- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 28 Apr 2020
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
With the support of the Wellcome Trust, the Durham Centre for Medical Humanities will become a nexus for world class medical humanities research. Spanning disciplines and periods, this research seeks to improve human health through an enhanced understanding of human experience. Over the next five years we will extend the significance and impact of existing medical humanities initiatives at Durham, while also fostering new ideas and projects within four distinct strands of work. Our central goals are to develop more effective ways of understanding human experience; to build interdisciplinary research projects that will enable us to influence clinical and health research, practice and policy; to transform views about and approaches to health care research by involving multiple stakeholders; and to promote and champion our approach across disciplinary, institutional and wider research contexts. Key to achieving these ambitious and longer-term goals will be an application for Wellcome Trust Centre status to continue our work beyond the period of this award.
The application is for a grant of £10,000 towards piloting a funding collaboration with Unlimited to provide one of the Main Research and Development (R&D) awards in the next Unlimited funding rounds ( Round 2). Details of the proposal, artists criteria and timelines have been separately provided to the Wellcome Trust (Saphia Bishop). A representative from the Wellcome Trust will be on the Awards Panel.
On January 1, 2018, California will enact a Senate Bill (SB27), making it the first state in the U.S. to ban nontherapeutic antimicrobial use in livestock production. This measure, designed to curb overuse of antibiotics in industrial food animal production, represents a singular opportunity for a natural experiment to rigorously evaluate the role of industrial livestock production on antimicrobial resistant bacteria in retail meat and human infections. We will leverage whole genome sequencing and expansive electronic health record data to determine whether an upstream, statewide policy to reduce antibiotic use in livestock production will have a downstream, beneficial impact on human health. We were recently funded by the US National Institutes of Health to study the impacts of this legislation on E. coli only. Here we are requesting funds to expand our sampling to include two common foodborne pathogens, Salmonella and Campylobacter. Specifically, we are requesting funds to bolster our baseline data collection during the time leading up to the implementation of the legislation (the next 6 months). We anticipate that, in response to decreasing antibiotic selection, antibiotic-resistant Salmonella and Campylobacter populations will decrease rapidly in poultry and on poultry meat resulting in fewer drug-resistant human infections.
Our goal is to establish a controlled human infection model (CHIM) for schistosomiasis in Uganda, with a view to advancing vaccine development for this important parasitic infection. The objective of this proposal is to engage with, and inform, relevant stakeholders in Uganda about controlled human infection models through A visit to Leiden. Four to five key Ugandan personnel will visit Leiden University Medical Centre where the CHIM for schistosomiasis has been established to observe procedures. A stakeholder meeting in Uganda. Key stakeholders will be invited to a 2.5 day meeting to learn about CHIMs, and to discuss ethical, regulatory and practical procedures in relation to an outline proposal to establish the model in Uganda.
Test Sites: Calder 30 Sep 2017
Test Sites is a series of Arts Catalyst curatorial co-inquiries around the UK into matters of concern connected with environmental change – such as flooding, pollution, and species loss. These co-inquiries are being conducted in the context of "planetary health": the understanding that human health and well-being are interdependent with our political, economic and social systems and the health of the Earth’s natural systems. At each site, invited artists will collaborate with local people and groups, as well as scientists, ecologists, historians, and local experts who study these systems and environments. The programme will take the form of collaborative art and science research, leading to site-specific artworks, events and films. In the Calder valley, we are working with artist Ruth Levene, in partnership with the Canal and River Trust, universities, and other groups, to research water governance in relation to human health and wellbeing and the resilience of communities and ecologies. Through the Calder Valley Test Site, activities that draw out the knowledge and expertise from other Test Sites, and other organisational development, Arts Catalyst will develop its expertise in curatorial co-inquiry and expand its capacity to work with research teams and universities.
Mapping and monitoring the global burden of antimicrobial-resistance/drug-resistant infections 30 Sep 2017
The increasing number and distribution of pathogens that are resistant to antimicrobial drugs is one of the greatest threats to global health, creating a potential health crisis from infections that were once easy to treat. Despite long-standing recognition of antimicrobial resistance (AMR, also known as drug-resistant infections, DRI’s) across many settings, there is surprisingly poor information about its current and historical geographical distribution and prevalence. This makes formal assessments of its burden difficult to gauge, limiting the ability to drive agendas to combat AMR/DRI. Through incorporating AMR/DRI into the Global Burden of Disease (GBD) Study, we will provide rigorous quantitative evidence to increase global awareness and surveillance of AMR/DRI, leading towards reductions in its morbidity, mortality, and cost. This work includes collation and synthesis of existing data; developing analytical methods to estimate the fraction of burden from causes attributable to AMR/DRI; and producing and incorporating estimates into interactive maps and visualizations for public access. Results will assess the burden of AMR/DRI over time and provide a benchmark for measuring impact of interventions on future burden. Analyses such as these are urgently required to provide an informed evidence base and quantification of the resultant burden of AMR/DRI on public health.
When viruses infect a cell, they need to hijack host machinery to produce their own proteins from mRNA, in a process called translation. The host cell requires several factors for translation, including proteins called eukaryotic initiation factors (eIFs). EIF4F plays a central role in this process and is a complex made up of the proteins eIF4A, eIF4G, and eIF4E. Together, these proteins act along with other factors to recruit the cellular machinery required for translation to begin. Influenza can promote the translation of its own proteins whilst host protein synthesis is impaired. As viral and host mRNA are highly similar, influenza virus was thought to only use the same mechanism of translation as the host. However several findings, such as the fact that influenza can translate its proteins without eIF4E, suggest that this is not the case. My hypothesis is that influenza can employ a different mechanism of translation from the host. I will use several RNA/protein analysis approaches to identify the key components required for influenza translation, and attempt to dissect the mechanism(s) of translation used by influenza. Identifying key differences between host and viral processes is important for identifying novel therapeutic targets.
Causal mechanisms in stroke subtypes 30 Sep 2018
Stroke describes an insult to the brain that is caused by a disruption of blood flow. There are different subtypes of stroke, which may be subdivided by the cause of the disruption to blood flow. The mechanisms underlying different stroke subtypes vary, and therefore so do optimal treatment strategies for each subtype. Individuals vary in their genetic make up. Genetic variants that are strongly associated with a particular trait can be used to investigate the effect of that trait on the risk of different stroke subtypes. For examples, if individuals with genetic variants that are strongly associated high blood pressure also more often suffer a particular stroke subtype, it would suggest that higher blood pressure causes that subtype of stroke. This technique is called Mendelian randomization, and has the advantage that genetic variants are randomly allocated, and so the genetic variants that any individual gets are not affected by their lifestyle or environment, preventing these factors from biasing the associations observed. During my fellowship, I will be using the Mendelian randomization technique to unravel the mechanisms that cause different subtypes of stroke.
The expression of the tumour suppressor gene, E-cadherin, has been found to be positively correlated with the expression of 31 human genes, which have 14 Drosophila homologues. Six of the Drosophila genes are not known to regulate/be regulated by E-cadherin. The aim of this project is to investigate whether E-cadherin regulates the expression of two top candidate genes, fusilli and grainy head, or conversely, if E-cadherin is regulated by them. In order to determine whether fusilli and grainy head regulate E-cadherin, expression of these genes will be downregulated with RNAi using the GAL4-UAS system in Drosophila, and the changes in E-cadherin amounts and localization will be quantified. Simultaneously, E-cadherin will be acutely overexpressed using GAL4-UAS in combination with the temperature-sensitive GAL4-inhibitor GAL80 in order to test if it has an effect on the expression of fusilli and grainy head. Changes in expression will be determined using RT-qPCR. Altogether, this project aims to reveal novel regulators or effectors of E-cadherin.
The regulation of gene expression is fundamental for cellular integrity and is partly achieved by the opposing action of repressive and activating histone modifications. One such histone modification is the tri-methylation of lysine 4 on histone H3 (H3K4me3), which is known to correlate with transcriptional activity. The SET1A complex is responsible for depositing the majority of H3K4me3 in mammalian cells and disrupting its function often leads to gene expression defects. However, the mechanisms by which SET1A regulates gene expression remain unknown. I will use the auxin-inducible degron system to rapidly deplete SET1A levels. A series of genomics technologies, including ChIP-seq and NET-seq will then be used to determine the effects of SET1A loss on chromatin architecture and transcriptional activity. Additionally, proteomics techniques will be used to identify the pathways perturbed upon SET1A loss, hence identifying the mechanisms by which SET1A supports active transcription and furthering our understanding of how gene transcription is regulated. This is essential for the development of novel therapies targeting genetic diseases in which the control of gene expression is perturbed.
Investigation of DNA methylation and brain connectomic bivariance, and the impact of early life environmental stressors 30 Sep 2018
Globally, around 15 million infants are born preterm each year (
Understanding missed diagnostic opportunities in patients with bladder and kidney cancer 30 Sep 2018
Early diagnosis of cancer is important for improved survival and patient experience. Reaching a diagnosis needs correct and timely collection of information from consultations, tests and follow-up of results. However, diagnosis can be difficult as non-cancerous conditions are common and cancer is quite rare. The use of tests forms a very important part in diagnosis, but this may also increase the time to cancer diagnosis. It is likely that what and when tests are done and how results are communicated can vary for different patients with the same cancer. These differences may represent missed diagnostic opportunities in some cases. In this project, I will explore how patients with kidney and bladder cancer are diagnosed. Bladder and kidney cancer will be studied together as patients usually present with blood in the urine or other urinary symptoms, and similar tests are done to look for both types of cancer. Despite the increasing trends and gender differences in how quickly these cancers are diagnosed, there is little information on how they are diagnosed. Therefore, studying this and whether there are delays in the use of tests is important to understand how we can improve early diagnosis of these cancers.
Uncovering Pseudomonas aeruginosa - Aspergillus fumigatus interactions that may facilitate pathogen development 31 May 2018
A wide range of bacterial and fungal pathogens colonise the lungs of CF patients. In this project, we will examine how two of these pathogens (P. aeruginosa and A. fumigatus) interact together and determine whether this interaction has the potential to increase tissue damage in the host or to exacerbate the production of toxins by A. fumigatus. We aim to establish whether co-culturing P. aeruginosa with A. fumigatus induces an increase in the synthesis and secretion of the immunosuppressive toxin, gliotoxin. In parallel we will establish whether exposure to A. fumigatus induces an increase in the production of tissue degrading enzymes by P. aeruginosa. Using conditioned medium we will assess the effect on growth, and the proteome of A. fumigatus and P. aeruginosa. Changes in the proteomic profile will be assessed using label free quantitative proteomics which will give an indication of the response of A. fumigatus or P. aeruginosa to each other. The results from this project will establish how A. fumigatus and P. aeruginosa affect their respective toxin and tissue degrading enzyme production. It will establish the proteomic changes occurring in each pathogen and indicate how these might adversely affect the host’s immune response.
Synthesis, characterisation and biological evaluation of a novel library of iminosugar compounds as inhibitors of Galactofuranosyl Transferase 2 inhibitors in Mycobacterium Tuberculosis 30 Sep 2018
The increasing prevalence of antimicrobial resistance (AMR) represents one of the greatest existential to humanity. Of particular concern is the emergence of multi-drug and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB) infections which significantly diminish the treatment prospects for patients. This means that there is a distinct need for novel anti-TB drugs with unique targets which will allow them to circumvent the resistance to conventional drugs. One such target is the Galactofuranosyl Transferase 2 (GalfT2) enzyme. This enzyme plays a key role in the generation of the alternating beta-1,5 and beta-1,6 furanose linkages which make up a significant portion of TB’s complex cell wall. Knock-out studies have shown that this enzyme is vital to TB viability making it an attractive drug target. Previous work in the Thomas group identified iminosugars as a weak inhibitor of GalfT2. The aim of this project is to synthesise a library of these iminosugar compounds and explore their efficacy as GalfT2 inhibitors using both whole-cell and enzyme assays. Structural elaboration will be performed, principally driven by in silico drug design which will attempt to improve the inhibitory properties. The hope of the project is to identify novel iminosugar compounds which can act as effective anti-TB compounds.
The cancer stem cell (CSC) theory postulates that skeletal muscle-specific cancers known as Rhabdomyosarcomas (RMS) result and recur due to a subpopulation of cancerous cells sharing stem cell-like properties including the ability to self-renew and proliferate. Building on previous work implicating Sonic hedgehog (Shh) signalling in muscle regeneration, this study will investigate the ability of adult skeletal muscle satellite cells (SC) to self-renew, following conditional knockout of Patched (Ptc), a tumour suppressor gene mutated in RMS. It is expected that upregulation of Shh signalling will deregulate SC behaviour, contributing to their transformation into CSCs, thus leading to RMS. Mice deficient for Ptc exclusively in SCs, produced using an inducible Cre-Recombinase under the control of the Pax7 promoter, will be used. Following induction of recombination, mice will be subjected to repeated injuries by unilateral injection of Cardiotoxin into the Tibialis Anterior muscle at intervals of 21 days. After the 3rd injury, muscles will be harvested and analysed by immunofluorescence to determine the effect of Ptc loss-of-function on SC self-renewal. This study will determine whether SCs give rise to CSCs when Shh signalling is disturbed, and contribute to RMS. This knowledge is crucial for designing novel therapies for the treatment of RMS.
Many neurological conditions such as multiple sclerosis (MS) are caused by damage to neurons and glial cells in the central nervous system (CNS) and the CNS lesion development consistently involves an inflammatory component. Recent research suggests that numerous immune cytokines are highly expressed in the CNS lesions of these neurological disorder patients and they play an important role in the development and remission of CNS inflammation, tissue damage and repair. Thus, understanding the complex modulatory roles of these cytokines in CNS is the key to developing future effective therapeutic strategies for these diseases. It was recently observed that cytokines such as IL-33 and IL-22 closely correlate with the severity of CNS inflammation. This summer project aims to further understand the expression and function of these cytokines in CNS tissues under normal and inflammatory conditions using a mouse model of MS disease.
Mitochondria are highly versatile compartments that exist within eukaryotic cells. They perform a myriad of functions, but most importantly are tasked with producing energy at a rate that meets an incessant cellular demand, allowing cells to dynamically move, grow and divide in response to environmental cues. Energy production by mitochondria is intricately orchestrated by complex protein machineries acting in exquisite collaboration with one another. Importantly, dysfunction of mitochondria leads to cell death and is a hallmark of a range of human diseases, particularly neurodegenerative pathologies such as Alzheimer’s and Parkinson’s disease. As a result, cells have evolved several quality control mechanisms to ensure that damaged mitochondrial components are degraded before they pose a threat to cell viability. In the most recently discovered mechanism, damaged mitochondrial proteins are dynamically clustered together, then trafficked away from mitochondria and towards a separate part of the cell, the lysosome, where they are destroyed. In my PhD project, I will investigate which proteins are transported away from the mitochondria in this fashion, and the mechanistic details of how this occurs. This approach will reveal novel insights into a key aspect of mitochondrial biology, and could enhance our understanding of mitochondria in neurodegenerative disease.
The Nobel Prize-awarded discovery of programmed cell death while studying Caenorhabditis elegans nematode cell lineage revolutionised biomedicine. Although pervasive across living organisms and despite incredible potential applications, organismal death remains understudied, partly due to the lack of reliable death-markers. In nematode worms, death is marked by an impressive blue fluorescence burst, allowing us to study events that immediately precede death. Using this marker, we found that alteration of conserved neuromuscular pathways can delay worm death. Death fluorescence, whole-brain imaging at single-cell resolution, and a transparent model organism with fully-mapped brain wiring provide unique opportunities to study how neurological processes modulate death. We will (1) generate a collection of transgenic worm strains expressing ratiometric calcium-biosensors tissue-specifically to follow individual neurone/muscle activities, (2) develop a new fluorescence imaging platform to monitor in parallel death fluorescence and brain activity, (3) produce a temporal map of neuromuscular activity in the moments leading to death. This could help us understand how death occur, when it becomes irreversible, and how it can be targeted pharmacologically to improve organ collection and preservation, extend safety windows for major surgeries (particularly in elderly patients), or even reverse it to some extent.
We wish to apply for funds to develop the malaria CHIM application. These are for a Co-investigators/stakeholders meeting to be held in Bangkok, Thailand, on 30th and 31st January 2018 and to support a writing meeting of the PIs in February 2018 in Kilifi, Kenya.