Cookies disclaimer

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

Current Filters

Recipients:
University of Oxford

Results

How do CHRND mutations disrupt AChR cluster formation? 27 Apr 2017

The project aims to utilise mutations identified in congenital myasthenic syndromes to study the interactions of the muscle acetylcholine receptor (AChR) and its anchoring protein, Rapsyn.Widely quoted publications suggest that Rapsyn interacts with the M3-M4 intracellular loop of the AChR alpha, beta and epsilon subunits, however we have identified several kinships in which mutations in the M3-M4 intracellular loop of the AChR delta subunit underlie a phenotype that mimics myasthenic syndromes caused by mutations in RAPSN. The project will use in vitro mutagenesis and cell culture experiments to investigate how mutations in CHRND impair agrin induced-AChR clustering in C2C12 myotubes. Variants identified in CMS patients, ie. p.(Glu381Lys) or p.(Arg376His) will be incorporated into expression constructs and transfected in chrnd-/- C2C12 cell that have been created using CRIPR/Cas9 techniques. Similar experiments will be performed following in vitro mutatagenesis that is designed to disrupt potential PKA, PKC and tyrosine kinase phosphorylation sites within the M3-M4 intracellular loop of the delta subunit. The effects of the mutations on agrin-induced AChR cluster formation will be assessed by using fluorecent-labelled alpha bungarotoxin and microscopy. This short project will provide novel data on how mutations within the AChR itself can impair the cluster formation.

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

Human Genetics and Disease Biology: Core Renewal for the Wellcome Trust Centre for Human Genetics 30 Oct 2016

Human genetics provides a unique and powerful tool for understanding normal biology, disease pathophysiology, and infectious mechanisms. The "genetic revolution" of the last decade has witnessed an explosion in knowledge of associated variants for individual traits. Looking forward, large population resources will facilitate a new paradigm, going from variants (individually or collectively) to multiple phenotypes, and new functional tools will help unlock causal genes and mechanisms. In parallel, genome sequencing will become routine in parts of clinical medicine. The Wellcome Trust Centre for Human Genetics (WTCHG), a large interdisciplinary research centre comprising 400 scientists in ~45 research groups, is one of the leading institutes, globally, in human genetics. Since its founding 21 years ago, the WTCHG has played a pioneering role in the progress and success of human disease genetics and mechanism research. Our focus is the development and implementation of novel approaches to exploit human genetics and uncover disease biology so as to improve healthcare. Critical to the Centre’s success is its lively environment which fosters collaborations between research groups across disciplinary boundaries, with research supported by seven Core teams. This application seeks core support to enable the WTCHG to continue its leading role in the field.

Amount: £15,178,415
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

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

Optogenetic analysis of the neural function of 5-HT-glutamate co-transmission 30 Sep 2017

This research investigates the relationship between 5-HT neurons and two key brain functions: sleep-wake changes and fear learning. Of particular interest is the role in these processes of glutamate co-released from 5-HT neurons. Two approaches will be used. One approach is based on recent evidence that glutamate is preferentially released from 5-HT neurons firing at low frequencies, whereas 5-HT is preferentially released at higher frequencies. The second approach is based on a mouse with glutamate deficient 5-HT neurons.In Oxford the research will have 3 main goals:i) Measurement of firing of identified 5-HT neurons during the sleep-wake cycle. This will be achieved using optotagging to record for the first time, the firing of identified 5-HT neurons during changes in sleep-wake activity.ii) Optogenetic manipulation of 5-HT neurons on sleep-wake activity. These experiments will optogenetically manipulate 5-HT neurons (using different stimulation frequencies) to establish the causal relationship between changes in 5-HT firing and sleep-wake activity.iii) Optogenetic manipulation of 5-HT neurons in mice with glutamate-deficient 5-HT neurons. These experiments will use a mouse with glutamate-deficient 5-HT neurons to further test the role of glutamate co-release.I will follow a similar research strategy to investigate the role of glutamate co-released from 5-HT neurons in emotional learning at NIH.

Amount: £80,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Improving health outcomes for looked after children and young people 25 May 2017

Previous research suggests that looked after children are less likely to be treated in the way that the statutory guidance on promoting the health and well-being of looked after children recommends, and that they receive worse healthcare in comparison to their non-looked after peers. They also have worse experiences of the health service, and due to complex and time consuming policies and procedures, are treated inefficiently or inappropriately. My POSTnote will seek to summarise the current policy context on promoting the health of looked after children and young people, consider any related issues that may need to be addressed in future policy and explore the latest research and information on how best to promote their health. By promoting their long-term health outcomes, care leavers should be more able to go on to lead successful and happy lives, in which they are able to contribute to society. By undertaking this fellowship I hope to better understand: The process of creating a rigorous POSTnote for parliamentarians How parliamentarians use research to inform policy The process of policy development The role of Select Committees, and The role of All Party Parliamentary Groups

Amount: £8,010
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

Mapping the quality of medical products – evidence to inform strategy and policy change 16 Jun 2016

Poor quality medicines are major neglected public health threats that jeopardise the lives of millions. Data on their epidemiology, public health burden and impact are scattered and dislocated. Because of this, they are often misinterpreted, confounding counter-measures. A unified repository is desperately needed. We aim to create an open access data-sharing platform of valuable information on the quality of essential medicines. This platform will provide crucial evidence to inform policy and model the impact of poor quality medicines on patient outcomes and drug resistance. This is essential to inform concerted interventions to improve global medicine quality. The system will be designed for the principal target users - medicine regulatory authorities, international organisations, pharmacists, physicians and research groups. The project will build on the success of the WWARN Antimalarial Quality Surveyor that tabulates and maps the distribution of antimalarial quality across time and location. New databases and interactive maps will be generated for antibiotics, anti-retrovirals, vaccines and essential medicines for diabetes and cardiovascular diseases. These will collate information from formal and grey medical and lay literature, including internet data from optimized text-mining technology developed by HealthMap, providing urgently needed and timely intelligence on the extent of the medicine quality problem internationally.

Amount: £914,993
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

Ultrasonic Delivery of Theranostic Anti-Cancer Agents 19 Apr 2016

Key words: platinum, controlled release, cancer, ultrasound, drug delivery This research develops a powerful new methodology for treating cancer with a highly specific, potent action and markedly lower side-effects, compared with existing therapies. It combines the potency of platinum anti-cancer complexes – encapsulated to prevent unwanted side-reactions – with the selectivity of drug release at a tumour afforded by focused ultrasound. We will synthesise new PtIV prodrugs designed for encapsulation and delivery using ultrasound; a novel approach for platinum drug delivery. Groups will be attached to the PtIV centre to aid tracking both in cellulo and in vivo. Once inside cancer cells, the PtIV complexes will be rapidly converted to PtII by intracellular reducing agents. The resultant PtII fragment is anticipated to form DNA lesions, ultimately inducing cell death. The PtIV prodrugs will be liposomally encapsulated, and the liposomes attached to large gas-filled microbubbles, creating a drug delivery vehicle. Ultrasound – focused at the site of a tumour – will destroy the vehicle, releasing the prodrug and enhancing the penetration of the prodrug into the tumour. We will investigate PtIV prodrug characterisation, release from the delivery vehicle, cellular uptake, reduction to PtII species, cellular distribution and cytotoxicity.

Amount: £351,122
Funder: The Wellcome Trust
Recipient: University of Oxford

Using Mendelian randomization to determine whether iron status is causally related to the risks of severe malaria and invasive bacterial infections in African children. 11 Nov 2015

Iron deficiency is common and iron supplementation improves developmental outcomes in African children. Despite these benefits, it is uncertain whether improving iron status might increase the risks of malaria and invasive bacterial infections. Observational studies indicate that higher ferritin concentrations increase the risk of malaria, but it is unclear whether higher ferritin levels are a cause or a consequence of infection. Alternately, randomized controlled trials of iron supplementation have reported inconsistent effects and few trials have been sufficiently powered to assess the risks of severe malaria or bacteraemia. The aim of the project is to determine whether iron status is causally related to the risks of severe malaria and bacteraemia using Mendelian randomization. This approach requires two steps. The first step is to identify common genetic variants that alter iron status by conducting a genome-wide association study in 4870 children in 5 African countries. The second step is to assess whether inherited variation in iron status influences the risk of severe infection within large case-control studies of 7,589 severe malaria cases and 2,530 bacteraemia cases with similar numbers of controls. This project is achievable through collaboration. The findings of the project will be used to inform public health policy.

Amount: £543,787
Funder: The Wellcome Trust
Recipient: University of Oxford

In Their Own Voices: Vulnerabilities & Abilities of Women, Children, & Families in Health Research 26 Jan 2016

Efforts surrounding the Millennium Development and Sustainable Development Goals have brought much needed attention to lessening the burden of disease shouldered by women and children, which is most severe in low-income countries. Lasting advances in women’s and children’s health will require improvement of health systems, environment, education, improved access to effective health interventions, including better ways to deliver care in rural, low-income settings. Innovations in each of these areas will require clinical, social science and implementation research. However, many of these women and children are considered to be vulnerable to harms, coercion or exploitation, making inclusion in even potentially beneficial research ethically concerning. While significant strides have been made to develop research ethics guidance for those working with vulnerable populations, critical gaps remain in our understanding of specific vulnerabilities in context, accompanying abilities, the role of social support in mitigating vulnerability, and individuals’ own perceptions of vulnerabilities and abilities. To address these gaps and to improve support and guidance for responsible research with women, children and families, we propose an interdisciplinary collaborative study with investigators in maternal-child health, infectious disease, and social science research across three international sites in the Wellcome Trust Major Overseas Programmes: Kenya, South Africa and Thailand.

Amount: £693,280
Funder: The Wellcome Trust
Recipient: University of Oxford

A Cluster for the Development of Dynamic 3D Nanoscopy 05 Jul 2016

Imagine if we could watch multiple molecules in living cells as they move and interact. This dream may seem years away, but it is now realistic to achieve real-time dynamic super-resolution imaging of multiple tagged proteins in three dimensions (3D) in cells and in tissues. This will allow biologists to discover large-scale patterns involving diverse structures including transport vesicles, ribosomes, and chromatin domains, all previously inaccessible because they lie in the gap between the resolution of electron (1- 2 nm) and light microscopy (200-300 nm). The "big picture" of cellular organization/information processing would emerge, with advances in understanding cell function in health and disease. While we can now do this in 2D, 3D imaging is needed to follow objects as they move out of the plane. Achieving 3D imaging is a major challenge and will require two orders of magnitude more information per cellular volume, and novel algorithms to classify, analyze, and visualize patterns from massive datasets. We propose specific innovations (Table 1) that, should allow us to achieve this over the next five years, given our team’s proven track record of success.

Amount: £729,183
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

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

Protein Antibiotics: Discovery, mode of action and development 05 Apr 2016

The rise of antibiotic resistant bacteria poses a catastrophic threat to humanity. Despite the pressing need, few new antibiotics have entered the clinic in the last 30 years. The situation is particularly urgent for multidrug resistant Gram-negative bacteria Pseudomonas aeruginosa and Klebsiella pneumoniae. We will address this problem through the use of bacteriocins, which are species-specific protein antibiotics made by Gram-negative bacteria during environmental stress. We recently discovered that pyocins, deployed by P. aeruginosa to kill neighbouring Pseudomonad spp, are more effective at protecting mice infected with an acute P. aeruginosa lung infection than tobramycin, the leading antibiotic used clinically for the treatment of pulmonary infections. Through this multidisciplinary, multicentre collaborative award, which brings together experts in bacteriocin structure and function (Kleanthous, Walker), pathogen genetics and genomics (Maiden, Parkhill) and animal models of bacterial disease (Evans, Taylor), we will (i) uncover the mechanism(s) by which pyocins translocate across the P. aeruginosa cell envelope, capitalizing on exciting new structural and microscopy data, (ii) investigate the efficacy of pyocins as antibiotics in animal models of disease, and (iii) initiate the first such studies on klebicins, bacteriocins that target Klebsiella pneumoniae.

Amount: £2,151,302
Funder: The Wellcome Trust
Recipient: University of Oxford

Improving the efficacy of malaria prevention in an insecticide resistant Africa 08 Dec 2015

Impressive reductions in malaria have occurred throughout sub-Saharan Africa over the past 12 years. However progress has not been geographically uniform and there are some high-burden countries where, despite good coverage with long lasting insecticide-treated nets (LLINs), the main preventative measure recommended by WHO, parasite prevalence rates and mortality from malaria remain obstinately high. Burkina Faso falls into this category. Despite two successful national LLIN distribution campaigns 60 % of children are persistently infected with malaria. Increased resistance to the pyrethroid insecticides used in LLINs and extensive transmission by mosquitoes biting outside the home, or at times when people are not protected by LLINs, are likely reducing the impact of LLINs but the relative importance of these poorly characterised vector factors, in relation to other human or health system factors has never been determined. This project will collect extensive empirical data and use models of malaria transmission to quantify the level of protection provided by LLINs in an insecticide resistant Africa. Via a detailed understanding of the factors limiting the efficacy of current tools we will identify the most cost effective, complementary interventions that would drive malaria transmission towards zero.

Amount: £35,942
Funder: The Wellcome Trust
Recipient: University of Oxford