- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 19 Mar 2019
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Public Engagement Provision. 03 Dec 2014
Collaborative outreach programme with Mark Withers and the Orchestra of the Age of Enlightenment (OAE): This programme builds on a history of collaborations between Russell Foster and musician Mark Withers dating back to 1997 which includes a major education project, A Celebration of Life on Earth", with the OAE. We will start our work from scientific research into sleep, the eye and body clocks. Sleep and the eye are themes that have occupied musicians for centuries, mainly with poetic or spiritual inspiration. The musicians of the OAE give us the opportunity to survey some of this work and to create new work with a scientific rather than a poetic inspiration. The programme divides into 4 phases: Phase 1 allows for the professional development and preparation of the projectteam of Russell Foster, Mark Withers, 8 members of the OAE, 4 Oxford University scientists, and teachers from participating schools. 2 days of scientific and musical exploration will be followed by a day long introduction to the work for participating teachers. Simultaneously, the team will prepare teaching materials for use by the project participants which will be made available via the internet to any schools not directly participating in the project that may wish to use them. Phase 2 takes the programme into 3 primary schools in the Oxford area, in eachof which up to 60 Key Stage 2 children from Years 5 or 6 will take part directly in the programme. The children will have a day of music and science workshops where they will explore body clocks, sleep patterns and data collection on the scientific side and look at how sleep has been represented in music over the centuries while experimenting with simple compositional techniques. Pupils will then have a period of 3 months to collect research data based on pupils' own sleep patterns and to devise related musical material. This work will be brought together in In its 3rd phase, the programme will visit 2 groups of secondary school music and science students (GCSE/A-level), each group for 3 days. Working with the scientific team, these groups will devise a point of departure based on sleep research which they will then use to compose musical works to be performed by the musicians from the OAE. Schools in phases 2 and 3 will be selected in conjunction with the existing local music hub. Phase 4 celebrates the work of the programme in 2 concerts, an afternoon concert for schools and an evening concert for a wider public. The pieces devised by participatingprimary schools will be performed in the afternoon concert and as a pre-concert event for the evening. Both concerts will contain the pieces written by the secondary school groups alongside existing repertoire based on sleep. The concerts will be presented by Russell Foster and Mark Withers and will put all of the music being performed in the context of the research being carried out by Russell and his team.
Public Engagement Provision 28 Oct 2014
Ageing societies and diseases of modern living require truly novel, efficacious and safe medicines. Increasing investment in R&D has not improved the efficiency of this endeavor. There is an urgent need for novel, validated drug targets. To facilitate this, the Wellcome Trust and other organisations have sponsored large-scale genome-wide association and sequencing studies in patients, identifying thousands of genes linked to human disease, some of which may become targets for pioneer drug disco very. However, this genetic output is not widely exploited because of the lack of data and research tools to prioritise targets. The SGC was created by the Wellcome Trust to systematically solve 3-D structures of novel human proteins, and subsequently to develop novel inhibitors for a subset of these proteins (epigenetic probes). The free availability of data and reagents has amplified its impact and stimulated research in industry and academic labs. This proposal addresses the bottleneck in translation of genetic associations to therapeutic strategies. We will build capacity and infrastructure to create early discovery tools (Target Enabling Packages) for genes nominated by genetics, disease biology and clinical experts. These tools, including protein structures, assays, and initial chemical matter, will provide much-needed links between genome sciences and target discovery.
Public Engagement Provision. 03 Dec 2014
Understanding problems in social behaviour after neurological insult is a topic of considerable public interest with potential relevance to a wide range of neurological and neuropsychiatric disorders. I have previously undertaken substantial engagement with the StrokeAssociation, for example in designing information sheets about cognitive problems after stroke, and this has extended to running workshops for carers and volunteers to inform them about cognitive problems and also training workshops for therapists who use the diagnostic screening tests my team has devised (our training workshops are part of the programme of trainingon cognitive problems, recommended by the Stroke Association). For the current programme I propose to extend these activities to disseminate (i) information on social problems in neurological patients (after stroke but also dementia) and (ii) use of the social cognition screening test that will be utilised in the research programme. I will also disseminate to therapists results that emerge from the rehabilitation work.
Public Engagement Provision 03 Dec 2014
The James Lind Alliance recently identified their 'Top 10' research prioritiesaccording to what stroke patients and their carers want. Cognitive therapies, long-term consequences of stroke and aphasia therapy were the top three priorities. My proposal will address all of these. Stroke patients with anomia and their families will be therefore be the main public beneficiaries of knowledge arising from this research. The results will inform them about brain and language recovery after stroke and potential new treatments that will directly improve their communication and quality of life.
Microfluidic Platform for Investigating the Kinetics of Extracellular Vesicle Induced Metastatic Niche Formation 21 May 2018
Extracellular vesicles (EVs) are believed to be important messengers in the progression of metastatic cancer that prime distant organs for tumour cell colonisation. However, due to an inadequacy of relevant tools, we have a poor understanding of how EVs distribute to, diffuse into and remodel organs into metastatic niches. The goal of this project is to develop novel microfluidic platforms for performing real-time continuous quantification of EV kinetics over multiple days in physiologically-relevant microenvironments. Towards this end, I propose three aims: Develop Microfluidic Metastatic Niche Platforms to explore the interaction of extracellular vesicles with liver tissue and vasculature. Investigate the kinetics of EV distribution, uptake and diffusion in liver and vasculature compartments of Microfluidic Metastatic Niche Platforms. Explore the influence of EV kinetics (distribution, uptake and diffusion) on the ability of cancer cells to attach, invade and proliferate in Microfluidic Metastatic Niche Platforms. The results of this project will enhance our understanding of metastatic cancer progression and will contribute valuable data for numerous follow-up studies aiming to inhibit or even prevent the development of metastatic niches.
Cryptococcal meningitis (CM) is an infection of the brain and surrounding tissues (the meninges). It is caused by a yeast called Cryptococcus and is responsible for approximately 180,000 deaths annually (26). The most effective drug is amphotericin B (AmB) which needs to be given for 2 weeks and causes dangerous side-effects. A modified formulation, liposomal amphotericin B (LAmB), may be easier to administer to patients because it can be given as a single dose, and appears to be as effective as 2-weeks of conventional AmB (12, 15, 23). This observation raises a number of questions: 1) What is the optimal dosing strategy for LAmB? I will measure drug levels and describe their relationship with reduction in Cryptococcus levels. 2) How does one dose of LAmB exert a prolonged effect? i will image the movement of LAmB in mouse brains and meninges to assess how long LAmB stays in these regions. During treatment for CM, the rate of decline of yeast in spinal fluid is highly variable (24, 25, 27). Therefore, another question is: 3) Do different groups of yeast vary in teir response to treatment? I will collect samples of Cryptococcus and characterise their survival ability in various conditions.
Clinical Characterisation of a Broad Spectrum of Genetic Variation in the General Population 30 Sep 2018
Inborn errors of metabolism (IEM) are severe and extreme changes in metabolism caused by mutations in a single gene. Recent large-scale human studies have shown that genes causal for IEM are associated with nutrients, or ‘metabolites’, in the blood. However, whether these associations cause disease or adverse health outcomes is unknown. In this project, I will use IEM genes identified in these studies to link genetic variation to clinical features in a large human population. To do this, I will assemble a list of IEM genes of interest that were identified in the literature and in large population datasets. I will then test for associations between the variants I find in these genes and a wide range of clinical features found in open-access population datasets. As the IEM genes used in this study have been associated with blood metabolites previously, linking variants in these genes to clinical features will shed light on the molecular mechanisms underlying genes and disease in the general population. Understanding how genetic variation affects disease will help identify novel therapeutic targets and enable health professionals to better manage disease risk.
The Global Climate and Health Forum is a one-day, high-level convening of global climate and health leaders designed to mobilize stronger health sector engagement in and commitments to climate action. The Forum will bring together 250 leaders from national and local governments, health systems, public health agencies, civil society, and international organizations to build the community of climate and health professionals, strengthen collaboration across sectors, and raise the health voice for climate action. The Forum will be held at the University of California, San Francisco on September 12th, 2018. The Forum is an affiliate event of the Global Climate Action Summit, and co-hosted by the UCSF Global Health Group, Health Care Without Harm, Global Climate and Health Alliance, and US Climate and Health Alliance. In order to make the Forum a truly global event, it is imperative that the Forum includes speakers and participants from low- and middle-income countries who are leading climate mitigation, adaptation, and resilience work in the most vulnerable regions and communities. Funding from the Wellcome Trust will be used to support five travel scholarships for participants from the global South, including all registration, travel, accommodation, and event-related expenses.
Compaction of the genome into chromatin helps to protect the genetic material but also causes problems in regard to access for essential processes such as transcription, replication and repair. Chromatin remodelling complexes alter the state of chromatin through a number of processes that includes chemical modifications of nucleosomes and sliding their position on DNA. Nucleosome sliding is catalysed by a number of protein complexes, one of which is the multi-subunit INO80 complex. INO80 contains an ATP-dependent translocase motor, that is common to all nucleosome sliders, but also a variety of other subunits, most of which have unknown roles. Furthermore, not only does it require two INO80 complexes interacting with a single nucleosome to promote sliding, but the complex also has an ability to "sense" the presence of other nucleosomes to space them evenly on DNA indicating interactions with multiple nucleosomes. The mechanism for this process is poorly understood, particularly at a molecular and structural level. INO80 is highly regulated in several distinct ways, including chemical modifications, small molecule effectors and subunit interactions but none of these are well understood. Finally, how the various subunits, many of which are ATPases in their own right, contribute to INO80 activities is also unclear.
Campylobacter jejuni is the leading cause of bacterial gastroenteritis and thus poses a significant health risk. The bacteria is part of the natural microbiome of the chicken caecum where it appears to function as a non-invasive commensal but in the human intestine the organism becomes invasive and pathogenic. The Ó Cróinín group have recently reported that DNA supercoiling plays a key role in inducing this invasive phenotype and that relaxation of DNA supercoiling is associated with an increase in invasion and the appearance of an invasion associated secretive. This group have also unpublished data which reveals that DNA supercoiling allows the bacteria to survive and grow under anaerobic conditions which normally do not support growth. Given the anaerobic nature of some areas of the human intestine this could indicate that relaxation of DNA supercoiling could be critical in allowing this bacteria to both secrete virulence factors as well as to survive and grow under anaerobic conditions. The aim of this study is thus to investigate and characterise the effect of DNA supercoiling on the ability of the bacteria to grow under anaerobic conditions as well as to compare the secretion of proteins by microorganisms grown under anaerobic and microaerophilic conditions
Suppression of adaptive immunity by Salmonella 28 Nov 2017
Dendritic cells (DCs) have a crucial role in the development of adaptive immunity to bacteria. DCs transport the intracellular pathogen Salmonella from intestinal Peyer’s Patches to mesenteric lymph nodes where they present bacterial antigens to CD4+ T cells using MHCII molecules. DCs also secrete cytokines that stimulate recruitment and activation of T and NK cells. Salmonella is a globally important intracellular pathogen that survives in DCs and interferes with the processes of DC migration, cytokine production/sensing and T cell activation. The overall goal of this application is to understand mechanisms by which Salmonella interferes with these processes. Recently we identified an effector of the SPI-2 type III secretion system (SteD) that reduces the number of mature MHCII molecules on the surface of DCs. A significant component of the planned work is to understand its mechanism of action in detail. We will use candidate-based and unbiased screens, along with molecular cell biological approaches to characterize mechanisms involved in suppressing DC migration, production of IL-12 and IFN-gamma-stimulated host cell signaling. Collectively, this research will advance the field by providing novel insights into different mechanisms by which a bacterial pathogen subverts the development of adaptive immunity.
The Alliance for Accelerating Excellence in Science in Africa (AESA), Wellcome Trust (WT) and the Institut Pasteur International Network propose a researcher mobility program which would support African researchers (who share our ambition) to break down language and cultural barriers that impede greater African research collaboration in the biomedical and health sciences.Over the next 5 years, we aim to support at least 50 researchers to undertake mobility favoring the enhancement of their scientific careers while also increasing the understanding and interconnections of the African research community within different cultural and linguistic environments. Where language is the barrier we will look for flexible ways of providing support and funding language training. The program will aim to; Strengthen scientific collaboration between Anglo and Francophone speaking African scientists Build language skills/capabilities in English and French among African scientists Improve cultural understanding between English and French speaking African scientists The program will build out from the DELTAS and H3Africa researcher communities and the Institut Pasteur network, Our indicator of success will be; By December 2020, 50 African researchers will have experienced the mobility program and report positively on breaking down language and cultural barriers to research.
Human Fcgamma receptors (FcgammaRs) are proteins found on the surface of immune cells. They bind to antibodies, which are produced by the body, in response to infection. Some antibodies produced recognise their own tissues and are found in many diseases, including rheumatoid arthritis and lupus. It has been shown that genetic changes in the FcgammaRs are found more frequently in rheumatoid arthritis sufferers compared to healthy individuals. This project will focus on FcgammaRIIa, which is present on cells which are responsible for the destruction of many antibody-bound objects. Through a combination of cutting edge techniques, spanning physics, biology, immunology and medicine, we will uncover fundamental information within this field. This information would aim to inform the production of effective therapies to treat diseases such as arthritis, which put a huge strain on the NHS every year.
The Type II Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is a programmable RNA guided endonuclease, which is effective at gene editing in mammalian cells. These highly specific and efficient RNA-guided DNA endonucleases may be of therapeutic importance to a range of genetic diseases. The CRISPR/Cas9 system relies on a single catalytic protein, CRISPR associated protein 9 (Cas9), which can be guided to a specific DNA sequence anywhere in the genome by the substitution of a 20-nucleotide sequence, complimentary to the particular target, within a single RNA molecule (sgRNA).A number of computer programs have been developed to predict the sgRNA that cuts the intended target most efficiently with the least off-targetting. I aim to identify, design and characterise sgRNA molecules that could be used to target mutant corneal dystrophy genes by using molecular biology techniques such as in silico identification of mutations in corneal dystrophy genes suitable for CRISPR/Cas9 gene editing with in vitro testing of selected guides, design of sgRNA to target the identified mutation and comparison of sgRNA design and off-target prediction tools.
Metagenomic approaches are generating a long list of health and disease states associated with the microbiome (the microbes inhabiting our digestive tract) but without mechanistic understanding. The challenges arise from the enormous complexity of the microbiome, including genetic, environmental and dietary variations, microbe-microbe interactions, and the cost associated with studying the microbiome using murine models. If the field is to move beyond association, simple, well-controlled and cost-effective models allowing unbiased high-throughput studies are needed. The nematode C. elegans is a genetically tractable model, ideally suited for mechanistic and causative studies of host-microbiome and microbe-microbe interactions shaping host physiology and metabolism. Aims: 1) Establish an experimental microbiome in C. elegans based on strains from the human microbiome associated with health, disease and ageing 2) Generate fluorescent labelled bacterial strains and perform real-time imaging of gut colonisation 3) Characterise the effects of the experimental microbiome on the microbiome-gut-brain axis during ageing The experimental microbiome in C. elegans will be an important contribution to the field, complementing existing models. It will allow me to establish important collaborations, form a basis for my future research and address one of the most important questions of modern biology: the effects of the microbiome on host physiology.
A structural investigation into the action of and resistance to ribosome-targeting antibiotics 30 Sep 2018
Antibiotics are crucial to modern medicine, allowing treatment of life-threatening bacterial infections and making many surgeries like transplantations possible. However, pathogenic bacteria are rapidly evolving to resist their effects. Protein synthesis is one of the main antibiotic targets in bacterial cells. I will use structural biology techniques, principally cryoEM and single particle image processing, to understand how both novel natural products and clinical antibiotics bind to the ribosome to bring about their inhibitory effects on protein synthesis. Furthermore, I will investigate the cause of toxicity of certain ribosome-binding antibiotics by examining how they bind to the mammalian mitochondrial ribosome. Finally, I will use a combination of cryoEM and protein X-ray crystallography to elucidate how certain ribosomal-protecting proteins form complexes with the ribosome in order to bring about antibiotic resistance. On an individual level, these studies will allow an assessment of the viability of novel natural products as suitable clinical antibiotics. More generally, they will contribute to our knowledge of how different classes of antibiotics target the ribosomes of pathogenic bacteria, and how these bacteria evolve resistance. This knowledge will help the development of methods to rationally design new ribosome-targeting antibiotics that are able to overcome or circumvent resistance.
Antimicrobials remain the main means to treat and control bacterial infections, but their efficacy is now compromised due to overuse in humans, animals, agriculture, with bacteria developing resistance that renders certain antibiotics ineffective. Infections due multi-drug resistant (MDR) bacteria have emerged as one of the most significant global threats to human and animal health in the 21st century. Thus, the development of new antibiotics, or better ways to deliver existing antibiotics more effectively, is an urgent priority. Polymyxins are "old" antibiotics that have re-emerged as the last resort for treating infections caused by MDR Gram-negative bacteria. There are two polymyxins in clinical use, polymyxin B and polymyxin E (colistin), but their low stability, unpredictable pharmacokinetics and nephrotoxicity still raise significant concerns. We hypothesize that nano-engineered carriers will be able to restore and/or enhance the efficacy of polymyxins against MDR Gram-negative bacteria by improving their pharmacokinetic profiles, compared to standard mono and dual antimicrobial formulations, whilst minimizing the risks of adverse systemic effects. We will develop and optimize novel self-assembled nanocarriers for the controlled delivery of polymyxins and assess their potential to treat more effectively bacterial-related infections. This data will make the basis for future grant applications under the AMR initiatives.
Surgery and chemotherapy, which preferentially kills dividing cells, are the main treatments for colon cancer: a common disease in the developed world. To develop better treatments requires defining the molecular events that cause tumours to grow so that these specific aberrations can be bypassed. Mutations in a gene called Adenomatous polyposis coli (Apc) are the most common molecular change identified in colon tumours. The Näthke lab recently discovered that APC protein (encoded by the Apc gene) binds to and regulates the abundance of another protein (MINK1) with roles in cell division and movement. This raises the possibility that faulty control of MINK1 by mutated APC could explain why cells in colon tumours divide excessively and migrate aberrantly. I will investigate the function and control of MINK1. Using cells grown in dishes and also cells that form mini-gut structures called organoids, experiments will be designed to determine whether and how MINK1 is required for Apc mutations to cause cancer, and how MINK1 affects the structure of the gut lining. These issues will also be addressed in mice whose guts lack the Mink1 gene. Results will help to decide whether human colon cancer can be treated by new drugs that target MINK1.