- Total grants
- Total funders
- Total recipients
- Earliest award date
- 08 Jun 2006
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Assessing human immune organ architecture in a humanised mouse model following schistosome egg injection 31 May 2018
This research will assess human immune organ architecture in humanised mice following injection with schistosome eggs. We will generate tissue samples from the spleen, lymph node and bone marrow from naive and schistosome-immunised mice to compare and contrast the localisation of CD4 T cells, B cells, macrophages, dendritic cells and eosinophils. We do not know much about whether these cells interact together in a way that produces a string type 2 immune response, this project aims to test this in an acute model of immunity.
Seizures in epilepsy and other neurological disorders have a devastating effect on patients and their families. Due to their amenability for genetic manipulation, mouse models of neurological disorders where seizures represent a significant comorbidity represent an exciting opportunity to pinpoint these alterations. One such disorder is the devastating neurological disorder, Rett syndrome (RTT) that affects 1 in 10,000 females. Seizures represent one of the most debilitating symptoms observed in RTT, are frequently atypical absence seizures, lead to a worsening of other symptoms and are often refractory to treatment. Despite their high prevalence, the underlying cellular and circuit mechanisms leading to the manifestation of RTT-associated seizures remain unknown. During this award, I characterise the mechanism of spike-and-wave-type discharges (SpW), a marker of atypical absence seizures, in a mouse model of Rett syndrome. Furthermore, I will evaluate whether reducing the activity of a particular subset of interneurons is sufficient to prevent the generation of SpW activity in these mice. Together, the results from this proposal will uncover the causally important cell types responsible for seizure manifestation in RTT and identify potential new strategies for the control or prevention of these seizures.
New perspectives for anti-viral therapy: The regulatory roles of genomic RNA in virus assembly, infection and evolution. 02 Dec 2015
The Archaeology of a Global Disease Vector 04 Dec 2017
Black rat (Rattus rattus) is a major pest and disease vector, implicated most famously in the 14th-century Black Death. In temperate climates, it is dependent on dense, generally urban settlements with regular communications, making it relevant to the spread of disease more broadly. Despite this significance, little is known about the European history of rats. Originating in sub-tropical Asia and reaching Europe by the Roman period, apparent post-Roman range contraction and subsequent medieval recovery are poorly documented, limiting understanding of rats’ role in disease—e.g. their distribution during the 7th-C Justinian plague remains obscure. Archaeological remains are the key resource for clarifying rats’ historical biogeography. This project will enable systematic realisation of their potential, by: convening a network of leading experts from multiple disciplines; evaluating current knowledge and identifying key outstanding questions; obtaining proof-of-concept for future zooarchaeological/archaeogenetic research. Activities include: an initial expert workshop; quantitative synthesis of existing archaeological data; targeted zooarchaeological research in under-studied areas; and pilot archaeogenetic research on rat and pathogen aDNA. Results will be disseminated via a session at the leading international zooarchaeology conference and a position paper, forming the basis for an ambitious future research programme. Keywords: Rattus, black rat, biogeography, plague, public health
EVIPNet Europe policy and research scoping tool 18 Jun 2018
I propose to develop a policy and research prioritisation tool for use by EVIPNet Europe countries to improve knowledge translation between research and policy. The goal would be to create a ranking system to help health policy decision-makers pinpoint high-priority policy issues that would benefit from research input in clarifying the problem or framing options for its solution. It should also aid research policy decision-makers to identify where to invest research resources, taking into account policy needs, to create implementable recommendations. Such a tool would encourage decision-makers to analyse quantitative data, for example the burden of disease, and qualitative information, such as public attitudes, and reach agreement when allocating resources to programmes. To create it I would complete a scoping literature review on the merits of various existing tools and combinations of tools. I would gather a variety of evidence, including systematic reviews of best practice, and case studies from the region that explain how these tools have been adapted to work in similar settings. I would consult with the EVIPNet country knowledge translation networks on their particular research and policy needs and challenges so as to select and adapt a context appropriate design for the tool.
The principal aim of the project is to identify the features of written examination questions that discriminate between students who have had substantial hands-on experience of practical work in GCSE science and those who have not. This project is important because recent changes in assessment mean practical skills are now wholly assessed through written examination questions. It is therefore essential to have a valid means of assessing practical skills that rewards students who have undertaken hands-on practical work. A series of classroom interventions will be developed in which students experience a practical activity either as hands-on practical work, a teacher demonstration, a video recording, or through a written description. Students will then complete written examination questions relating to the interventions. The outcomes will be: examples of questions that discriminate between students with different levels of hands-on practical experience, together with insights into characteristic, generalisable features of such questions guidance for examiners to support them in question writing evidence of the validity of the use of written questions to assess practical skills with a view to informing future iterations of the science curriculum. The project Advisory Group comprises representatives of the Awarding Organisations, Ofqual, the learned societies, ASE and science teachers.
How do we use past experience to guide behaviour and how does this process break down in specific patient populations? I will develop a novel experimental-computational tool to understand how individuals transform memories of previous events into generalised models of the world that allow them to behave appropriately in the future. For past experience to guide behaviour, we need to extract generalities or patterns across a set of events. Pattern extraction allows us to predict what will happen in novel but related situations. I will develop a new experimental technique in healthy humans (based on rodent research), where participants are required to extract patterns across a set of past events in order to make accurate predictions about future events. I will build computational models to predict and explain behaviour at the level of individual people. The models will assess what pattern a participant has extracted, and how this differs from the pattern that would optimise future predictions. Critically, when an individual is not behaving appropriately, the experimental-computational technique will reveal what is impaired and why. In the future, this technique will be used as a microscope to pinpoint impairments in memory-guided decision-making in patient populations.
Legacies of War Trauma 31 Aug 2016
By bringing together scholars from the fields of Health Security, Sculpture, Literature, Gender, War Studies, History and practitioners from the British Military, two interdisciplinary and multi-institutional workshops will uncover and document the cultural and military legacies of war trauma. The goal of the first workshop, The Military Legacies of War Trauma, will explore how traumatic rhetoric has evolved alongside military strategy and the technologies of war throughout modern history to impact our perceptions of the military body and mind. The goal of the second workshop, The Cultural Legacies of War Trauma, will build on the first workshop and explore the broader impact of war trauma on society through the study of policy and cultural output: we intend to identify how war trauma has shaped societal attitudes towards the military and vice versa. The workshops will lead to output in the form of a co-authored article in Critical Military Studies, a special edition of Literature and Trauma Studies and more media-based pieces including a co-authored article in BBC History Magazine and a radio programme pitched to BBC Radio 4. The longer-term aim is to apply for a Wellcome Hub Award proposing a six-person Network for the Interdisciplinary study of War Trauma.
Probing the role of outer membrane transport processes in host-pathogen interactions using computational and single-molecule biophysical approaches. 31 Jan 2017
The outer membrane (OM) of Gram-negative bacteria is a significant protective barrier. It is composed of an inner leaflet of phospholipids and an outer of lipopolysaccharide (LPS) with OM proteins (OMPs) that span the membrane. Recently OMPs have been shown to be inserted at discrete and non-uniform locations across the membrane, where they remain due to restricted lateral diffusion. These ‘islands’ are pushed to the poles by cell growth, with new material inserted at mid-cell. OM turnover during bacterial growth may have a role in immune system evasion. One key mechanism regulating human immune responses is the assembly of complement components on the OM nucleated by immunoglobulin binding. This process can lead to lysis of bacteria through insertion of pore complexes in the OM. Complex formation depends on localised clustering of antibodies, which is constrained by the location and molecular diffusion of antigens in the OM. In this project we will use computational and single-cell biophysical techniques to test our hypothesis that spatial confinement of LPS and OMPs near their insertion sites influences activation of the antibody-mediated complement pathway. We will test our hypothesis in Escherichia coli and Salmonella typhimurium, where immune evasion has a key role in pathogenesis.
Characterising the composition of low temperature air plasma to assess applications for wound infection and healing 31 Jan 2017
Wound infections, coupled with increasing antibiotic resistance are a global issue, and low temperature plasma (LTP) presents an interesting alternative treatment strategy as it has been shown to be bactericidal and to promote wound healing. LTP is characterised by a low degree of ionisation, a non-thermodynamic equilibrium and a dry reactive environment. Here, we propose the development of a nano-/microsecond pulsed, kilohertz repetition frequency air plasma. The plasma will be characterised both experimentally and computationally, in terms of reactive oxygen and nitrogen species concentrations, optical emission and temperature. This is of interest when considering LTP as a low-cost wound treatment, as air plasma should not require expensive bottled gases, thus decreasing running costs and increasing transportability. In terms of biological interaction, the aim is to use the characterised plasma to correlate plasma composition with (1) the difference in tolerance to oxidative stress between bacterial and eukaryotic cells and (2) the effects of plasma on the dynamics of healing-related gene expression in epithelial cells post wounding. The project should offer new insights into the development and characterisation of air plasmas, and their potential for use in biomedical applications, in particular wound infection and healing.
Eating the poison: characterisation of the molecular basis of antimicrobial peptide resistance in pathogenic Escherichia coli 29 Aug 2014
Cationic antimicrobial peptides (CAMPs) are produced by the human immune system as a defence mechanism against invading bacteria. However, bacteria have evolved resistance to CAMPs by transporting them into the cell for degradation, preventing them from disrupting the bacterial membrane and therefore promoting infection. This project aims to characterise the ability of the Sap system transporter protein, SapA, to bind and transport a range of CAMPs. The project will incorporate aspects of structural biology, computational modelling and genetic and microbiological work. This interdisciplinary integrated approach will enable an accurate understanding of the Sap system. Structural studies of SapA via x-ray crystallography will allow analysis of how SapA is able to bind long CAMPs, which is unusual amongst ABC transporters. Docking and modelling of the solved structures with a compound fragment library will enable the design of potentially tighter binders than CAMPs, identifying possible new drugs to bypass the resistance mechanism. Moving into the functional studies, susceptibility tests with genetically modified bacterial strains to express increased/decreased levels of peptidases will identify whether CAMPs are broken down by peptidases once transported into the cell. This will help identify the mode of CAMP resistance in bacteria and possibly another drug target.
Modelling pathological wound healing 17 Jan 2014
Wound healing is a complex process consisting of several overlapping stages mediated by a network of signalling molecules. Mathematical models have been extensively applied to this area of study, however theoretical investigations generally focus on a single stage of the process in isolation, and fail to incorporate the role of signalling molecules such as cytokines in mechanistic detail. Recent experimental studies have suggested that the timing of events such as cell proliferation play an important role in determining healing outcomes, but this hypothesis is yet to be studied using mathematical approaches. We aim to produce a more complete mathematical model of the overall wound healing process, using ordinary and partial differential equation approaches to describe the underlying molecular and biophysical mechanisms. Model predictions will be compared to in vivo experimental findings, making use of quantitative measures of features of the repair process (such as epithelial proliferation rates) wherever possible. The models will be refined accordinglyand used to investigate the effect of delays in the onset of cell proliferation on healing outcomes
Children Learning About Second-hand Smoke (CLASS II): A pilot cluster randomised controlled trial 17 Nov 2014
The principal question for our planned follow-on definitive trial is: What isthe effectiveness and cost-effectiveness of a school-based intervention,‘Smoke Free Homes’ (SFH) in reducing children’s exposure to second-hand smoke (primary outcome),frequency and severity of respiratory illnesses, healthcare contacts, school absenteeism, smoking uptake andin improving their lung function, quality of life and school performance?Prior to conducting a definitive trial to answer the above question, we wish to first conduct a pilot trial thatinforms the parameters required for conducting the definitive trial. Our specific research questions for thispilot study are therefore to ascertain:1. What are the recruitment and attrition rates for schools (clusters) and children?2. What is the feasibility and acceptability of measuring the primary and secondary outcomes?3. What is the likely effect size and its variance in relation to the primary outcome measure?4. What is the Intracluster Correlation Coefficient (ICC) among children for the trial outcomes?5. What is the fidelity of delivering ‘Smoke Free Homes’ in schools?6. What are the costs associated with delivering ‘Smoke Free Homes’ through schools?7. What would facilitate and hinder in scaling up ‘Smoke Free Homes’ in schools and their curriculum?8. What is the frequency and nature of any adverse events?
The ubiquitous tyrosine kinase, Src, has a fundamental role in signalling pathways that drive proliferation, adhesion and migration. Src is enriched in the brain, but also undergoes alternative splicing in neurons to yield N1- and N2-Src. The N-Srcs have small inserts in their SH3 domain, a region involved in substrate specificity and kinase activity, and have been implicated in neuronal development and as a prognostic indicator of the childhood cancer, neuroblastoma. We and others demonstrated that the N-Srcs drive neuronal morphology by rearranging the actin cytoskeleton. To discover the physiological substrates of N1-Src, we undertook a pulldown using the N1-Src SH3 domain. A promising candidate was N-WASP, a regulator of the Arp2/3 complex that promotes actin polymerisation and has been implicated in neurite outgrowth in neurons. This project aims to confirm if N1-Src acts through N-WASP to elicit neurite outgrowth. The specific goals are to i) investigate the tyrosine phosphorylation of N-WASP by N1-Src and ii) establish the effect of manipulating N-WASP activity upon N1-Src-dependent neurite outgrowth in cells. The project will therefore provide an excellent grounding in molecular research approaches and insight into the function of a gene relevant to neuronal development and disease.
York, Combating Infectious Disease: Computational Approaches in Translational Science (CIDCATS). 22 Jun 2015
The research will focus on analysing protein-nucleic acid interactions in the framework of large assemblies. Although the main emphasis is on X-ray analysis, several complementary techniques such as electron microscopy, mass spectrometry, surface plasmon resonance, polarisation anisotropy and analytical ultracentrifugation, which provide insight into the assemblys composition and the strength of interaction, will be applied. Key goals: (1) To continue investigations into the mechanism of DNA t ranslocation by double-stranded DNA viruses, using motor proteins of several bacteriophages belonging to Siphoviridae. To characterise interactions between the large and small terminase proteins, portal protein and DNA. To analyse the three-dimensional organisation of the motor using a combination of X-ray structural analysis with electron microscopy. To understand how structural events associated with ATP hydrolysis are coupled with the mechanical translocation of DNA. (2) To understand the st ructure-function relationship for several tRNA modifying enzymes, with particular focus on human hDus2 protein linked with lung cancer. To characterize protein interactions with tRNA and determine the crystal structures of protein-tRNA complexes. (3) To use structural knowledge on the viral motor and other oligomeric assemblies for pilot studies aimed at engineering a stable molecular device that can be used for transfer of genetic information in a controlled fashion.