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Results

Tissue Repair 30 Sep 2017

Not available

Amount: £2,655,000
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Molecular basis for heterochromatin formation in the African trypanosomes 31 Jan 2017

Histones are some of the most well-conserved proteins between eukaryotic species and specific post-translational histone modifications often trigger the same cellular responses in different organisms. However, the histones of Trypanosoma brucei, the causative agent of sleeping sickness, are more divergent than the histones in other organisms. In most eukaryotes, heterochromatin is formed by adding methyl groups to Lys9 of histone H3. Trypanosomes lack the H3K9 residue and heterochromatin formation in these parasites must be specified by a distinct mechanism. This project aims at uncovering the histone modifications that mediate trypanosome heterochromatin formation. Next-Generation mass spectrometry analysis will be performed to survey histone modifications in the different developmental forms of T.brucei. Additionally, the composition of the trypanosome heterochromatin will be characterised using several alternative strategies including: fluorescent tagging of putative readers, writers and erasers of heterochromatin-associated histone modifications; isolating trypanosome nuclei and enriching for lamina-associated chromatin; and CRISPR/Cas9 or TAL targeting of GFP to repetitive elements in T.brucei.

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

Organisation of pericentromeric chromatin in Saccharomyces cerevisiae 31 Jan 2017

Successful cell division relies on faithful chromosome segregation. Central to this process is sister chromatid cohesion by cohesin that topologically entraps sister chromatids. Cohesin shows increased association with chromosomal regions surrounding the centromere, called pericentromeres. Pericentromeric cohesin is crucial during both meiosis and mitosis. In meiosis I, when homologous chromosomes segregate, pericentromeric cohesion is protected from separase-dependent cleavage ensuring that sister chromatids stay together until they segregate in meiosis II. In mitosis and meiosis II, pericentromeric cohesin facilitates chromosome biorientation by establishing preferred kinetochore geometry for capture by microtubules. How exactly pericentromeric cohesion facilitates chromosome biorientation is unknown. It was proposed that pericentromeric cohesin establishes intramolecular linkages allowing the pericentromere to adopt a cruciform structure. This would facilitate a back-to-back geometry of kinetochores and would promote kinetochore capture by microtubules from opposite spindle poles. This project aims to characterise the conformation of the pericentromere in budding yeast. I will examine how the conformation of pericentromeric chromatin responds to the presence and absence of tension that is exerted on chromosomes during biorientation. The research will extend to mitotic and meiotic cells, with wild type and cohesin-deficient backgrounds. Ultimately, this will further our understanding on how kinetochore geometry facilitates accurate chromosome segregation.

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

STING/NET23: a transmembrane shuttle at the nuclear envelope to regulate innate immune responses 31 Jan 2017

The innate immune response (IIR) is the cell’s first line of defence against pathogens. STING/NET23, an ER and nuclear envelope (NE) resident transmembrane protein, is a key host cell adaptor involved in IIR signalling. STING/NET23’s role at the ER in triggering signalling cascades in response to cytosolic dsDNA is well understood, but its NE role and its function in response to viral RNA is unclear. Previous work in the lab has indicated novel NE roles for STING/NET23 at the centre of a highly redundant signalling network linking 17 NE specific binding partners to IRF3/7 transcription factors. Moreover, it appears to act as an NPC peripheral channel shuttle, redistributing binding partners involved in IIR signalling upon IIR induction. Intriguingly a number of these partners are known to bind RNA, pointing to a role for STING/NET23 in IIR signalling against RNA viruses. This project aims to assess NPC peripheral channel shuttling of STING/NET23 and its binding partners using super resolution microscopy and identify RNA targets of STING/NET23 partners during viral infection. This could resolve two conundrums in the field regarding transmembrane transport between the nuclear and cytoplasmic faces of the NE and how STING/NET23 is able to mediate IIRs to RNA viruses.

Amount: £34,605
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Validating the effect of Rlf and Scml2 on somatic cell reprogramming 27 Apr 2017

Oct4, Sox2 and Nanog (OSN) are important pluripotency transcription factors that play an important role in embryonic stem (ES) cell self-renewal. Oct4 and Sox2 are also key factors in reprogramming somatic cells into induced pluripotent stem (iPS) cells. In a recent study, proteins interacting with OSN on chromatin were identified by chromatin immunoprecipitation followed by Mass spectrometry named ChIP-SICAP (Rafiee, et al, 2016). Independently, the Kaji lab performed a genome-wide knockout screening using a guide RNA (gRNA) library of 90,000 gRNAs to identify detrimental and essential genes for reprogramming. The screening data indicated that knockout of little characterized OSN-associated protein, Rlf or Scml2, decreases or increases reprogramming efficiency, respectively, while knockout of neither gene demonstrated obvious phenotype in ES cell self-renewal. The goal of the project is to evaluate the effects of knockout and overexpression of Rlf or Scml2 on reprogramming. For this purpose, I will make vectors which can express reprogramming factors and gRNA or cDNA simultaneously, and perform reprogramming. By counting resulting iPSC colony numbers and comparing with a control condition which does not express Rlf or Scml2 gRNA/cDNA, I will investigate roles of Rlf and Scml2 in reprogramming.

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

Engineering a Functional Synthetic Thymus 17 Jul 2018

T-cells, the central executors of adaptive immunity, are generated in the thymus. Thymus biology is intricate, reflecting the complex processes that control its seeding with haematopoietic progenitors, and subsequent T-cell commitment, differentiation and repertoire selection. Physiological T-cell repertoire development and selection is not yet possible outside the native organ. Recent advances, including the advent of T-cell immunotherapy, have brought thymus biology into the spotlight, and the capacity to recapitulate and control thymus function would open enormous possibilities for novel immune-mediated therapies for cancer, inflammation, immunodeficiency and autoimmunity. Our collaborative aim is thus to create a fully functional, synthetic, thymus organoid, as a tractable enabling system for basic research and a therapeutic source of functional T-cells. To achieve this, we will decipher the molecular and cellular mechanisms that control development and function of the epithelial cell compartment of the thymic stroma which provides the organ’s specialist functions by integrating cutting-edge stem cell biology with biomaterials engineering, single cell time-and-space-controlled transcriptomic interrogation and advanced mathematics. The project outputs will be transformative for understanding the synthetic formation of a primary lymphoid organ and for studies of T-cell maturation with its translational potential for new immunotherapeutics including thymus replacement or regeneration.

Amount: £3,643,500
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Differentiation Competence of Pluripotent Cells 16 Jun 2018

We will provide image analysis software that can extract information about how cells form functional and morphological networks in tissues or organoids based on 3D imaging data. These methods would be useful for understanding the cell-cell interactions that govern tissue formation, repair, and pathology. This software is built on a data-exploration framework for that enables flexible interrogation of complex datasets. This framework is designed to be readily extensible. New segmentation methods from other groups can be incorporated into this single data-exploration system. By investing in a sustainable open-source format and providing a flexible database for data exploration we enable the most effective use of data and provide an environment for collaborative exploration of rich datasets. Key words: Image analysis, software documentation, data interrogation, cell-cell interactions.

Amount: £16,872
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Regulation of fission yeast cell polarity by stress-signalling pathways 10 Apr 2018

Cell polarity is essential to eukaryotic cell organisation and function and important in cell/tissue homeostasis and disease. Cdc42 and other Rho-family GTPases have widely-conserved, central roles in cell polarity. Using fission yeast Schizosaccharomyces pombe, we discovered that Cdc42-mediated cell polarity is regulated by the stress-activated protein kinase (SAPK) pathway, involving MAP kinase Sty1, homologous to mammalian p38. Although the SAPK pathway is known to regulate gene expression in response to stress, our work suggests that stress signalling regulates cell polarity post-translationally, via novel pathways. Our overall goal is to understand, at a molecular level, how SAPK activation leads to Cdc42-module regulation, through combined proteomics, genetics, imaging, and biochemistry approaches. We will identify polarity-specific substrates of Sty1 and determine how they influence Cdc42 and its interactors. We will also study the two different Cdc42 guanine-nucleotide exchange factors, as we have shown that they have distinct roles in polarity regulation and are oppositely affected by stress. We will also determine how SAPK-regulation of cell-polarity is integrated with other signalling pathways, including nutrient stress/TOR signalling, cell-cycle control, and the cytoskeleton. This work in a model eukaryote will provide insights into potential roles of stress signalling in cell polarity in humans and pathogenic fungi.

Amount: £1,039,434
Funder: The Wellcome Trust
Recipient: University of Edinburgh

The role of TRIM25's RNA-binding activity in RIG-I/Interferon pathway. 04 Dec 2017

I recently discovered that the TRIM25 E3 ubiquitin ligase, which is a key factor in the innate immune, RIG-I/Interferon type 1 response to RNA viruses, is an RNA-binding protein that recognises specific host RNAs and regulates their stability. This important finding redefines our understanding of the regulation of host RNA metabolism and opens new questions about the fundamental mechanisms of cell biology and innate immunity. My overall goal is to discover new phenomena occurring at the interface between RNA biology and human disease. Here, I will focus on what role does newly identified RNA-binding activity of TRIM25 have in innate immune response to 5'-ppp-RNAs and Influenza A infection. Towards this aim, I will address the following: How does the RNA-binding activity of TRIM25 affect its ability to stimulate the RIG-I/Interferon signalling pathway? The outcome of this research will redefine our understanding of the control of RIG-I/Interferon signalling pathway and has huge potential to open up novel research avenues in the field of innate immunity and RNA biology.

Amount: £87,429
Funder: The Wellcome Trust
Recipient: University of Edinburgh

AI and health: exploring affect and relationality across three sites of intelligence and care 26 Jul 2018

We aim to develop novel approaches across a multidisciplinary network of collaborators to explore affect and relationality in the design and applications of artificial intelligence (AI) in health. We will explore different dimensions of "intelligence" – physical, interpretive and emotional – as practical accomplishments in the construction and use of AI and examine the implications of incorporating AI into formal and informal care relationships across different health contexts. Our key research questions are: How are assumptions about (health) practices embedded in AI development? How is affect, implicitly or explicitly, rendered in health-related AI? How is AI changing relationships of (health) care? What does and should constitute "affective and relational AI"? In order to address these, we will undertake exploratory case-studies across different health related contexts: AI and robotic surgery (physical intelligence) AI and digital pathology (interpretive intelligence) AI at the interface of health and social care (emotional intelligence) This work will produce novel insights into the multi-dimensional and socially-mediated ways in which "intelligence" as well as "artificiality" are being delineated and (algorithmically) configured in the context of care. This will lay the foundation for future collaborative inquiry into the affective relationality of AI and health.

Amount: £57,897
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Macrophage-epithelial communication promotes lung repair after injury 25 May 2017

Lung epithelial injury is the near-universal sequela of multiple pulmonary insults. Rapid restoration of mucosal integrity prevents impaired gas exchange and superadded bacterial infection, but aberrant tissue repair is a frequent, often fatal, outcome in disease. Despite this, no current treatments target homeostatic repair processes. Macrophages are pivotal for efficient tissue repair but how they communicate with epithelium to achieve this remains poorly understood. During injury, macrophage engulfment of apoptotic cells or exposure to inflammation-associated cytokines leads them to release extracellular vesicles (microvesicles) and insulin-like growth factor-1 (IGF-1). IGF-1 inhibits epithelial engulfment of apoptotic cells but enhances epithelial microvesicle uptake. Furthermore, increased leukocyte-derived microvesicles and elevated IGF-1 correlate with improved patient survival from lung injury, suggesting this macrophage-epithelial communication system may deliver key anti-inflammatory, pro-reparative signals. Indeed, macrophages release extracellular factors that enhance epithelial proliferation (integral to repair) and proliferation is reduced by attenuating epithelial microvesicle uptake. My central hypothesis is that lung macrophage-epithelial communication is enhanced following lung injury and promotes repair. My key aims are to investigate: How macrophage-derived signals influence lung epithelial responses Mechanisms governing lung epithelial uptake of microvesicles Signals delivered by macrophage microvesicles to epithelium, and whether they promote repair after injury

Amount: £770,022
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Challenging trypanosome antigenic variation paradigms using natural systems 11 Jul 2017

Antigenic variation (AV) is a common mechanism used by pathogens to evade host immunity and ensure infection chronicity. Recently the capacity to study AV at a molecular and population-level has expanded through systems level approaches. However, there is urgent need to challenge existing paradigms by assessing temporal (early vs. chronic infection) and spatial (tissue compartment) influences on the pathogen antigen repertoire, as well as pathogen genotype and host context. Here, we will quantitate and derive models to parameterize antigen diversity and infection chronicity in African trypanosomes. These are an exemplar of AV where population-scale antigen mRNA sequencing is tractable and underlying molecular regulators of infection are identified and manipulable. Critically, we will extend the trypanosome AV paradigm beyond the limited infection model commonly used to date, i.e. Trypanosoma brucei in mice. Thus, we will (i) quantitate the contributors to AV in chronic bovine infections for the clinically-relevant pathogens T. congolense and T. vivax, relating this to conventional infections in mice (ii) determine the contribution of identified molecular regulators of AV, parasite development and tissue compartmentation, and (iii) use the derived information to build mathematical models to interpret and unify molecular and population-level understanding of AV in these clinically-relevant infections.

Amount: £2,070,288
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Origins of pathogenic interferon in neurolupus 30 Sep 2017

Origins of pathogenic interferon in neurolupus

Amount: £233,447
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Decoding adaptive immunity: high-throughput sequencing and characterisation of the immune repertoires produced during parasitic infections 30 Sep 2018

Despite extensive research, there remains no effective vaccine licensed for any human parasitic infections. This has been attributed to a lack of knowledge available regarding the development of naturally acquired immunity to such infections. Following pathogen exposure, clonal expansion of T and B-cells occurs, generating repertoires of lymphocytes that are a distinct response to the pathogen. High-throughput sequencing, in combination with proteomics, now provides the opportunity to study these immune responses in precise detail, delineating components of protective immunity and identifying their critical antigenic targets, providing unparalleled insights in to the mechanisms underlying immunity to a pathogen. By sequencing T and B-cell repertoires produced during parasitic infections, we aim to document conserved T cell and antibody responses that convey protection, and identify what antigens they are targeting, to inform vaccine design. Key goals are to provide proof of principle for this approach using a controlled animal-model of the malaria parasite Plasmodium chabaudi, before analysing human acquired immunity in Schistosomiasis. We aim to document TCR and antibody sequences that are elicited during immune responses to these parasitic infections, identify conserved ‘public’ antibody signatures generated and characterise their antigenic targets, thereby addressing the key knowledge gaps that have precluded effective vaccine design.

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

Conserved Epitopes in Rosetting PfEMP1 Variants: Prevalence will Inform Potential as a Therapeutic Target in Severe Malaria 30 Sep 2018

Rosetting, where parasitised red blood cells bind to non-parasitised red blood cells, has consistently been associated with severe forms of Plasmodium falciparum malaria. There is therefore interest in the development of anti-rosetting therapies which aim to alleviate the microvascular obstruction caused by rosettes. However, the highly polymorphic nature of the parasite-derived antigen family, Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), responsible for rosetting has made this challenging. A recent report showed that polyclonal sera from rabbits immunised with the N-terminal domain of two rosette mediating PfEMP1 variants showed extensive recognition of heterologous rosetting parasite lines. These cross-reactive antibodies suggest that conserved epitopes exist on some rosette mediating PfEMP1 molecules. Here, we propose to develop a monoclonal antibody targeting one of these cross-reactive epitopes. This will allow us to characterise the epitope, and to estimate the percentage of severe malaria clinical isolates displaying this target. Fundamentally, the work proposed here aims to determine whether one of the cross-reactive epitopes recognised by the rabbit cross-reactive polyclonal sera has therapeutic potential, either as a target for a molecular therapy, or as the basis for a vaccine against rosette mediated disease.

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

Development of a proteome-wide assay to measure phosphatase substrate dephosphorylation rates in human cells 31 May 2018

Temporal ordering of cellular events during mitosis is crucial for accurate cell division. Temporal control is dynamically regulated by reversible phosphorylation by the opposing activities of kinases and phosphatases. Recent work in yeast has suggested that intrinsic differences in substrate phosphorylation rates by kinases are important for imposing temporal order. Compared to kinases, much less is understood about the full repertoire of phosphatase substrates in human cells and how dephosphorylation rates vary among substrates. To address this gap in knowledge, I will develop a screen to measure substrate dephosphorylation rates in cells using purified phosphatases and fixed human cells. These methods on fixed, permeabilised cells provide an opportunity to measure biochemical properties of proteins in the context of a static, but intact macromolecular environment. The project will be a collaborative effort between the Welburn and Ly laboratories. I will first express and purify the mitotic phosphatases in the Welburn lab and then perform phosphatase reactions on fixed human cells in the Ly lab. I will focus on PP1gamma and PP6, phosphatases that have been previously shown to be important in regulating mitotic progression. The assay will then be used for large-scale characterization of substrate dephosphorylation kinetics by mass spectrometry-based phosphoproteomics.

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

The dynamic role of macrophages in spinal cord repair in larval zebrafish 30 Sep 2018

Unlike mammals and humans, zebrafish can repair their spinal cords after injury. Mutant fish that lack macrophages, an immune cell critical for tissue repair, do not regenerate as well. I aim to understand the function of macrophages in efficient spinal cord repair. To do this I will manipulate the macrophages’ ability to clear dead cells and debris from the injury site, a process called phagocytosis, and observe how this alters regeneration. Furthermore, macrophages can release a variety of immune-related signalling molecules that are important for resolving inflammation at the injury. These molecules, called cytokines and chemokines, are intrinsically linked with phagocytosis and successful repair, so I also aim to visualise and quantify real-time changes in the expression of these molecules during repair and how they contribute to successful regeneration. Ultimately this project will advance our understanding of the role of the immune system, and macrophages, in supporting successful spinal cord regeneration in zebrafish.

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

Modelling microglial activation in human neuroinflammatory disease 31 May 2018

Abnormal activation of the innate immune system within the brain has been linked with a spectrum of brain pathologies, including dementias and neuroinflammatory diseases. Microglia are brain-resident immune cells capable of responding to external circulating cytokines. Recent evidence from mouse models has shown that type I interferon proteins can activate microglial cells, leading to increased phagocytic activity and increased ingestion of synapses on neighbouring neurons. This enhanced synaptic pruning has been hypothesised to drive aspects of neuroinflammatory disease such as neurolupus, where there is prominent activation of the antiviral type I interferon response. The research will involve cell culture of human microglial cells using an induced pluripotency stem cell (iPSC) system and subsequently examine the effects of type I interferon proteins on their function. I will differentiate iPSC cells to iPSC-derived microglia, and evaluate the phenotypic characteristics of these cells using immunocytochemistry, FACS analysis and functional engulfment assays. I will then evaluate the effect of type I interferon on the phenotype and function of these cells. Key Goal 1. To grow and characterise microglia from human iPSC Key Goal 2. To examine the effect of type I interferon on human microglial cells

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

Regulation of tissue neutrophil function and survival by the interplay between oxygen and metabolite sensing pathways 28 Nov 2017

Neutrophils are essential for host defence but widely implicated in disease. A fine balance exists between maintaining effective host pathogen responses and limiting host-mediated tissue damage. Innate responses to bacterial challenge are critically regulated by oxygen availability. We have implicated different components of the HIF/hydroxylase pathway in regulating these outcomes. We also showed exposure to hypoxia can reprogramme subsequent neutrophil responses to infection. More recently, we observed that changes in oxygen availability and HIF/hydroxylase activity are associated with alterations in neutrophil metabolic status. I propose that neutrophil adaptation to oxygen and nutrient deprivation at inflamed sites is a consequence of interplay between HIF/hydroxylase activity and metabolic specialization, which defines the magnitude and duration of the neutrophilic response. The goals of this proposal are therefore to: 1. Define the mechanisms by which hypoxia reprogrammes the inflammatory response. 2. Dissect the mechanisms by which HIF/hydroxylase pathway members regulate neutrophil metabolism and subsequent biological function. The ultimate goal is to identify tissue-specific factors that can be targeted to limit detrimental inflammation whilst preserving systemic immunity. This is an area of significant clinical need, with no current strategies that target neutrophil mediated inflammation either in the context of sepsis or chronic inflammatory disease.

Amount: £1,642,423
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Medicines in pregnancy: predicting harms and benefits of antenatal corticosteroids 06 Dec 2017

50% of pregnant women are prescribed drugs in pregnancy, but there are significant knowledge gaps about the safety, optimum dosage and long-term effects of medications in pregnancy. I will use innovative methodology to create new, big datasets for the study of medicines in pregnancy. Within this Fellowship I will focus on antenatal corticosteroid treatment (ACT), as there is a pressing need to establish its safety. I will extract clinical data about ACT from unstructured text entries in electronic health records (NHS Lothian) using GATE natural language processing software. These data will be linked to coded outcomes in maternity/neonatal/perinatal mortality/child-health/education databases. I have secured agreement from international researchers to form a consortium for the study of pregnancy treatments. They will contribute ACT data from birth registries, population cohort studies and trials. I will perform individual patient data level meta-analyses of the above datasets (1.5 million women) for comprehensive study of the effects of ACT on perinatal mortality and childhood neurodevelopment and develop predictive models for harms and benefits. The results will improve ACT prescribing, which is likely to reduce morbidity and mortality. My longer-term vision is to apply these techniques more widely to allow pharmacoepidemiological studies of other pregnancy medications.

Amount: £1,117,931
Funder: The Wellcome Trust
Recipient: University of Edinburgh