- Total grants
- Total funders
- Total recipients
- Earliest award date
- 23 Jan 2006
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Prisoners as patients: Homosexuality and same-sex desire in German prisoner of war camps in the United States during World War II 19 Oct 2010
The project will study the experience of German soldiers who were caught in sexual activities with other prisoners while in captivity in the United States during World War II. The U.S. Army considered these prisoners 'sexual psychopaths' and ordered that they should be transferred to hospitals for treatment if deemed 'reclaimable'. Nothing has so far been written about these prisoners and little is known about their experience. The key goal of this project is to change that by locating primary sources dealing with this little known chapter of World War II history and by publishing the results in a journal article.
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.
Transformations: Encountering Gender and Science 16 Jun 2018
The Rethinking Sexology team’s historical research has uncovered important material on the relationship between medical authority and ‘patient’ experience and the development of diagnostic categories/treatment protocols. We propose a public engagement programme that invites young trans people (age 16-25) to explore this material, co-conduct new research, including an oral history project, and develop an ambitious programme of creative responses leading to a performance and exhibition in four relevant high-profile venues across the UK. The plan of action has been developed during an extensive consultation period with key stakeholders, in which ideas and methodologies have been fully tested. The programme is led by the Rethinking Sexology (RS) team who has an outstanding track record in field-leading engaged research and public engagement. The team’s experience will be complimented by collaborating with a uniquely qualified group of writers, performers and youth-facilitators, known for their pioneering and award-winning work with the trans community, with whom the RS team already has long-standing collaborative relationships. The programme will deliver a set of exceptionally innovative activities that will empower young people to: contribute to and enhance health and humanities research and public engagement practices; investigate clinical and diagnostic protocols and transform clinical dialogue; shape public debate through high-quality creative outputs (exhibition/performance) that promise to be intellectually, artistically and emotionally powerful and stimulating. The co-production model at the heart of the programme will feed systematically and continually into ongoing research activities, enabling the project to stand as a beacon of good practice in engaged research and public engagement.
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.
Macromolecular Mechanisms of Microsporidia Infection Investigated by Cryo Electron Tomography 21 May 2018
Microsporidia are eukaryotic, intracellular parasites that infect most animals, including humans. They cause debilitating disease in immunocompromised individuals and are partly responsible for the global decline in honeybee populations. To infect a host cell, microsporidia employ a harpoon-like apparatus called polar tube (PT) that rapidly ejects from the spore, penetrates the membrane of a target tissue cell and transports the spore content (sporoplasm) into it. I propose to investigate the so-far unknown macromolecular architecture and mechanism of the PT using state-of-the-art cryo electron tomography (cryoET). The key goal is to examine the cellular machinery that facilitates PT release, sporoplasm transfer and target membrane penetration. This research will provide 3D molecular maps of the PT in action and thus detailed and dynamic understanding of the microsporidian infection pathway. The research will enrich our knowledge of fundamental cell biology, establish microsporidia as a eukaryotic model system for cryoET, inform new medical approaches to treat microsporidiosis and help fight the decline in honeybee populations. Seed Award funding will pave the way for my career as new independent group leader in the UK, with a high impact biomedical profile and will offer a plethora of opportunities to collaborate with academia and industry downstream.
The development of insulin resistance and anabolic resistance during muscle disuse: what is the role of fuel integration? 08 Nov 2017
Skeletal muscle atrophy, which occurs during short-term disuse, is thought to be due to the development of anabolic resistance of protein metabolism and insulin resistance of glucose metabolism, although their cause is currently unknown. The primary research aim of this fellowship is to establish the role of muscle fuel availability and integration in disuse-induced insulin and anabolic resistance. In collaboration with the Medical School, I will perform two randomized, placebo-controlled studies in which young, healthy participants undergo 2 days of forearm immobilisation with placebo, Acipimox (to decrease plasma lipid availability), Formoterol (to stimulate glycolytic flux), or dietary branched-chain amino acid (BCAA) manipulation, to alter substrate availability. I will combine the arteriovenous-venous forearm balance technique, that I have recently established in Exeter, with stable isotope amino acid infusion and repeated forearm muscle biopsies to quantify muscle glucose, fatty acid, and BCAA balance, oxidation, and intermediary metabolism (including muscle protein synthesis), both fasted and during a hyperinsulinaemic-euglycaemic-hyperaminoacidaemic clamp. Two periods of research at the University of Texas Medical Branch will enable me to develop skills in mass spectrometry tracer analyses and develop a network of collaborators in the USA, both crucial for my future career investigating disuse-induced muscle atrophy.
Neurobiological mechanisms of emotional relief in adolescents with a history of sexual abuse 06 Dec 2017
Adolescents who experienced childhood sexual abuse (CSA) engage in non-suicidal self-injury (NSSI) more frequently than peers exposed to other forms of abuse or no abuse. NSSI serves an important function of relief from acute negative affect. Despite providing temporary relief from distress, NSSI is also linked to higher rates of suicide and hospitalisations and the effectiveness of current clinical interventions is limited. This may be attributed to a lack of understanding the neurobiological and behavioural mechanisms that underlie NSSI as a relief function in particular in youth who experienced CSA. To address this gap, the study aims (1) to model brain activity during distress and emotional relief (i.e., NSSI) in adolescents with and without a history of CSA using functional magnetic resonance imaging and (2) to examine if adolescents with CSA select actions to 'escape' an aversive context more quickly and often compared to non-abused peers. The ultimate goal of this translational research is to understand the neurobiological and behavioural mechanisms that confer vulnerability to NSSI following CSA (Stage 1) in order to develop effective intervention and prevention strategies to keep vulnerable teenagers safe (Stage 2) . Keywords: sexual abuse, non-suicidal self-harm, relief, functional magnetic resonance imaging, translational research
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.
Antibiotic resistance is a growing healthcare concern worldwide. The rise in the number of resistant bacteria is not being matched with an increase in new antibiotics or treatments. Novel ideas harnessing modern technology therefore need to be applied to address this problem in a timely manner. In this work, a phage encoded assembly system will be assessed for its potential application as a "switch" to control bacterial proliferation. By genetic manipulation of cells and viruses, protein expression, purification and high-end electron microscopy, the structure of a virus-encoded machinery in its host bacterial cell membrane will be determined in different conformational states. Furthermore, pilot experiments will be carried out to express and purify individual protein components for downstream mechanistic and high-resolution structural studies. The knowledge gained will provide many further avenues for research on our quest to develop advanced bactericides and synthetic cell-based treatments, and will deepen our understanding of bacterial pathogenicity in crops and animals, including humans. Funding for this proposal will also open up a multitude of downstream opportunities for collaboration with academia and industry, and importantly will provide me with the means to launch the crucial next stage of my career as an independent investigator.
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.