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Results

Nanomagnetism in cancer treatment: How Iron Oxide Nanoparticles can be used to target therapies to the brain 31 May 2018

Iron Oxide Nanoparticles (IONPS) are a class of nanoparticles used in targeting therapies towards tumour sites. The emerging field of nanotechnology has garnered a lot of interest in tumour therapy especially for brain tumours. IONPS can be coupled with an anticancer drug and with the use of magnetic field (Muthana et al., 2015) can be ‘steered’ towards a desired site within the body. This technology would hope to increase the amount of drug concentration to the tumour site which also means that the amount of drug delivered systemically could be reduced. In this project, the student will learn how to use FEMM (Finite Element Mathematical Modelling) to create magnetic array (a special arrangement of magnets) to optimise the magnetic field strength. This will be tested through a range of in-vitro experiments for its efficacy. Laboratory training will include isolating human peripheral mononuclear cells (PBMCs), flow cytometry to examine PBMCs cell viability/cell death following the addition varying concentrations of IONPS. Data analysis will involve using a software called FlowJo (used for flow cytometry) and Prism software to carry out statistical analysis. The student will be able to learn how to operate a confocal microscope, carry out immunohistochemistry and processing tissue samples.

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

‘Epidemic Encephalitis and the Intersection of General and Mental Health Service Provision in Sheffield, 1917-1951’. 08 May 2018

Parity of esteem between mental and physical health has become a rhetorical keystone of twenty-first century political manifestos and health policies. Nonetheless, mental health services are defined by long waiting times and underfunding, challenging the idea that parity has been achieved. This PhD thesis will situate this agenda within the history of health care provision in Britain, demonstrating that although this concept has shaped policy for over a century, implementing it in practice has recurrently failed. To navigate the complexities of this issue, focus will be on the outbreak of Epidemic Encephalitis in Sheffield which had high incidence rates throughout this national epidemic during the 1920s and 1930s. Epidemic Encephalitis was characterised by mental and physical symptoms, and transcended the boundaries between these separate medical approaches. This thesis will present a practical analysis of how this condition was studied and treated by Professor Arthur Hall from the University of Sheffield and his contemporaries, which will demonstrate that despite progressive legislation, mental and physical health care remained institutionally and therapeutically separate. In revealing how and why parity of esteem failed in practice in this city and beyond, this research will offer insights for current policymakers, medical practitioners and the public.

Amount: £85,740
Funder: The Wellcome Trust
Recipient: University of Sheffield

The Clostridium difficile S-layer in infection and transmission 30 Nov 2016

The surface exposed, semi-rigid proteinaceous S-layer of Clostridium difficile has been linked to several key pathogenicity traits including colonisation and activation of inflammatory immune responses. Recent isolation and characterisation of a spontaneous S-layer mutant has revealed an inability of this strain to initiate fatal disease in the hamster model and severe sporulation defects. These observations infer a pivotal role in infection and transmission, which requires further investigation to provide greater molecular understanding of the role of the S-layer in C. difficile disease. Isolation of this strain, and the availability of the molecular tools to allow manipulation of SlpA, the major protein of the S-layer, provide a unique opportunity to determine the fundamental role of this structure in disease. We will combine our joint expertise to unravel the molecular details of S-layer structure and function, including its link to effective sporulation, transmission and specific role in infection. Further, the opportunity to express 13 previously identified clinically relevant variants of this protein within a single strain, will allow definitive conclusions regarding the specific role of SlpA in colonisation, immune activation and disease severity. Such information is crucial to our understanding of C. difficile biology and the future development of effective therapeutics.

Amount: £1,217,249
Funder: The Wellcome Trust
Recipient: University of Sheffield

Modelling synaptic and intrinsic plasticity in the somatosensory cortex 04 Dec 2017

Somatosensory plasticity is as key ingredient of sensorimotor learning; a better understanding of the plasticity mechanisms involved would yield insights for neuroprosthetics, motor rehabilitation, and chronic pain. In the somatosensory cortex, changes in the hand representation have been described under stimulation paradigms lasting only a few hours. Conversely, other evidence shows that cortical representations are stable over long periods of time. These disparate results raise the question of whether different plasticity mechanisms, operating on different timescales, might be involved. Recent advances in neuroimaging techniques have allowed us to observe and track plasticity in the human brain, leading to novel insights into the timescale and extent of sensorimotor learning. However, inferring specific plasticity mechanisms from these data has been challenging, as observed cortical changes are often compatible with multiple mechanisms. Here, we focus on two forms of plasticity: synaptic plasticity, which determines which specific inputs will excite a cortical neuron, and intrinsic plasticity, which determines the neuron’s overall responsiveness. We propose a computational framework that will track the effects of these two mechanisms on sensory cortical representations and make predictions that can be empirically tested using existing fMRI paradigms.

Amount: £99,605
Funder: The Wellcome Trust
Recipient: University of Sheffield

Developing tissue-engineered dysplastic oral mucosa models to study the extracellular matrix (ECM) in oral squamous cell carcinoma (OSCC) progression 31 May 2018

Cancer progression is determined by the interaction between tumour cells, stromal cells (fibroblasts and leukocytes) and other components of the microenvironment such as the extracellular matrix (ECM). The ECM is predominantly deposited by dysplastic and cancer-associated fibroblasts (CAF) and play key roles in cancer progression. Although considerable evidence exists demonstrating a role for dysplastic fibroblasts and CAF in oral squamous cell carcinoma (OSCC), little is known about their influence on ECM: tumour interactions. This project aims to generate and begin to characterise novel tissue-engineered 3D constructs using dysplastic-derived ECM, as a native scaffold to accurately model tumour:ECM interactions in OSCC progression.

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

Development of novel antagonists of the cell surface adrenomedullin 2 receptor for the treatment of pancreatic cancer 01 Oct 2017

Pancreatic cancer is the 10th most common cancer, but in the next 15 years, it will become the second highest cause of cancer-related death. Unlike almost all other cancers, the prognosis has not changed in the last 30 years. After diagnosis, outcomes are very poor, with 1-year and 5-year survival rates of <25% and <5% respectively. The best current therapies offer only a few months of increased life expectancy, and patients’ quality of life is poor despite palliative treatments. There is clearly a pressing need for better treatments for pancreatic cancer. A team from the University of Sheffield led by Professor Tim Skerry, with Peakdale Molecular and Sandexis Medicinal Chemistry have been awarded Seeding Drug Discovery funding to develop selective antagonists of the adrenomedullin-2 receptor. Adrenomedullin is a hormone involved in cancer growth and spread, which also has important roles in the control of blood pressure. Adrenomedullin acts through two different receptors one of which mostly regulates blood pressure. The other has important roles in cancer biology. The team have shown that in model systems, blockade of the receptor reduces tumour growth and spread. They will develop their existing novel lead compounds to block the adrenomedullin-2 receptor and inhibit its important roles in cancer, while keeping its normal functions.

Amount: £100,000
Funder: The Wellcome Trust
Recipient: University of Sheffield

How Does the Interplay of PI3-kinases at the Phagosomal Membrane Co-ordinate Pathogen Killing? 30 Sep 2018

Animals (including humans) are protected from bacterial infection by patrolling innate immune cells. Neutrophils (the most abundant phagocytes) engulf their prey into membrane-bound phagosomes, enabling targeted, segregated and highly concentrated microbicidal activity. Phosphoinositide 3-hydroxykinase (PI3K) signalling regulates many aspects of neutrophil function and PI3K-derived phospholipid mediators accumulate at the phagosomal membrane to facilitate killing. However, the identity of the PI3K isoform(s) involved, the mode of delivery to the phagosome, and the extent to which pathogens subvert this process have not been determined. Our novel preliminary data show that the lipid messenger PIP3 (a product of PI3K activity) waxes and wanes at the phagosomal membrane, reflecting ‘quantal’ delivery from an unidentified cellular organelle, with subsequent changes in phagosomal pH. I will undertake a detailed exploration of this critical process using the genetically tractable zebrafish, which allows high resolution in vivo imaging of neutrophils in relevant infection models. I will determine the dynamics of PI3K signalling in response to a range of pathogens,quantifying PI3K-derived phospholipids at the phagosomal membrane. My results will inform our knowledge of PI3K signalling in neutrophil bactericidal activity, and may suggest how these processes might be manipulated to enhance pathogen killing.

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

Identifying Brain Areas and Locating Neurons Involved in Zebrafish Memory Formation 31 May 2018

The aim of the proposed project is to define the brain areas of zebrafish larvae involved in memory formation. The cellular basis of memory formation is synaptic plasticity: a change in synaptic strength during long-term potentiation (LTP) and depression (LTD). Molecular details of both LTP and LTD are well understood but exactly how memory is stored in changes in synaptic efficacy is unclear. Transparent zebrafish larvae may be an ideal model organism to address this problem. It has been found that zebrafish are able to remember specific objects, showing that they have declarative memory. It is, however, unknown what parts of the fish brain are responsible for novel object memory formation. In this project, I aim to identify and locate zebrafish neurons that undergo long-term plasticity during memory formation. For this purpose, I will 1) perform behavioural experiments in which fish will memorise certain objects and then 2) perform in situ-hybridisation defining the expression of genes whose expression is triggered upon long-term potentiation and/or long-term depression. These include the immediate early genes Homer 1a, Arc and c-fos. The proposed project will contribute to the establishment of zebrafish as a model organism to study circuit mechanisms of memory.

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

Analysis of the meiotic events that cause Exo1 phosphorylation and the phenotypic significance of this PTM 27 Apr 2017

The conserved protein Exo1 is an important endonuclease/exonuclease required in the DNA damage response for 5’ to 3' end resection, and during crossover designation in meiosis. The host laboratory has discovered a novel post translational modification (PTM) in Exo1 that arrises following Spo11-DSB during yeast meiosis. This summer research project will determine which steps in the meiotic recombination pathway lead to Exo1 phosphorylation and investigate which Kinase catalyses the PTM. I will also contribute to determining which amino acid is phosphorylated, so in the longer term, non-phosphorylatable mutants can be made to understand how the PTM affects DSB repair during meiosis. Whole cell extracts of mutant yeast strains that either cannot progress through the DNA repair pathway or lack a kinase activity will be tested for the presence/absence of phosphorylated Exo1 periodically as the cells undergo meiosis. I will also prepare meiotic cultures for protein extraction and enrichment of PK tagged Exo1 for Mass Spectrometry analysis to map the phosphorylation event. I will use various cell culture and biochemical techniques like protein extraction and quantification, western blots and immunoprecipitation. This yeast model will develop understanding of Exo1 function in higher eukaryotes as yeast Exo1 is homologous to the human Exo1.

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

How is embryonic development timed and scaled? 05 Jul 2016

How embryonic development is timed and scaled remains enigmatic. Understanding the underlying mechanisms remains a central challenge in biology, since these mechanisms coordinate the growth and patterning of all tissues and organs and when disrupted are likely to form the basis of many congenital disorders. My recent work on the developing chick wing demonstrates a pivotal role for intrinsic timers in limb development. In this fellowship, I will build on preliminary data and elucidate the molecular nature of intrinsic timing mechanisms. I will define the intrinsically and extrinsically regulated transcriptome to build a picture of how these processes control embryonic limb development. I will determine the degree to which developmental time can be reset and ask if this gives insights into constraints that are imposed on limb regeneration. Finally, I will advance this work by asking how extrinsic signals and intrinsic timing mechanisms interact to scale growth and patterning in relation with species-specific gestation rates.

Amount: £1,144,343
Funder: The Wellcome Trust
Recipient: University of Sheffield

Learning disabled people’s intimate lives: Accounting for Austerity 30 Jun 2016

This proposal seeks funding to host a two-day participatory Research Meeting in which we will use design fiction methods to critically explore and identify the significant impacts of recent austerity policies upon the intimate, sexual and emotional lives of people with learning disabilities. Our aim in the Meeting is to co-produce and design future inquiry: identifying areas of concern; designing research questions; planning impact; and undertaking the necessary planning involved in high quality co-produced disability research alongside people with learning disabilities and their organisations. Specifically, the Meeting will bring together self-advocates (people with learning disabilities) and their organisations, and academics, practitioners and researchers, to share concerns, knowledges, and experiences of the ways in which austerity politics are reshaping intimate citizenship for learning disabled people – that is, their rights to personal, intimate and sexual life and access to family, love, sex, kinship, friendship, and community. We will learn from design fiction, ‘a method of critical design that uses fictional and narrative scenarios to envision, explain and raise questions about possible futures for design and the society’ (Tanenbaum 2015), in order to imagine alternative futures, work through key concepts and ideas in accessible ways, and strategize future innovative inquiry and impact.

Amount: £5,240
Funder: The Wellcome Trust
Recipient: University of Sheffield

The role of “soft skills” in life outcomes of children and young people 31 May 2016

The grant will be used to fund a one-day interdisciplinary (Economics and Psychology) workshop on the specific topic of: ‘The role of "soft skills" in life outcomes of children and young people’. ‘Soft skills’, such as emotional intelligence, social/interpersonal skills, and sense of agency are increasingly being identified as important factors in explaining various life outcomes; these include (mental and physical) health outcomes directly, and outcomes, that affect health indirectly, including educational achievements, earnings, subjective wellbeing, and a variety of risky behaviours (crime, drug abuse and alcohol consumption etc.). The available evidence indicates that while the foundations for soft skills develop during early life, they remain malleable over the life cycle. Therefore, research that focuses on soft skills – their measurement, outcomes, and development –is likely to be particularly important in shaping an effective public policy agenda in this area. The workshop will be a novel interdisciplinary collaboration, which will provide an interactive platform for active researchers and policy-makers, from a range of backgrounds and institutions, with an interest in child development and soft skills. The event will aim to stimulate debate, promote collaboration and interdisciplinary thinking, as well as shape future health and well-being research and policy agendas.

Amount: £3,690
Funder: The Wellcome Trust
Recipient: University of Sheffield

Symposium on the ethics of an innovative approach to healthcare trial design 29 Feb 2016

Usual care or new treatment, which is best? In an ideal world, healthcare systems would integrate research and healthcare and provide the answers to this question. Historically however, research and healthcare have been seen as conceptually distinct, and in practice have distinct oversight regimes, and different approaches to informed consent. Recently, the innovative 'cohort multiple randomised controlled trial (cmRCT) design (Relton et al, 2010) attempts to bridge these differences by encouraging a 'tailored' approach to informed consent for the patient in health research, rather than 'full disclosure' of information to the research participant. To date 18+ funded and ethics committee approved studies in the UK, Canada and Netherlands are using the cmRCT design with it's 'tailored' approach to informed consent (and reporting high recruitment and consent rates). This symposium will address key questions relating to the 'tailored' approach to informed consent used in the cmRCT design; namely, what information is conveyed, to whom, and when. Researchers using/ interested in the design together with leaders in bioethics, informed consent research and comparative effectiveness trial design will discuss the acceptability of the 'tailored' approach to informed consent for trials designed to inform routine healthcare decisions by patients and their healthcarers.

Amount: £14,752
Funder: The Wellcome Trust
Recipient: University of Sheffield

Investigation of Calcium influx in endothelial cells under flow. 01 Apr 2016

Endothelial cell (EC) function is affected by forces generated by flowing blood on the artery wall (wall shear stress, WSS). Unidirectional WSS occurs in unbranched areas of the arteries, which are protected from atherosclerosis, while oscillatory WSS occurs at branch points, where the majority of atherosclerotic plaques are found. ECs can sense force via multiple mechanoreceptors, which induce calcium signalling in response to WSS. Although ECs can distinguish between unidirectional and oscillatory WSS, the mechanisms that control this are unknown. This projects aims to determine the origin of Calcium signalling, which is recorded as a response of endothelial cells to the applied flow. Ca2+ signalling originates either from Ca2+ influx from the media into the cell or from Ca2+ release from the intracellular stores of the endoplasmic reticulum. To discriminate between these two sources, it will be compared flow- induced Ca2+ mechanoresponse in Ca-containing and Ca-free media under unidirectional and 1 Hz oscillatory flow. If the Ca2+ originates from the media, then the cell response/ Ca2+ influx should be decreased in Ca-free conditions. On the other hand, if the Ca2+ is released from intracellular stores, then the response should insensitive to the Ca levels in the media.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University of Sheffield

Manipulation of host hypoxia signalling as a therapeutic strategy for mycobacterial infection 29 Oct 2014

Therapeutic strategies that target pathogens are failing and TB has re-emerged as a leading cause of global mortality with 1.3 million deaths yearly (WHO, 2012). There is an unmet need for novel, host-targeted therapeutics that upregulate the immune response to infection to complement current antimicrobials. Tissue hypoxia is a potent activator of leukocyte responses via activation of host hypoxia inducible factor (HIF) signalling. I hypothesise HIF signalling is a host-response that if therapeu tically activated, will improve the host response to infection. My overarching aim is to test this hypothesis in vivo. In a zebrafish mycobacterial infection model, I have shown that genetic upregulation of HIF prior to infection leads to higher levels of bactericidal nitric oxide in neutrophils and to reduced burden of infection. These data support an emerging paradigm where neutrophil killing of mycobacteria is essential for disease control and identify HIF and NO as effective targets for int ervention against mycobacterial infection. Combining genetic approaches with dynamic live-imaging, I will address the following hypotheses: 1) HIF activation is a host antibacterial response that is actively downregulated by Mm at a critical tipping-point of infection; and 2) Pharmacological upregulation of leukocyte Hif is a viable therapeutic strategy for mycobacterial infection.

Amount: £884,205
Funder: The Wellcome Trust
Recipient: University of Sheffield

Institutional Strategic Support Fund FY2013/14 14 Oct 2013

The 2022 Futures initiative will make the step change required to ensure that our research can make the significant developments needed to address some of the world’s biggest challenges Imagine:Imaging Life is a major strategic project to establish a unique and world-leading microscopy resource in Sheffield. The combination of three very different imaging approaches; cryo-electron microscopy, atomic force microscopy and super-resolution optical microscopy within this centre of excellence is the focus for a growing community of interdisciplinary researchers, who will apply these powerful technologies to the visualisation of biological structures and molecular interactions to a level or resolution not presently achievable. The Florey Institute for Host-Pathogen Interactions will establish Sheffield as an international hub for the understanding and treatment of infectious diseases. Medical Humanities Sheffield (MHS) was granted university centre status in 2013 and has grown to a membership of over 170 academics and practitioners across the university and the NHS, including Sheffield Teaching Hospitals, Sheffield Children’s Hospital and Primary Care Trusts Enhancing facilities:1) A post-doctoral fellow providing essential academic input to a new Biological Mass Spectrometry Facility funded by Yorkshire Cancer Research and UniversityISSF 05/142investment.2) Significant capital investment to support the University’s flagship Imagine: Imaging Life Initiative to enable the purchase of new Atomic Force Microscopy, Cryo-Electron Microscopy and image capture equipment. This supports investments made by the University, EPSRC and MRC and leveraged an additional £650K award from The Wolfson Foundation to fund laboratory refurbishments. Translational development:A second business manager within the Sheffield Healthcare Gateway supporting new translational activities to work with a new HEIF-5 business manager and associated biddable funds to bridge projects at the crucial stage between proof of concept and commercial development. 18 projects have been supported including two subsequently awarded MRC DPFS and one Wellcome SDDI funding.Public Engagement:ISSF, University funds and an RCUK Catalyst award were combined to support the recruitment of a new Public Engagement Team to deliver on the University’s new PE Strategy, providing central support to a range of initiatives across the whole University. Funds were also used to support specific initiatives including: 1) The University’s Festival of the Mind programme, ISSF contributed to eight individual collaborative bioscience projects as part of the extensive public engagement activities across the city; 2) Life: A Festival of Health, From Head to Toe which delivered 42 events over six days, involving 2,300 members of the public and school groups.Developing careers:Post-Roberts provision for Early Career Researchers (ECR) by funding one of two dedicated life science development posts and delivering two ECR Crucible programmes; ISSF significantly increased participation in this scheme by funding the attendance of double the number of bioscientists than could be provided by core funding alone, and by supporting increased funds for small grants. Six project grants were awarded to life scientists all of which were developed into RCUK submissions, including one to an ECR appointed as a Vice-Chancellor’s Fellow in January 2014.

Amount: £500,000
Funder: The Wellcome Trust
Recipient: University of Sheffield

Virtual coronary physiology: an angiogram is all you need? 29 Nov 2012

Disease inside the heart’s arteries kills more people in the UK than anything else. Dr Julian Gunn and his team at the University of Sheffield have developed a computer system called 'VIRTU', which predicts blood pressure changes inside coronary arteries.This is important because doctors make better decisions regarding when and how to treat patients with coronary artery disease if they have these blood pressure measurements. Currently, doctors have to insert a metal wire inside the heart to measure artery pressures. This is time-consuming and requires special equipment, staff and medicines. Although this invasive technique saves lives and money, more than 95% of patients do not receive the procedure and thus do not get the benefits that it can provide.VIRTU provides a solution to this problem since it only needs X-ray pictures and does not require any wires, drugs, or additional time, equipment or staff. This project aims to improve the speed and accuracy of VIRTU and test it in people with more complicated coronary disease so that eventually it can be used in all patients. The research will make VIRTU 'patient-ready' and will deliver all the advantages of the current invasive technique (i.e. reduced deaths, heart attacks and cost) whilst being less invasive and usable in 100% of patients.

Amount: £254,718
Funder: The Wellcome Trust
Recipient: University of Sheffield

Development of light and electron microscopy facilities at University of Sheffield. 14 Oct 2010

In order to understand biological processes, it is necessary to be able to visualize individual components in their natural cellular, tissue or organismal environment. The aim of this proposal is to facilitate such visualization by developing new electron microscopy approaches within the Electron Microscopy (EM) Facility and maintaining and further developing the Wellcome-funded Light Microscopy Facility (LMF) at the University of Sheffield. The LMF is a multiuser facility that provides access to confocal microscopy which is widely used to study biological processes in living and fixed tissues. Our existing confocals are heavily used and usage is predicted to increase in the next year. One instrument is greater than eleven years old and one aim of this application is to replace it so that our users' requirements may be accommodated. Our current EM facility allows the sectioning of tissues and cells embedded in resin and sectioned at room temperature. While this provides us with usefu l ultrastructural details of cells, it is not usually compatible with antibody-labelling of molecular components. We are therefore requesting funds for freeze substitution equipment that will enable us to perform immunogold labelling of specific proteins in samples with well-preserved morphology.

Amount: £175,133
Funder: The Wellcome Trust
Recipient: University of Sheffield

Pathogenomics of Staphylococcus aureus: identification of novel virulence traits. 20 Nov 2012

Despite a wealth of recent work, the genetic attributes that determine the pathogenicity of Staphylococcus aureus remain poorly understood. Breakthroughs in genomic sequencing and in-vivo modelling have allowed development of a novel approach to identify genetic determinants of disease. Using a high-throughput model of systemic S. aureus infection in zebrafish embryos, I have screened closely related strains for differences in pathogenesis in the model. We have proved the principle of this a pproach as clear differences in pathogenesis can be determined between related strains and genomic comparison has revealed candidate genomic fingerprints associated with pathogenesis. These are currently being investigated to identify the constituents of the pathogenome. The proposed research allows us to scale up this project and screen prospectively collected hospital acquired methicillin-resistant S .aureus strains from across the country, to examine strain phenotype in the zebrafish model. A pplying whole genome sequence analysis, I will build a database of putative virulence determinants and subsequently test their role in pathogenesis. This will inform the use of a mammalian model of infection. The output from this model will have wide applications such as the proposal of new vaccine targets and the realisation of anti-staphylococcal therapies tailored to individual strains and therefore patients.

Amount: £222,695
Funder: The Wellcome Trust
Recipient: University of Sheffield