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Recipients:
University of Oxford

Results

Mechanical testing of tendons and ligaments 27 Apr 2017

The mechanism for collagenous connective tissue damage is little understood. The micromechanics of collagenous tissues is important to understand as it may contribute to injury prevention and be useful in designing treatments for pre existing tissue damage. Bontempi et al in 2009 theorised a relationship between the the probability density function of the stretch value of individual fibrils and the 2nd derivative of stress with stretch. This relationship gained experimental backing in 2016. Recent research suggests that fibrils fail in the order they are first recruited. Combining this model with Bontempi's work suggests fibrillar level damage can be found by performing a stress - stretch test in vivo. However the relationship between order of recruitement and failure is yet to be experimentally proven. A collagen fibril is considered recruited once it is straight enough to bear load and be treated as a Hookean material. During my research I will be tracking fibrils from point of first recruitment to failure. A tensile loading rig will be used with a microscope to image the tendons at different stretch levels.

Amount: £0
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

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

What causes major depression? 08 Dec 2015

The objective of this proposal is to discover genetic loci that impact on risk for major depressive disorder (MDD). Our previous Wellcome funded work in China developed a consortium that delivered the first replicated genome-wide significant loci influencing MDD. We now want to take that success forward. Success depends on access to a large, suitably characterized, clinical sample. Of all common diseases, MDD requires most attention to the quality and nature of phenotyping. This is because MDD likely represents a broad neurobiological syndrome with multiple inter-locking etiologic pathways rather than a single disease entity with a clearly defined pathophysiology. We aim to collect 24,000 cases of recurrent major depression and 24,000 screened controls, using a collection strategy that maximizes clinical severity and homogeneity. Together with our existing sample of 12,000, the total sample will be 60,000, sufficent to identify at least 30 genetic risk loci. This will transform our understanding of the origins and nature of MDD, providing a starting point for improvements in mental health care.

Amount: £4,157,946
Funder: The Wellcome Trust
Recipient: University of Oxford

An Analysis Of The Animal/Human Interface With A Focus On Low And Middle Income Countries 30 Sep 2016

Fleming Fund: supporting surveillance capacity for antimicrobial resistance The animal/human interface with a focus on low and middle-income counties Stephen Baker – Oxford University Clinical Research Unit, Viet Nam Our core research themes aim to make defining contributions to the understanding of infectious diseases transmission and susceptibility; to develop new tools to prevent, control and treat antimicrobial resistant (AMR) organisms; improve clinical outcomes of the major endemic and emerging infectious and non-infectious diseases; and enhance public health policy in the region. Our unparalleled network of units, partnerships and collaborations, developed over time and spanning every level, enable us to deliver world-class research across these themes.

Amount: £21,091
Funder: The Wellcome Trust
Recipient: University of Oxford

A messenger role for NAADP in the central nervous system 11 Feb 2016

Stimulus-dependent combinations of multiple Ca2+-mobilizing messengers generate specific spatio-temporal Ca2+ signals which are decoded into distinct cellular responses. Cracking this Ca2+ code requires a detailed understanding of the spatial/temporal choreography of the messengers, proteins and organelles that generate these Ca2+ signatures. The three major messengers regulating Ca2+ signalling are inositol trisphosphate (IP3), cyclic ADP-ribose (cADPR) and nicotinic adenine dinucleotide pho sphate (NAADP). Whilst IP3 and cADPR activate Ca2+-release channels of the neutral endoplasmic reticulum (ER), NAADP is unique in evoking Ca2+ release from acidic endo-lysosomes: a new role for these important organelles. Our recent work suggests that two-pore channels (TPCs) a novel family of endolysosomal channels are the target Ca2+ channels for NAADP. Whereas IP3 signalling is relatively well understood, NAADP signalling is less clearly defined. This proposal seeks to clarify fundamen tal aspects of NAADP signalling, particularly the mechanisms by which cellular stimuli induce changes in NAADP levels, how NAADP mobilizes Ca2+ from endo-lysosomal stores (in particular the precise roles of TPCs), and the specific roles of endo-lysosomal Ca2+ stores in (patho)physiological processes.

Amount: £138,439
Funder: The Wellcome Trust
Recipient: University of Oxford

Using the immune system's trojan horse for vaccination 11 Feb 2016

Viral infections trigger an immune response characterized by induction of type I interferons (IFNs) that mediate many aspects of the host defence programme. Nucleic acids are often a molecular signature of infection and are detected by germline-encoded receptors that induce IFN expression. These innate sensors survey different subcellular compartments. We propose to study the detection of DNA in the cytosol, which is important not only during many bacterial and viral infections, but also in auto immune and autoinflammatory diseases and in DNA vaccination. However, the IFN inducing signalling pathways and the particular DNA sensors triggered by cytosolic DNA remain unknown or incompletely understood. The project includes four inter-related aims that individually and collectively ensure success. Firstly, we will study Aicardi-Gouti res syndrome (AGS), a monogenic autoinflammatory disease and model for other interferonopathies. We hypothesize that reverse transcribed cDNA from endogenous retroviruses triggers cytosolic DNA sensors in AGS. Secondly, we wish to identify cytosolic DNA sensing pathways detecting exogenous retroviruses such as HIV-1. Thirdly, we will establish the DNA virus Varicella zoster virus as a model to identify molecular players in cytosolic DNA sensing. Lastly, we will investigate the contribution of RNA polymerase III and RIG-I to DNA sensing. These projects constitute an integrated programme that will (i) identify cytosolic DNA sensors and pathways, (ii) establish new models, and (iii) define the role of cytosolic DNA sensing during infection with clinically relevant viruses and in autoinflammation. These ground-breaking studies will have potential impact on infectious disease, autoimmunity, DNA vaccination, and vaccine adjuvants.

Amount: £127,471
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural analysis of unconventional kinetochore proteins in Trypanosoma brucei 08 Jun 2016

Faithful chromosome segregation is essential for the proliferation of all organisms. Although studies in popular model eukaryotes have found that macromolecular kinetochore complexes assemble onto centromeric DNA to facilitate segregation, it is not known whether this mechanism applies to all eukaryotes. To uncover fundamental principles of eukaryotic segregation machinery, I am studying kinetochore functions in Trypanosoma brucei, an evolutionary distant eukaryotic parasite. No kinetochore prot eins has been identified and thus how trypanosomes segregate their chromosomes remains a black box. In my pilot study, I carried out a localization-based screening and proteomics and identified 12 kinetochore proteins. In this proposal, I aim to identify the complete kinetochore proteomes in T. brucei. Identified kinetochore proteins will be characterized using various techniques both in vivo and in vitro to reveal the molecular mechanism of chromosome segregation in trypanosomes. By revealing w hich features are fundamental and which are species-specific, I aim to understand the design principles of kinetochores that facilitate chromosome segregation with exquisite accuracy. Understanding the mechanism of chromosome segregation in trypanosomes is also medically important to develop better treatment for these diseases.

Amount: £178,556
Funder: The Wellcome Trust
Recipient: University of Oxford

Inflammation associated modulation of DNA methylation: An investigation into the genetic determinants and transcriptional consequences 18 May 2016

Chronic inflammation is pathologically and genetically implicated in conditions as diverse as Alzheimer’s disease and cancer. DNA methylation helps determine cellular activity and is frequently aberrant in malignancies. Given methylation is sensitive to the environment, understanding the effects of immune activity whilst considering genotype is of high importance. This application proposes to develop unpublished data where I observe stimulation with Toll-like receptor agonists leads to significant, highly delineated, genome-wide changes in monocyte DNA methylation in a genotype dependent manner. Notably, genes frequently mutated in cancer are enriched amongst those displaying immune triggered demethylation, suggesting a direct link between inflammation and mutagenic pressure. I will characterize the pathophysiological importance of these observations by describing the kinetics of differential methylation and describing the effects on gene expression. I will investigate how the local chromatin environment is influenced by changes in DNA methylation using ChIP-seq to histone and TET proteins. I further aim to explore whether changes in methylation are detectable at the single cell level. By developing a comprehensive panel of inflammation sensitive methylation sites I will explore whether these changes can be observed in clinical samples from cancer and infection, furthering our understanding of how past inflammatory events modify future responses.

Amount: £1,068,876
Funder: The Wellcome Trust
Recipient: University of Oxford

Zika and Chikungunya – emerging arboviral threats in Vietnam and SE Asia? 22 Jun 2016

The emergence of the Zika virus (ZIKV) in the Western Pacific and Latin America has underscored the challenge of controlling vector-borne viral infections. There is negligible data on the prevalence of ZIKV and chikungunya virus (CHIKV) in Vietnam. Thus, the aims of this fellowship are: 1/ To ascertain whether ZIKV and CHIKV have been circulating in Vietnam during the last 5 years. A diagnostic RT-PCR test will be performed to test the presence of ZIKV or CHIKV RNA in >8,000 acute plasma samples from patients with undifferentiated fever, and a negative diagnosis for dengue, based on laboratory tests. The expected outcome is a greater understanding of the geographical range of ZIKV and CHIKV in Vietnam and SE Asia, which is important for local diagnostics, clinical and public health management strategies, and global burden estimates. 2/ Assess the relative susceptibility of field-reared, Vietnamese Aedes aegypti and Ae. albopictus mosquitoes to infection with ZIKV and CHIKV by oral infection, with a virus spiked into healthy donor blood. Irrespective of whether these viruses are currently circulating in Vietnam, it is nonetheless prudent to test the susceptibility of local mosquitoes to these viral pathogens, as a critical element in risk assessment for Vietnam.

Amount: £123,029
Funder: The Wellcome Trust
Recipient: University of Oxford

In vivo microscopy system to probe microbiome link to inflammation 16 Jun 2016

The microbiome has been shown to impact immune responses in the gut and throughout the body. While there are many multiphoton microscopes available in the UK and at the University of Oxford, none of these systems combine the features necessary to image fluorescent reporters in tissues under varying conditions of inflammation or are juxtaposed to a state of the art germ free animal facility. Wellcome Trust funded investigators at the University of Oxford request a microscope specialized for in vivo imaging of inflammatory processes in multiple impacted tissues. The special features of the system will be large field of view, high scan rate and innovative use of a spectral detector array and dual laser multiphoton excitation. The system will be situated in the Kennedy Trust of Rheumatology animal facility, which will include both specific pathogen free and germ-free/gnotobiotic mice. We request a Zeiss 880 laser scanning microscope with non-descanned and spectral GaAsP detectors with a set of conventional lasers to combine the complementary strengths of multiphoton and single photon excitation with conventional non-descanned detectors and highly sensitive spectral detectors that can be used in different combinations to enable flexible imaging approaches for challenging inflamed tissues.

Amount: £284,088
Funder: The Wellcome Trust
Recipient: University of Oxford

Open access block grant award 30 Sep 2016

Not available

Amount: £85,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Oxford - Neuroscience 30 Sep 2016

Not available

Amount: £131,616
Funder: The Wellcome Trust
Recipient: University of Oxford

Oxford - Neuroscience 30 Sep 2016

Not available

Amount: £131,616
Funder: The Wellcome Trust
Recipient: University of Oxford

University of Oxford - Chromosome and Developmental Biology 30 Sep 2016

University of Oxford - Chromosome and Developmental Biology

Amount: £131,616
Funder: The Wellcome Trust
Recipient: University of Oxford

Oxford - OXION 30 Sep 2016

Not available

Amount: £131,616
Funder: The Wellcome Trust
Recipient: University of Oxford

Oxford - Genomic Medicine and Statistics 30 Sep 2016

Oxford - Genomic Medicine and Statistics

Amount: £131,616
Funder: The Wellcome Trust
Recipient: University of Oxford

Investigating the structure and functional role of gut tertiary lymphoid organs in inflammation 02 Mar 2016

Regulatory T cells play a key role in controlling the inflammatory response in the intestine but little is known about their positioning in the tissue in relation to the T effector and antigen presenting cell populations that they control. Tertiary lymphoid organs (TLOs) are organised lymphoid aggregates which are present in gut under homeostatic and inflammatory conditions. Currently little is known about the natural history of TLO’s during the initiation and perpetuation of bacteria-driven intestinal inflammation and their relationship to the antigen specific effector and regulatory T cell response. Here using state of the imaging technologies and novel methods to track bacteria-reactive T cells we will: 1) Characterise the natural history of TLO’s and their relationship to the regulatory and effector T cell response in intestinal inflammation and repair. 2) Use micro-array analysis of total gene expression of TLOs using laser capture microdissection to identify key pathways that control the TLO response. 3) Investigate cell trafficking within TLOs through blocking of known cytokine and receptor pathways using live imaging. These studies will shed light on the functional role of TLO’s in intestinal homeostasis and inflammation, and may identify interventions that manipulate TLO’s as novel therapeutic targets.

Amount: £261,485
Funder: The Wellcome Trust
Recipient: University of Oxford

Linking MRI and microscopy for multi-scale neuroscience: Mechanisms, diagnostics and anatomy 05 Jul 2016

MRI has tremendous potential to provide diagnostic and mechanistic insights into brain health and disease in living subjects, but is limited by its poorly defined relationship to histology. My group has pioneered techniques for combining MRI and histology that will enable us to define these relationships to provide more biologically interpretable MRI measures. We will construct models relating MRI and histology both from the bottom up (using microscopy to predict MRI signals) and top down (predicting histopathology from MRI). The top-down approach will use machine-learning methods to predict histological stains from in-vivo MRI, providing "virtual neuropathology" for improved diagnosis in living patients. The bottom-up approach will use electron and optical microscopy for hyper-realistic predictions of the MRI signal with the goal of identifying novel MRI signatures relating to mechanisms of neural health and disease. My group is poised to leverage our unique expertise within a comprehensive research program spanning scales (microscopic to macroscopic), species (rodent to humans) and expertise (physics to neuroscience). We will deploy these methods with neuroscience collaborators for: (i) virtual neuropathology in ALS; (ii) mechanisms of experience-induced plasticity; and (iii) high-resolution neuroanatomy. A primary output will be the "Oxford Digital Brain Bank", a freely available data repository.

Amount: £1,793,980
Funder: The Wellcome Trust
Recipient: University of Oxford

Fakes, fabrications and counterfeits: interrogating the social, political and ethical features of pseudo-Global Health 31 Aug 2016

For many decades STS scholars have examined the boundaries between science and pseudo-science, quackery and authentic scientific methodology. These examinations of so-called pseudo-scientific practices, concepts and methods have yielded great insight into the porous divide between what counts as seemingly authentic and inauthentic science. Drawing on concepts and methods developed within STS, this symposium seeks to interrogate areas considered pseudo-global health, namely practices and methods that are deemed inauthentic. Ideas of pseudo-global health have dominated the discourse in the growing markets of counterfeit drugs, equipment and vaccines, to data fabrications and fakes. Such activities are often regarded as undermining ‘real’ global health initiatives and goals. These discussions are premised on ideas that ‘real’, ‘unreal’, ‘authentic’ and ‘inauthentic’ global health is clearly recognisable and moreover, that all global health actors value the same thing(s) – namely that a particular view of authenticity or realness overrides all other concerns. This meeting seeks to address the absence of methodological and theoretical attention given to exploring the social, political and ethical value in pseudo-global health activities. We seek to interrogate the binary positions between ‘real’, ‘pseudo’, ‘authentic’ and ‘inauthentic,’ and elucidate what is often buried in these concepts: the people, processes and agendas.

Amount: £6,292
Funder: The Wellcome Trust
Recipient: University of Oxford