entail experiments that span cellular and systems levels of neuroscience, and that capitalise on my experience in developing novel applications of optogenetic tools. Using the mouse as a model system, I will examine the hypothesis that diurnal changes in intracellular chloride contribute to sleep-wake associated changes in cortical brain states and synaptic plasticity. To achieve this, my key goals are as follows. (i) I will establish the cellular and systems mechanisms that regulate the diurnal variation of intracellular chloride in mouse cortex. (ii) I will examine how diurnal chloride variation affects cortical network oscillations across the sleep-wake cycle. (iii) I will investigate the physiological impact of diurnal chloride variation upon cortical synaptic plasticity, by examining learning mechanisms during the day and night.

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

Dissecting the antibody response to Plasmodium falciparum-infected erythrocytes 09 Nov 2016

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.

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

Human sensitivity to short-wavelength light in non-image-forming vision: Toward a mechanistic understanding of the impact of blue light on sleep and circadian rhythms 09 Nov 2016

Short-wavelength (blue) light takes priority in many functions associated with the non-image-forming (NIF) visual system, including pupil size and regulation of melatonin secretion. The human retina contains two short-wavelength sensitive photoreceptors: the blue-sensitive (S) cones (~440 nm) and the recently discovered photopigment melanopsin (~480 nm) expressed in a subset of retinal ganglion cells. Previous research has focused on the melanopsin contributions to NIF responses, but very little is known about how S cones contribute to and interact with melanopsin in these functions. Using the method of silent substitution which allows for the selective isolation of photoreceptor classes and by studying patient groups with S-cone anomalies, we will study the S cone and melanopsin inputs into pupil control and circadian mechanisms. In Aim 1, S cone and melanopsin inputs into the pupil will be characterised in controls and S-cone patients and related to sleep-wake actigraphy. In Aim 2, the spatial topography of S cone and melanopsin pupil inputs will be characterised using a novel spectral-spatial modulator. In Aim 3, S cone and melanopsin inputs into melatonin suppression will be characterised. In short, we will systematically characterise the receptor mechanisms that mediate the effect of short-wavelength light on circadian regulation in humans.

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

Myeloid effector cells in inflammation 27 Apr 2017

Dysregulation of inflammation underlies a range of chronic inflammatory disease. By increasing our understanding of inflammatory mechanisms we may be able to identify specific therapeutic targets to treat disease. Using a murine model of acute, resolving inflammation, with zymosan as stimulus, we create a physiological inflammatory system where we can observe the spatiotemporal relationship of monocytes, macrophage and neutrophils which predominate this response. These observations in a controlled setting will give us insights into how these cells interact to orchestrate an inflammatory response. Gain of function IRF5 is associated with a range of autoimmune and inflammatory disease and promotes an pro-inflammatory phenotype in monocytes and macrophages. We will manipulate the system using mice deficient of IRF5 to modulate the monocytes phenotype and will be able to study the impact on neutrophil function and activation. These findings have the potential to be translated into more complex physiological systems and present new pathways for the study of disease.

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

Assessing the effect of the Xrn1 exoribonuclease on global and specific rates of protein synthesis 27 Apr 2017

Gene expression is a complex process requiring the coordination of transcription, transcript turnover, translation and proteostasis. When coordinated, these processes can be adapted to allow cells to respond to changes in growth rate and during differentiation. How these processes are coordinated remains a long-standing question. The exoribonuclease Xrn1 is proposed to coordinate transcription and translation via control of steady-state RNA levels and may be part of the mechanism. In this proposal we intend to test one aspect of the proposed model: that Xrn1 regulates steady-state RNA levels and this in turn affects steady-state protein levels. We predict that rates of protein synthesis will change as steady-state RNA levels change and this relationship will be disrupted in cells lacking Xrn1. To assess rates of protein synthesis, we will pulse label cells with puromycin and use a specific antibody to assess the degree of global and specific protein puromycylation in the presence and absence of Xrn1. By assessing rates of protein synthesis for specific proteins we will be able to relate this to levels of protein, transcripts and transcription in the WT and xrn1Delta strains, obtain preliminary data to validate our hypothesis and if encouraging to support a larger scale analysis.

Amount: £0
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

An integrated approach to the muscle Z-disk: from atomic structure to human disease 05 Apr 2016

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.

Amount: £615,549
Funder: The Wellcome Trust
Recipient: University of Oxford

Ebola Data Sharing Platform 30 Sep 2016

The purpose of the Platform is to assemble and harmonise all available clinical, laboratory and epidemiological data on Ebola virus disease in order to inform evidence based policy and practice; ultimately improving patient outcomes, reducing the impact of future outbreaks and saving lives. The impact of the Platform will extend beyond Ebola as a new model of governance for data sharing in tropical and emerging infectious diseases. The development and sustenance of this unique tri-partite collaboration partnership will open novel opportunities to implement research in emerging and re-emerging infections.

Amount: £200,000
Funder: The Wellcome Trust
Recipient: University of Oxford

A new mass spectrometry platform for membrane protein lipid interactions 04 Aug 2016

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.

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

Understanding cancer drug transport through nucleotide-sugar transporters 05 Oct 2015

My research seeks to develop a mechanistic understanding of peptide and drug transport in the human body via the mammalian PepT1 and PepT2 proteins, members of the proton coupled peptide transporter family of plasma membrane transporters. PepT1 and PepT2 are responsible for the absorption and retention of dietary protein in the form of small peptides and also for the majority of beta-lactam antibiotic transport in the small intestine. The US Food and Drug Administration recently identified PepT1 and PepT2 as clinically important transport proteins, further underlining their important role in drug transport. A growing number of antiviral and anticancer drugs have been modified to utilize PepT1 to improve their absorption following oral administration. PepT1 and PepT2 represent excellent targets for the efficient and controlled delivery of drugs into the human body as their peptide binding site can accommodate a wide range of molecules of differing size, hydrophobicity and charge, enabli ng chemically diverse peptides and drug molecules to be transported. My research into the structure and function of the bacterial homologues provides very promising evidence that PepT1 and PepT2 can be targeted more intelligently if we only had the necessary molecular insight into how peptides and drugs are recognized and transported. My research goal is to provide this insight using state-of-the-art structural, biochemical and functional analysis with the long-term vision of improving the bioav ailability of new and existing drugs by targeting them for transport via PepT1 and PepT2. To achieve this I need to address the following questions: 1. Does drug transport via PepT1 and PepT2 operate with the same mechanism as that for natural peptides or via an alternative mechanism? 2. How are binding and transport linked and what features of the protein and binding site determine ligand affinity, specificity and transport rate? 3. Can we improve the recognition of transported beta-l actam antibiotics and apply this knowledge to new classes of drug molecule such as antivirals? 4. What role does post-translational regulation have in controlling peptide transport in the mammalian cell and what are the implications for our understanding of eukaryotic membrane protein function? These questions form part of an integrated and coherent work program that address the relationship between peptide and drug transport through PepT1 and PepT2. Without the insights gained from crystal structures, insightful biochemical analysis and in vitro kinetic data investigating the effects of post translational regulation on human peptide transport, our ability to understand the roles played by PepT1 and PepT2 in drug transport will be inadequate, limiting our ability to utilize these proteins for improving drug transport in the future.

Amount: £136,431
Funder: The Wellcome Trust
Recipient: University of Oxford

Assessing the safety of low dose primaquine in Plasmodium falciparum infected African children with glucose 6 phosphate dehydrogenase deficiency 02 May 2016

Malaria remains a major problem in tropical countries, especially in Africa. Insecticide treated bednets and new powerful antimalarial drugs have led to a reduction in the number of malaria deaths. However malaria control remains poor in many areas, and if we are to eliminate and eventually eradicate the disease from the world we will require the use of all the tools at our disposal.One potentially very valuable tool, currently underused, is the antimalarial drug primaquine, which is uniquely able to kill the mature male and female sexual forms of the malaria parasite. Research has shown that primaquine greatly reduces the malaria offspring in the mosquito and thus effectively reduces transmission of the disease. So, primaquine looks to be a good 'transmission blocker' and, if used widely in patients, may reduce malaria transmission and contribute to the elimination of malaria in a community.Unfortunately primaquine has one major disadvantage. It can damage the red blood cells and cause anaemia in individuals who carry a very common genetic abnormality deficiency of an enzyme called glucose-6-phosphate dehydrogenase, G6PD for short. This deficiency is much more common in men because of the way it is inherited. This is called haemolysis. This is a real downside of primaquine, though this problem has mainly been seen when primaquine is given in high doses for many days. However, for its 'transmission blocking' effects on the malaria parasite only a single, low dose of primaquine is thought to be required. This is considered by most experts to be too little primaquine to cause a major problem with haemolysis. Despite this many malaria control programmes are unwilling to use primaquine because they consider it too dangerous. You can test for G6PD deficiency but this requires test kits and staff to administer them. Many countries cannot afford to test millions of malaria patients before giving primaquine. In 2012 the World Health Organization (WHO) concluded on the basis of the available evidence and expert opinion that single low dose primaquine was safe to use even in malaria patients with G6PD deficiency. However the WHO also called for more research.Four years later virtually no one is using low dose primaquine because that research has not been done. If we can show beyond doubt that low dose primaquine is safe in G6PD deficient children with malaria, malaria programmes would feel much happier giving it and we could then go to the drug companies and ask them to make primaquine that is suitable for children.To see if single low dose primaquine is as safe as experts think we plan to study over 1,500 children with malaria attending outpatients in two hospitals in Uganda and one in the Democratic Republic of the Congo. Using a simple test for G6PD deficiency we will find 750 children with malaria who have G6PD deficiency, and 750 who have normal G6PD levels. Within these two groups we will, on a random basis, give half of the patients normal antimalarial treatment and the other half normal antimalarial treatment PLUS single low dose primaquine. We will then watch the children very carefully to see whether giving primaquine causes more anaemia than not giving primaquine, and whether this occurs particularly in the G6PD deficient group. We need to have comparison groups of children who do not receive primaquine and some children who do not have G6PD deficiency as malaria itself causes haemolysis, as can G6PD deficiency in some circumstances even without primaquine treat. Our aim is to unpick the effects of G6PD deficiency, malaria, and primaquine administration to really be sure whether in all circumstances giving low dose primaquine is safe.If this research shows that giving single low dose primaquine is safe, this will enable WHO and national governments to recommend safe treatment regimens that will both cure the patient and also prevent transmission of malaria to other children.

Amount: £363,765
Funder: The Wellcome Trust
Recipient: University of Oxford

Identification of T-cell epitopes for vaccine targets against melioidosis in North East Thailand. 30 Sep 2016

A greater understanding of immunity to infectious diseases is desirable to improve treatments and vaccine design, especially for intra-cellular organisms which are harder to prevent and cure. One such organism is Burkholderia pseudomallei, a Gram negative bacterium which causes melioidosis in humans which carries a high mortality. The goal of this study is to demonstrate the CD8 response in patients acutely unwell with melioidosis and define key epitopes for vaccine design. 280 patients with ac ute melioidosis in North East Thailand will be studied, both with and without diabetes mellitus. Peripheral blood mononuclear cells will be isolated locally and used to evaluate T-cell responses by ex vivo IFN-gamma ELISPOT and flow cytometry to a panel of candidate proteins and peptides from B.pseudomallei. Cells from people with diabetes in the region and from unexposed healthy control subjects will be used as controls. Information from HLA typing and from the current consortium at the Immune Epitope Database will be used to identify candidate proteins and peptides, and responses to 9-mer peptides will be studied. Other studies of neutrophil function and acute phase response will be studied in parallel to produce a unified dataset covering several aspects of innate and adaptive immune responses.

Amount: £241,835
Funder: The Wellcome Trust
Recipient: University of Oxford

An Empirical Study of Children and Adolescents' Perspectives on Testing Minors for their Genetic Predisposition to Psychiatric Disorders 10 May 2016

Predictive genetic testing for psychiatric disorders could help prevent or delay the development of debilitating conditions. However, the complex inheritance, incomplete penetrance, and variable expression in the genes underlying mental disorders make such testing a relatively poor predictive instrument. Empirical studies investigated the socio-ethical impacts of such testing from the perspectives of adult patients, family members, psychiatrists, and geneticists, who highlighted the risk of promoting a deterministic stance on psychiatric conditions, of discrimination against and stigma of the individuals tested, and the potential negative effects on family relationships. However, no systematic study has investigated minors’ perspectives. This is an important gap in the debate, as minors are likely to be the main target of psychiatric genetic testing. Therefore, the aim of my research is to investigate children and adolescents’ perspectives on testing minors for their genetic predisposition to psychiatric disorders. My research will assess whether their concerns confirm those expressed in the academic literature and it will provide a more inclusive account of the public’s opinions, thereby promoting an ethically robust application of scientific discoveries in this field. I will conduct a systematic review of the ethics literature on psychiatric genetic testing in minors and a systematic qualitative interview study.

Amount: £93,065
Funder: The Wellcome Trust
Recipient: University of Oxford

Cognitive Factors in Adjustment to Social Trauma 30 Sep 2016

Socially traumatic events that may include rejection or humiliation in the context of bullying can have lasting and debilitating psychological effects. This project will investigate the nature of these effects, explore maintaining mechanisms of psychopathology, and develop and pilot a specific intervention to improve functioning in adults suffering after experiencing social trauma. It will build on cognitive models and existing treatments for posttraumatic stress disorder (PTSD) and social anxiety disorder (SAD). First, there will be a detailed investigation of social trauma and its effects in young people using surveys, interviews, and secondary analyses of cohort data. Negative effects may include intrusive memories, negative appraisals of self and others, safety behaviours, and disrupted post-event processing. The nature of psychopathology related to social trauma will be validated against existing measures of PTSD, SAD, and depression. A series of experimental studies on appraisals of social threat and qualities of social interactions will distinguish those struggling more and less severely after social trauma and fulfil the second goal of identifying maintaining mechanisms. The final goal is to develop and evaluate a procedure for updating problematic social trauma memories in a pilot case series. Overall, this project will help improve psychological treatments following social trauma.

Amount: £247,640
Funder: The Wellcome Trust
Recipient: University of Oxford

Activity-dependent plasticity of long-range sensorimotor connectivity. 02 Dec 2015

This proposal will consider when and how activity-dependent plasticity of long-range brain connections occurs, and will assess its behavioural significance. The programme will include work ranging from cellular level studies of the underlying biology in rodents, and basic science studies in human volunteers, through to proof of principle trials in clinical populations. The proposal includes the following work packages: 1. Manipulating activity These projects use neurofeedback to alter hu man brain activity in order to test whether modulating activity in specific sensorimotor circuits can produce rapid and bidirectional changes in brain connections and change behaviour. 2. Manipulating behaviour. This programme will test whether reduced limb use results in altered functional and structural connectivity. 3. Underlying biology Studies in transgenic rodents will assess whether myelin change contributes to plasticity of brain connections. Secondary questions concern the role of sleep in observed changes in brain connections and behaviour. 4. Boosting plasticity of brain connections for rehabilitation In our final work package, we will apply principles established from the basic science programme described above to stroke rehabilitation. First, we will assess whether neurofeedback can be used to rebalance motor-related activity after stroke. Second, we will test whether improving sleep quality after stroke can affect rehabilitation outcomes, due to the importa nce of sleep for consolidation of motor learning.

Amount: £2,481,628
Funder: The Wellcome Trust
Recipient: University of Oxford