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Recipients:
University of Oxford
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Results

Bone Morphogenetic Protein signalling and stromal-epithelial interaction in intestinal inflammation and carcinogenesis. 05 Apr 2017

The intestinal mucosa is a complex ecosystem and the epithelium has a dynamic relationship with underlying stroma. Key aspects of intestinal homeostasis and disease states, including inflammatory bowel disease and cancer are characterized by the interdependence of the epithelial and stromal compartments. Inter-compartmental cell-signalling pathways regulate intestinal epithelial cell fate determination in homeostasis, and transient perturbation of these networks is required in the physiological response to inflammation and injury. This promotes epithelial stem cell behaviour, cell proliferation and migration as part of a wound healing response. However, failure of restoration of homeostatic control in chronic inflammation, or pathological disruption of signalling can result in neoplasia initiation and progression. In resultant tumours, optimally selected somatic mutation spectra differ and reflect these variable influences on lesion pathogenesis. This proposal will explore these concepts using disruption in Bone Morphogenetic Protein signalling and it's pleiotrophic antagonist Gremlin1, as exemplars of the paradigm. Specific goals include: 1. Identifying stromal cell populations expressing Grem1 in intestinal regeneration and tumour desmoplasia. 2. Assess the functional role of BMP disruption in these conditions. 3. Using mouse models to test therapeutic manipulation of BMP signalling. 4. Using somatic mutation analysis to generate molecular biomarkers of Grem1 initiated tumourigenesis.

Amount: £1,792,405
Funder: The Wellcome Trust
Recipient: University of Oxford

Investigating the functional basis of shared genetic etiology across autoimmune diseases 26 Oct 2016

Autoimmune diseases are a diverse set of conditions afflicting ~10% of the population worldwide, they pose a substantial personal and socioeconomic burden, and they have no cure. Currently prescribed treatments have variable efficacies and can be associated with severe side effects such as malignancies and even fatal opportunistic infections. Designing improved therapeutic strategies requires a better understanding of the pathways that drive these conditions to achieve an optimal modulation of the immune system. Investigating the biological consequences of disease-associated genetic variants provides an avenue for delineating critical pathophysiological mechanisms. However, for each of these conditions, tens to >100 different loci have been found to influence disease risk. Therefore, prioritization is required, and the approach taken in this proposal is to focus on genetic variation shared across multiple autoimmune diseases, including a polymorphism in the tyrosine kinase 2 (TYK2) gene that protects against no fewer than 11 such conditions. The key goals of this research are to (i) investigate the molecular basis of shared genetic risk across autoimmune diseases; (ii) elucidate the downstream signatures and impact of shared genetic risk to help define key disease pathways; and (iii) investigate how key disease pathways can be fine-tuned for maximal benefit.

Amount: £1,009,370
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

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

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

Investigating the role of cyclin-dependent kinases in the regulation of DNA repair by non-homologous end-joining 27 Apr 2017

DNA double-strand breaks (DSBs) are highly toxic lesions that can drive genome instability and cancer. In human cells, most DSBs are repaired by the non-homologous end joining (NHEJ) pathway, except when they occur during DNA replication or mitosis when NHEJ is toxic and can generate chromosomal translocations. NHEJ must therefore be tightly regulated to maintain genome stability. However, little is understood about how the core NHEJ repair machinery is regulated. PAXX is the last core NHEJ factor to be identified, and may be a substrate for cyclin-dependent kinases (CDKs). A highly conserved residue in PAXX, S148, matches the consensus for phosphorylation by CDK1/2, and preliminary data indicate that it is indeed phosphorylated by these kinases. The aim of my project is to generate human cell lines expressing PAXX-S148 mutants that either prevent or mimic phosphorylation (Ser>Ala or Ser>Glu) on this site and investigate how expression of these PAXX variants impacts on DSB repair. Key goal 1: produce human cell lines expressing wild-type or mutant fluorescent PAXX variants and examine their DSB repair capacity and sensitivity to ionising radiation Key goal 2: investigate when CDK-dependent phosphorylation of PAXX occurs during the cell cycle

Amount: £0
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

Analysis of neurodegenerative diseases progression, at a single cell level, with Deep Neural Networks 30 Sep 2017

The aim of the project is to investigate neurodegenerative diseases, by determining novel neuronal cell phenotypes, classify them and to develop a step wise neurodegenerative diseaseprogression map. Stem cells differentiation technology allows scientists to access neurons involved in pathology of various neurodegenerative disease, however, there is big gap in good methods to investigate diseases at the single cell level. Thus, I will imagine organelles of iPSC derived neurons at a super-resolution level with 3D-SIM. Cellular heterogeneity will be investigated with the deep neural networks (DNN), which can detect numerous phenotypes of neurons and classify them into various heath states, this will allow us to produce a step wise disease progression map for PD and FTD in vitro models. Key goals:Goal 1: Develop and train DNN to detect cellular phenotypes (University of Oxford);Goal 2: Develop neurodegenerative disease progression map (University of Oxford)Goal 3: Understand why DNN grouped neurons into the particular classes (NIH);Goal 4: Undertake CRISPRi screens and DNN will be used as a readout (NIH).This project could set a scene for developing novel analysis methods for neurodegenerative diseases, it can produce a step wise disease progression map and reveal novel interventiontargets.

Amount: £80,000
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

China Kadoorie Biobank (CKB) prospective study of 0.5 million adults 16 Jun 2016

CKB is a blood-based prospective study of 512,000 adults, recruited during 2004-8 from 10 diverse regions of China, with extensive data collected at baseline and subsequent resurveys using questionnaires, physical measurements, and stored biological samples. By 1.1.2014, 25,000 deaths and ~1.5M coded disease events had been recorded among participants, through linkages with death and disease registries and national health insurance systems. Genome-wide data are being generated (first phase: ~100,000 participants by Q3/2016), along with blood biochemistry and multi-omics data for nested case-control studies of specific diseases. We are seeking renewal of two-year funding to support core activities to maintain, enhance and share the resource through: (i) continued follow-up of cause-specific morbidity and mortality and hospital records through electronic linkage to health insurance systems; (ii) validation, clinical adjudication and detailed sub-phenotyping for selected diseases (e.g. stroke, IHD, cancer); (iii) maintenance and management of extensive and uniquely large and complex datasets; (iv) enhancement of collaboration and data sharing with the wider scientific community; and (v) maintenance and development of administrative and technological systems underpinning the infrastructure, sample storage and resurvey. The CKB resource will improve our understanding of disease aetiology, risk prediction and development of new therapies, and should benefit populations worldwide.

Amount: £1,737,405
Funder: The Wellcome Trust
Recipient: University of Oxford

Establishing a feeder EM facility for South Parks Road Oxford 05 Apr 2016

In the last two years a convergence of a new generation of cryo-electron microscopes, with the first generation of direct electron detectors, and new algorithms for image analysis have enabled the routine determination of the structure of macromolecular complexes by EM. It is now possible to look directly at molecules as small as 150-200 kDa with an electron microscope and determine their atomic resolution structure; even more revolutionary, tomographic methods allow direct imaging of the internal machinery of cells at the level of single molecules. These advances are bridging the resolution gap between light microscopy and molecular structures. The goal of this proposal is to make our own research part of this revolution. We request funds to purchase two cryo-EM that will allow the collaborative group immediately to accelerate their own research and to nucleate an advanced cryo-EM facility in the South Parks Road science campus of Oxford University. This facility is also part of an Oxford-wide strategic plan, further integrating structural biology, and ensuring that the co-PIs, and others, can effectively generate the preliminary data needed to justify access to the Titan KRIOS microscopes that are now installed at Harwell as a national facility.

Amount: £2,146,619
Funder: The Wellcome Trust
Recipient: University of Oxford

In vivo investigation of the PARP-1 regulator, HPF1/C4orf27 04 Aug 2016

Poly(ADP-ribosyl)ation is a post-translational protein modification, synthesised by the PARP family of enzymes, that consists of long chains of repeating ADP-ribose nucleotide units. Through the modification of a variety of mediator proteins, PARPs control a number of cellular processes that are critical for genome stability, including DNA repair, regulation of chromatin structure, transcription, apoptosis and mitosis. However, the molecular players involved in these pathways and their mechanism s of regulation remain poorly understood. In recent years, blocking the PARP-regulated pathways using small-molecule inhibitors has become a promising strategy for treatment of cancer and acute cardiovascular conditions. For example, cell-permeable inhibitors targeting the PARP enzymes involved in DNA break repair demonstrated efficacy against certain types of cancer, such as hereditary breast or ovarian cancers. The intriguing alternative approaches to the chemical inhibition of PARPs include t argeting downstream protein effectors of PARP signalling and targeting PARG, the major enzyme that removes poly(ADP-ribosyl)ation. In the proposed studies, we will utilise a combination of biochemistry, cell biology and structural studies to improve our understanding of the function and regulation of PARG enzyme, and also to attempt developing the first specific cell-permeable human PARG inhibitors. Another goal of our studies is to screen for novel PARP-regulated DNA repair factors. Some of the identified proteins will be further characterised to elucidate their exact biochemical functions and regulation in DNA repair. Furthermore, we will explore the potential of these proteins to be exploited as targets for small molecule inhibitor design and cancer therapy.

Amount: £165,310
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

RCT to evaluate an intervention for depressed HIV-positive women in the perinatal period, to enhance child development and reduce maternal depression 02 May 2016

Rates of HIV are very high amongst pregnant women in parts of sub-Saharan Africa (SSA) with, for example rates of over 30% in antenatal clinics in South Africa1. Many receive their diagnosis during pregnancy as partof screening to prevent mother-to-child transmission (PMTCT). Depression is very common amongst these women, with up to 40% screening above the threshold for depression2, 3. Perinatal depression is associatedwith poor adherence to antiretroviral treatment (ART)4, 5, low clinic attendance, suicidal ideation6 and lowrates of breastfeeding7. Of major concern is the evidence of negative effects on fetal outcomes, children'sgrowth and cognitive development7. Improving the wellbeing of mothers and infants requires effectivetreatment of HIV and perinatal depression8. Although treatment of depression improves adherence to HIVtreatment by >80% 5, there is no established effective treatment for perinatal depression in SSA for motherswith HIV. The aim of this study is to develop and test the feasibility and acceptability of a six-session intervention targeting perinatal depression in HIV-positive women. The intervention will utilise Behavioural Activation (BA), which has been shown to be as effective as Cognitive Behaviour Therapy (CBT) in high-income settings9. BA is much simpler than CBT to deliver, especially by non-specialist health workers withlimited training in under-resourced settings. This early phase study is needed to develop, standardise and pilot the BA intervention and test its feasibility. The study will provide treatment for 70 pregnant women and follow them to 3 months postnatally. The outcomes of the main study will include: maternal depression, child emotional and cognitive development and growth, adherence to ART, initiation and maintenance of breastfeeding, infant HIV testing and vaccinations. This work will be conducted at the Africa Centre for Health and Population Studies, a large demographic surveillance site in South Africa with a high HIV prevalence.

Amount: £591,322
Funder: The Wellcome Trust
Recipient: University of Oxford

Institutional Strategic Support Fund 07 Sep 2016

Not available

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

Defining host and viral factors that are associated with hepatitis B virus control and clearance in Caucasian and African adults. 19 Nov 2015

HBV accounts for a significant global burden of liver disease. This project is founded on the urgent need to characterise T cell responses in order to enhance our understanding of differential outcomes of infection, and underpin future immunotherapeutic strategies. I will recruit a multi-centre cohort of adults with chronic hepatitis B infection (CHB) in Africa and the UK, to study factors associated with immune containment of HBV. Viral activity will be assessed using serum markers (HBeAg s tatus, HBsAg level, HBV DNA viral load). I will undertake deep sequencing of full length virus, first to identify patterns of selection of viral polymorphisms, and then to correlate these with changes in these biomarkers. Secondly, as CD8+ T cells may contribute to HBV suppression, I will use a computational algorithm to identify sites of HLA Class I mediated selection in HBV. These footprints can be used to identify sites of novel T cell epitopes and to identify polymorphisms that may impact on viral fitness. I will assess the impact of host factors that may have influence on this immunological containment, including age, gender and HIV co-infection. Overall, these data will provide unique insights into HBV immune control.

Amount: £1,023,974
Funder: The Wellcome Trust
Recipient: University of Oxford

An intervention to reduce the use of antimicrobials in chicken production in Vietnam. 26 Nov 2015

The proposed research will investigate the reduction of antimicrobial use (AMU) levels in chicken production in the Mekong Delta (Vietnam) by providing farmers with a locally-adapted veterinary support system. A randomised before and after controlled trial will be carried out on 120 randomly selected chicken farms. Following, a 12-month (observational) baseline phase, there will be a 18-month intervention phase, with random allocation of farms to one of three arms: (1) Free provision of Farmer T raining and a Farm Health Plan (FTHP) delivered through veterinarians; (2) Replacement of medicated with non-medicated feed, in addition to free FTHP; and (3) No intervention (control). Farms will be longitudinally visited to collect data on AMU (measured in grams of active principle of each type of antimicrobial), health and productivity. The design will capture (1) reductions in AMU (2) the impact of any reductions of the proposed intervention on AMR in commensal enteric bacteria in a random s ubset of farms (15 per arm); and (3) economic trade-offs between the costs of the intervention and gains as a result of savings in antimicrobial usage, improved animal health and productivity, and reductions in AMR in animals and the environment.

Amount: £949,112
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
Amount: £1,279,523
Funder: The Wellcome Trust
Recipient: University of Oxford