- Total grants
- Total funders
- Total recipients
- Earliest award date
- 09 Jun 1998
- Latest award date
- 29 May 2020
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Salmonella enterica serovar Typhimurium (STM) is the leading cause of gastroenteritis worldwide. Its outer membrane contains an abundance of lipopolysaccharide (LPS), of which the O-antigen is the outermost component. Modification of the OAg can contribute to the ability of Salmonella to evade host immunity, and we have shown it alters the absorption of specific bacteriophage. In STM O-antigen acetylation is carried out by GtrCBTP1 and OafA, modifying the rhamnose and abequose moiety respectively. These are inner membrane bound O-antigen acetyltransferases that function on the periplasmic side of the inner membrane to acetylate the O-antigen during its biosynthesis. The modification by OafA confers the O:5 serotype of Salmonella and GtrCBTP1 confers resistance to lysis by BTP1 bacteriophage. In this project the student will identify residues important for function in GtrCBTP1 and OafA, through mutagenic analysis and subsequent functional analysis based on serotype change and phage resistance. These OAg acetyltransferases are widespread in salmonellae, giving broader biological relevance. Understanding the biological process of O-antigen acetylation in Salmonella therefore can inform the larger protein family, and may open new avenues for disease control.
Type 1 Diabetes (T1D) is increasing in pre-school children, and the treatment the Government NHS system provides is financially unsustainable. The complex pathways concerning how B cells are involved in the development of T1D remain elusive. However, the Green Lab's recent novel findings revealing that the thymus is a principal target of autoimmunity in T1D and that thymic B cells are key in this event have re-evaluated our knowledge of the T1D process. In my research, I aim to aid in the achievement of translating these novel finding from mouse to man. By engrafting Human Pluripotent Stem Cells (HPSCs) into a specific strain of humanised mice (NSG-SGM3) which are devoid of key molecules required to develop a murine immune system (including a thymus), we hope to stimulate de novo formation of functional thymic tissue that resembles that seen in young diabetic children. NSG-SGM3 also have a NOD background, meaning their thymic stromal tissue contain genes which predispose T1D. Comparative studies looking at thymic tissue between NSG-GSM3 and NOD mice will be key in determining whether HPSCs promote thymus neo-genisis in humanised mice, as well as determining if our humanised mouse model recapitulates thymic B cell abnormalities of NOD mice.
The proposed project will help test whether chronic activation of the innate immune system can lead to inflammation in the brain that contributes to neuro-degenerative processes that may manifest in a similar way to premature aging. Specifically, we will be focusing on what occurs following infection with Leishmania donovani, a parasite prevalent in Africa and India that causes the disease visceral leishmaniasis which affects internal organs such as bone marrow, spleen and liver. Visceral leishmaniasis was for a long time thought to be excluded from the CNS, however we will be looking for evidence of parasites and unusual activation of the brain's resident macrophages, microglia, which may lead to physical damage of CNS tissue, with potential long term impact on mental health. I will evaluate infected murine brain tissue for evidence of markers of microglial activation and inflammatory response as well as for the presence of the parasite itself.
Complex traits play roles in various human diseases, with multiple genes being implicated, as identified by genome-wide association studies. The advent of genome-editing techniques such as CRISPR/Cas9 has ushered in the idea that these genes can be repaired to cure the disease, as shown for monogenic hereditary disorders. However, it is unclear whether these will be able to repair conditions influenced by multiple genetic factors, and the complexity of multicellular eukaryotes makes it difficult to predict the outcome. Herein, the fission yeast, Schizosaccharomyces pombe, could provide a useful tool, as its comparatively smaller genome and ability to breed strains facilitates studies of accurate quantitative genetics. However, this model requires improvements before it is suitable. The tendency for wild-type strains to self-mate causes difficulties when conducting inter-strain crosses. Therefore, we propose to engineer stable heterothallic strains to guarantee outbreeding using a counter-selectable Cre/loxP construct to remove the H1 box at the mat1 locus. We will then test to confirm that transformation has been successful and determine whether they are h+ or h-. This allows a simpler and more reliable approach to inter-strain mating, allowing for the production of larger library of genetically diverse strains for the analysis of complex traits.
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.
The host lab investigates post-transcriptional mechanisms that regulate expression of immune checkpoint membrane proteins in human primary dermal lymphatic endothelial cells (HDLECs) and dermal fibroblasts and recently demonstrated that PD-L1 is regulated by miR-155 (Yee et al., 2017, JBC). It has been suggested by others that resistance to therapeutic PD1 blockade is associated with alternative immune checkpoints in cancer cells, specifically the Gal9/TIM3 signalling axis. In this project, expression of Gal9 will be measured in unstimulated cells and cells treated with TNF and/or IFNg and upon over-expression or inhibition of miR-155. Experiments will be performed in both HDLECs and fibroblasts. Using already available small RNA sequencing data in the lab, miRNAs that can potentially suppress Gal9 expression and are significantly regulated upon treatment of HDLECs with TNF and IFNg will be identified. This will allow us to propose post-transcriptional regulatory networks that operate in non-transformed cells to control expression of a therapeutically relevant immune checkpoints. Training will include becoming familiar with cutting edge concepts in immunology and post-transcriptional gene silencing and techniques in primary cell culture and determining protein and mRNA expression, as well as extracting information from large transcriptomics datasets and using online in silico tools.
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.
Gene modulation for protein ZO-3 and its effects on urothelial barrier formation, function and recovery. 31 May 2018
The question I propose to address is what role ZO-3 plays in urothelial barrier function and repair. I will tackle this by assessing how ZO-3 knockdown influences urothelial barrier tightness and the speed of urothelial repair. I will conduct various experiments to prove this including; CRISPR-Cas (or shRNA as contingency) gene deletion, immunoblotting (claudin3 analysis) and TER for measuring the strength of the urothelial barrier. I predict that ZO3 inhibition (knockdown) will result in a weaker barrier but an increase in recovery time. I think the loss of ZO-3 may increase recovery time as it may aid in recruiting key repair machinery involved in reforming the tight junction, therefore its loss would slow the time it takes to repair. This, in turn, may shine a light on how bladder cancer may be able to metastasize due to weak urothelial barriers, caused by mutations in ZO3 gene and become a new therapeutic target for malignant bladder cancer.
Digital Spatial Profiling in biomedical research 05 Jul 2018
The key aim of this application is to provide capacity for medium throughput targeted transcriptomic and protein expression analysis appropriate for, but not limited to, analysis of scarce and challenging clinical samples. Capital equipment costs are requested for the purchase of a Nanostring Digital Spatial Profiler (DSP) Instrument together with a nCounter Max Analysis System. The DSP will become available commercially in late 2018 and provides a unique approach to non-destructive multiplexed immunohistochemistry and gene expression profiling. Maintenance costs for a five-year period are also requested. To ensure effective, open access to this equipment for researchers across the region, salary support for a dedicated technician for a period of five years will be provided in kind by the University of York. This new 5 year post will be based in the Dept. of Biology’s Biosciences Technology Facility, a core facility with an international reputation for training and technology development in the area of imaging and cytometry. Continuation of this post beyond 5 years will be funded through new grant applications based on the use the instrumentation.
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
A taste of hard work: assessing the utility of ancient tartar to track exposure to respiratory irritants of occupational origin in ancient skeletal remains 23 Jan 2018
My proposed cross-disciplinary research will elucidate the potential of ancient tartar to reveal exposure to a variety of respiratory irritants and their links to health in past societies by unlocking the signature of inhaled/ingested occupational debris and pollutants generated during crafting. Applying state-of-the-art microscopic methods in Archaeology and Physics, and working both with experimental archaeology and ancient skeletal material, my project aims to: analyze the full range of micro-particles (dietary and environmental) entrapped within the tartar of Roman and Medieval individuals to assess exposure to respiratory irritants, with a strong focus on those of occuational origin; characterize exposure to and inhalation of microscopic particles and pollutants produced during selected craft activities (e.g., pottery, textile production, woodwork) using experimental archaeology (i.e. microscopic occupational ‘signatures’); critically assess how micro-debris in calculus can be linked to other archaeological parameters to elucidate the involvement of ancient individuals in crafty activities and their link to health; expand our understanding of air pollutant exposures associated with traditional craft production, often carried out within developing societies as a means of poverty alleviation.
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.
MA Medical History and Humanities 11 Jul 2018
The MA in Medical History and Humanities is an interdisciplinary course jointly run by the Departments of History and English, which draws strength from the range of expertise located in both departments. It is open to people with backgrounds in other humanities disciplines, as well as those with social science, science and public health backgrounds with an interest in the medical humanities. The course is shaped by cutting-edge international research spanning the fields of medical history, literary study, sociology, philosophy, health sciences and policy. Students can explore historical, literary, social and cultural perspectives on illness and health, general well-being, issues of public health and the history of medicine. They also examine the links between history, the humanities and policy to gain advanced skills in analysis and critical reflection. Students take a core module which introduces key concepts, methods and debates in medical history and humanities. A strong programme of option modules are offered with students choosing from a range of topics in medical history, the humanities and beyond. Research training also provides essential grounding in graduate-level research skills: selecting research topics, large-scale project management, locating secondary and primary materials, storing and ordering findings and presentation techniques.
The Promise of 'Wellness': Understanding Alternative Dietary Practices in Precarious Times 23 Jul 2018
From ‘green juice’ to ‘golden milk’, ‘energy balls’ to ‘spiralised squash’, ‘activated charcoal’ to ‘bullet-proof coffee’, a whole host of supposedly health-enhancing dietary practices have become popular in the UK under the auspices of ‘wellness’. While such trends generate significant media attention and are cause for concern among medical professionals, they remain poorly understood and frequently trivialised. This study will be the first to interrogate the social, economic, and political forces underwriting the rise of wellness culture in Britain and account for its distinctly gendered contours. Rather than debating what actually constitutes ‘healthy eating’, it will use the tools of social and cultural analysis to understand why scientifically unfounded dietary trends are flourishing. Ethnographic methods will explore the glamorous trappings and mundane entanglements wellness generates in women’s everyday lives, and investigate how health practitioners grapple with the proliferation of anti-expert nutritional guidance as manifest online and in clinic. The project represents an original investigation into the cultural mediation of health. Key goals include: - Understanding why women embark on alternative dietary regimes. - Situating the rise of wellness culture within the broader cultural politics of austerity. - Finding ways to enhance communication on issues of food and diet.
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.
The world-renowned York Structural Biology Laboratory (YSBL) plans to expand its technical capability beyond the established techniques of X-ray crystallography and NMR spectroscopy into cryo-electron microscopy with a regional CryoEM hub, opening up structural biology on large, complex systems to a diverse regional user base. Our bid is aligned with partners in Newcastle and Durham, and will dovetail with complementary regional capabilities in Leeds and Sheffield, and with the national facility, eBIC (see letters of support). Key goals include viral structure determination, dissection of supramolecular assemblies and motors, and exploitation of major health-related protein-protein complexes in mammalian systems and bacteria. CryoEM in York will meet growing demand for which existing regional capacity is insufficient. It will also build upon YSBL’s significant crystallographic methods expertise, providing a focus for pioneering new methods developments in partnership with eBIC. We propose a cost-effective and sustainable 200 kV microscope, which will enable both single-particle work and screening of more challenging tomography samples for subsequent analysis at 300kV facilities. The University of York is supporting the bid by establishing a professorial-level CryoEM post, allocating the time of an Experimental Officer, investing a £1M philanthropic donation and committing £1.7M for the necessary building infrastructure.
Health inequalities diminish lives and blight communities. Although the determinants of health inequality are well known, policy makers have repeatedly failed to address the issue effectively, and many public health interventions unwittingly worsen inequalities because they disproportionately benefit those with greater resources. This is also a scientific failure. The analytical tools used to inform policy lack a substantial perspective on equity, focusing on averages rather than social distributions, leading to inequitable solutions. In an age of social division driven by rising inequality, new approaches to health policy are urgently required. We propose to re-engineer health policy research. We will develop rigorous methods for measuring the equity impacts of health and social policy interventions, and apply these methods to assess the effectiveness of major public health and healthcare initiatives. In doing so, we will improve our understanding of the structural, behavioural and organizational barriers to delivering equitable health outcomes. Our programme will equip researchers with the necessary tools for measuring equity impacts, and provide policy makers with vital information on who gains and who loses from their decisions. Our ultimate aim is to enable fairer health policy decisions, leading to better health across society.