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Results

A CRISPR/Cas9-Based Screen for Novel Actin Dynamic Factors 27 Apr 2017

The project will focus on understanding critical aspects involved in the biology of the apicomplexan parasite Toxoplasma gondii (T. gondii), an obligate intracellular parasite that can infect every warm-blooded animal including humans. T. gondii, the causative agent of toxoplasmosis, is of medical importance for human health as an infection can cause severe damage in the developing foetus and immunocompromised persons. In addition, T. gondii serves a model organism for Plasmodium falciparum, the aetiological agent of malaria. In order to invade the host cell apicomplexan parasites rely on their acto-myosin system. Furthermore, recent research highlights the importance of parasite actin during intracellular parasite development. It is thus important to identify and characterise factors involved in the regulation of actin dynamics. Here, cutting edge molecular tools including conditional CRIPSR/Cas9-systems will be applied to screen a subset of essential genes in T. gondii for novel factors involved in the regulation of actin dynamics. Investigating how the parasites regulate these filaments will give valuable insights into how apicomplexan parasites establish infections in their host.

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

Role of intralaminar thalamic nuclei in absence epilepsy 30 Sep 2018

Seizures in absence epilepsy are characterised by brief lapses in consciousness and cessation of ongoing behaviour. They occur concurrently with aberrant rhythmic electrical activity across the whole brain in the form of oscillations named Spike and Wave Discharges (SWDs). It is widely agreed that SWDs are generated in the cortico-thalamo-cortical (CTC) circuit that consists of neurons that run within and between the cortex and the thalamus. The activity of neurons in many components of the CTC circuit are already well characterised, apart from that of the intralaminar nuclei of the thalamus (ILNs), a group of neurons that respond in an abnormal, yet consistent way during seizures. The electrical activity of single neurons in the ILNs will be recorded and manipulated in order to physiologically characterise them and understand how changing their firing pattern can alter SWDs. The techniques required to achieve this are too invasive to be completed in humans, therefore, these methods will be undertaken in genetic and pharmacological rodent models of absence epilepsy. This work will provide a better understanding of the role of ILNs in the generation and spread of SWDs and in CTC circuit function, potentially leading to novel therapeutic approaches in absence epilepsy.

Amount: £0
Funder: The Wellcome Trust
Recipient: Cardiff University

Assessing the anticancer properties of Biocyanin SLH 31 May 2018

Haemocyanins are oxygen-carrying proteins found in the haemolymph of molluscs and gastropods. They are of interest to biotech and medical research as strongly immunogenic carrier proteins, for making antibodies to conjugated peptides and for use as cancer vaccines. In addition, direct application of haemocyanin to tumours has been shown to produce an anticancer effect, and haemocyanins from several species including keyhole limpet have shown promise in the treatment of bladder cancer, colon cancer and melanoma. Particularly striking are their lack of toxicity and adverse effects. Recently, Mikota PLC have developed protocols for the purification of a new haemocyanin, Biocyanin SLH, from the slipper limpet Crepidula fornicata. The main aim of our proposal is to test the potential of Biocyanin SLH as an anticancer agent, by incubating it with a panel of cancer cell lines and assessing its ability to induce cell death. In addition, we will investigate the signalling pathways involved in the anticancer action of Biocyanin SLH, determining whether cell death occurs via apoptosis or necrosis, and analysing cellular production of stress molecules. Finally, we will label Biocyanin SLH with a fluorescent dye to track its interaction with cells using confocal microscopy. Keywords: haemocyanin, cancer, cell death.

Amount: £0
Funder: The Wellcome Trust
Recipient: Cardiff University

Communication between immune and stromal cells is key to immunological memory within pathogen infected tissues 10 Apr 2018

Pathogens trigger an accumulation of immune cells in the infected tissue. Incoming immune cells adapt to their new environment, communicating with infected stromal cells to ensure pathogen control. Tissues do not immediately return to homeostasis following pathogen clearance. Some pathogen-specific T cells remain, differentiating into Tissue Resident Memory cells (Trm). The tissues’ stromal cells also retain an imprint of the infection with prolonged expression of immune-related genes. Currently, we have only limited understanding of the cells and molecules involved in establishing and maintaining these infection-induced changes and how immune and stromal cell communication impacts on protective immunity. These are key question for vaccines that aim to induce immune protection within tissues to provide rapid protective immunity. This proposal is based on our findings that antigen-presentation and inflammatory cytokine production drives prolonged changes in lung CD4 Trm cells and epithelial cells and fibroblasts. Our key goals are to define the mechanistic basis for these changes by identifying the cells and molecules that influence the generation, maintenance and protective responses of infection-altered immune and lung stromal cells. This research will provide a conceptual breakthrough in our understanding of how cell commination influences protective memory and novel insights relevant to improved vaccine design.

Amount: £1,161,008
Funder: The Wellcome Trust
Recipient: University of Glasgow

Harnessing the potential of embryo-derived pancreas organoids to model early tumorigenesis 04 Dec 2017

Epithelial tissues maintain homeostasis through competitive cell-cell monitoring systems that detect and eliminate defective or mutant cells1-3. Retention of damaged or mutant cells would impair tissue function and initiate tumourigenesis. We have identified an evolutionarily conserved mechanism of cell competition that drives the segregation and elimination of Ras-transformed cells from simple epithelia4-6. KRas mutations (KRasG12D) are the principal oncogenic drivers of human pancreatic ductal adenocarcinoma (PDAC)7, making it an ideal model to test the significance of KRas driven cell competition. Our current data show that KRasG12D cells are lost from healthy pancreas tissues, suggesting that the normal niche may prevent early tumourigenesis. Current experimental pancreas models limit our ability to probe the biology of cell competition at the cellular level. The goal of this proposal is to grow fully differentiated pancreas organoids in culture, mosaic for KRasG12D expression. Organoids recapitulate the cellular complexity, plasticity and spatial organisation of tissues8,9. We will combine this accessible cell-based platform with advanced imaging techniques, to determine how the normal cell niche prevents expansion of KRasG12D cells, and how additional p53 mutations drive disease. Future work will investigate Eph-ephrin signalling and changes in cell polarity in early tumorigenesis.

Amount: £91,480
Funder: The Wellcome Trust
Recipient: Cardiff University

Investigating the relationship between the cerebellum and cognition in both health and disease 30 Sep 2018

The cerebellum is traditionally ascribed only a role in motor coordination. With it containing more neurones than the rest of the central nervous system combined and with connections with almost every other area of the brain concerned with cognition, this seems exceptionally unlikely. Indeed, studies utilising magnetic resonance imaging (MRI) increasingly show strong cerebellar activity associated with cognitive processes. This is still a greatly understudied area with only a few groups researching this. We, therefore, wish to investigate the role of the cerebellum in cognition using large imaging datasets, our own high-field imaging capabilities at Cardiff and various cerebellar-specific MRI processing tools which have not yet been applied to this question. This will allow us to see how well peoples’ cognitive performance in various domains correlates with cerebellar activity and structural differences. Additionally, recent evidence suggests cerebellar structural differences in schizophrenic patients. We wish, therefore, to also investigate if schizophrenia diagnosis and genetic risk for schizophrenia similarly alters cerebellar structure and, if so, at what time during development, if certain cognitive domains are particularly affected and if cerebellar metabolite levels differ in schizophrenic patients compared to non-schizophrenic controls.

Amount: £0
Funder: The Wellcome Trust
Recipient: Cardiff University

Mechanisms of ubiquitin signalling in Parkinson's Disease 28 Nov 2017

Neurodegenerative disorders, including Parkinson's Disease and dementia with Lewy bodies, are devastating diseases, with no known cure. They share a common histopathological feature, in that the deposits of insoluble aggregates found in the brains of patients are heavily modified by ubiquitin. Several genes that are associated with neurodegenerative disorders encode E3 ubiquitin ligases. One such ligase, Parkin, is mutated in > 50% of autosomal recessive juvenile parksinsonism (ARJP) cases. Furthermore, Parkin is found in the inclusions deposited in the brains of sporadic Parkinsonism patients. Parkin signalling is complex and heavily regulated, and our understanding of how it targets substrates is not well understood. This proposal aims to define the complete catalytic cycle of Parkin function, how proteins are targeted, how ubiquitin is relayed through the catalytic intermediates to target conjugation. This will require a combination of structural biology and chemical biology to capture individual states, and biochemistry to identify molecular determinants of Parkin activity. Understanding these catalytic processes at the molecular level, will not only impact on our understanding of the regulatory events taking place in vulnerable neurons, but will also provide the atomic detail needed to develop pharmacological compounds capable of restoring or disrupting enzyme function.

Amount: £1,390,536
Funder: The Wellcome Trust
Recipient: University of Glasgow

The mammillary bodies and memory: from encoding to consolidation 17 Jul 2018

The mammillary bodies (MBs) are critical for memory but their specific functions have remained largely elusive. Historically, the MBs were associated with memory encoding, however, our recent findings suggest an as yet unexplored role in memory consolidation, both at the cellular and at the systems level. The proposed research will use multi-level, comparative approaches to investigate the contribution of the MBs to post-encoding processing, during wakefulness and sleep. The combined rodent/human methodologies will take advantage of the unique benefits provided by each line of research. The application of convergent techniques with rodents (inactivation, calcium-imaging, electrophysiology, behaviour) will interrogate the contributions of the MBs to different stages of memory processing, both in an intact system and when the system is disrupted. Complementary research with humans will address similar questions. fMRI will help to assess diencephalic contributions in the intact system. The impact of damage to the MB system on aspects of sleep-related consolidation will also be assessed. Together, this research will provide a comprehensive analysis of post-encoding memory processes and support the development of wide-reaching models of MB function.

Amount: £1,563,892
Funder: The Wellcome Trust
Recipient: Cardiff University

INSTITUTIONAL TRANSLATION PARTNERSHIP AWARD (iTPA): CARDIFF UNIVERSITY 30 Sep 2018

The Cardiff institutional Translational Partnership Award (iTPA) aims to embed a more translational culture within the university's academic staff. It will combine the educational and community-building activities needed to assist researchers with industrial engagement and help them align their research outcomes with industrial needs. The iTPA will also provide fund projects during the so-called Translation-of-Concept phase for projects where proof-ofconcept has already been established. These activities will all be coordinated by a Translational Research Lead whose role will be to identify clear bottlenecks, gaps and barriers to translation of Cardiff science and identify the key external partners needed to provide an external, market-informed viewpoint in collaboration with the University's Commercial Development Team.

Amount: £600,000
Funder: The Wellcome Trust
Recipient: Cardiff University

The relevance of hydrogen sulfide signalling in dietary restriction induced longevity 31 May 2018

Dietary restriction (DR), typically reduced food intake relative to ad libitum fed controls, is the most widely used intervention to slow ageing, increase lifespan and healthspan. Precisely how DR acts to induce its effects is unknown, although recent findings suggest that the gasotransmitter hydrogen sulphide (H2S) may underlie the beneficial effects of DR. H2S can also attenuate accelerated ageing phenotypes in progeroid models. In this project I will utilise different strains of ILSXISS mice that show differential responses to DR- from lifespan extension to lifespan shortening. DR-induced longevity in ILSXISS mice is correlated with increased liver H2S production but this is not observed in strains that show lifespan shortening under DR. The key goal of this project is to investigate components of the transulfuration pathway (TSP); the primary pathway in which H2S is synthesised/metabolised within cells. To this end I will measure protein and transcript levels using western blotting and qPCR of key TSP components (e.g. Cystathione- beta-synthase, cystathione-gamma-lyase, rhodanese, sulphide- quinone reductase-like). I will then examine whether commonality exists in these parameters within the liver following DR in ILSXISS mice with comparison with other tissues such as the brain.

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

A sticky situation: confronting the challenges of bacterial surface adhesion 31 May 2018

Certain bacterial species can colonise to form biofilms- large structures which protect bacteria from physical and chemical removal e.g. antibiotics. If adhered to biomedical implants, bacteria can cause repeated infections which couldn't be treated by antibiotics and therefore would lead to the removal of the implant. In some patients, this would result in repeated invasive surgery. Our interest is in crystalline biofilms which can block urinary catheters and cause catheter-associated urinary-tract-infections (CAUTI). The main bacterium causing CAUTI is E. Coli in which E. Niba et al. (2008) isolated 110 genes involved in the formation of biofilms. Mutations in key genes will be created using Lambda red recombination which is a highly efficient and well established method for creating precise gene deletions. Deletions will be confirmed using PCR and sequencing. The deletion mutants will be analysed for biofilm formation using a bioflux system which generates shear force by continuous flow of liquid. This is an open system ensuring nutrients are available and thereby favouring biofilm formation. Both pathotypes and their respective mutants will be tested for the capacity to form biofilms at a range of temperatures. Data from the above experiments will be quantified using ImageJ software.

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

Molecular Mechanisms of Cortical Development 30 Sep 2018

EIEE9 (Early Infantile Epileptic Encephalopathy 9) is a rare genetic condition caused by mutations in the PCDH19 (Protocadherin 19) gene. The disorder affects heterozygous females and is characterized by epileptic seizures and cognitive impairment. PCDH19 is a cell-adhesion molecule that mediates cell-cell interactions during cortical development and it is thought to play an important role in neuronal migration and synapse formation. Researchers think the disease is caused by "cellular interference": PCDH19 is located on the X chromosome and - due to random X-inactivation - heterozygous females have a mixed population of PCDH19 positive and negative cells which are unable to correctly interact with each other leading to defective circuit formation and disease. We aim to create a transgenic mouse model that will enable selective labelling of PCDH19 expressing cells. This mouse model will be a valuable tool to investigate interactions between PCDH19+ and PCDH19- cells during cortical development and to study circuit formation. We will combine our transgenic mouse with recently developed techniques for synaptic tracing to characterize the neuronal circuits in which PCDH19+ neurons are involved by identifying those neurons that connect to PCDH19+ cells.

Amount: £0
Funder: The Wellcome Trust
Recipient: Cardiff University

Alpha-GABa receptor modulators for the treatment of cognitive impairment associated with Huntington’s disease 01 Oct 2017

Huntington's disease is a fatal genetic disease characterised by a movement disorder that is accompanied by a decline in cognitive function and changes in mood and behaviour. The decline in cognitive function may precede the movement disorder by a decade or more and is a very important component of the functional disability associated with the disease. There is, however, no effective treatment for enhancing cognitive performance in Huntington's. Professor John Atack at the University of Sussex aims to identify novel drugs that can enhance cognitive performance in subjects with Huntington's disease to address a large unmet medical need.

Amount: £747,573
Funder: The Wellcome Trust
Recipient: Cardiff University

Designing unconventional peptide modifications to universally enhance CD4+ T-cell activation 28 Nov 2017

The CD4+ T-cell response is of fundamental importance in generating effective immunity to pathogens and cancer. The interaction of the CD4+ T-cell receptor (TCR) with peptide presented by HLA class II heterodimers (pHLA-II) is the central point of the adaptive immune response. Overwhelming evidence suggests the affinity of this interaction dictates the efficacy of T-cell activation (Panhuys et al Immunity 2014), and indeed, the fundamental importance of TCR:pHLA-II affinity was illustrated in a cohort of long term HIV controllers (Benati et al JCI 2016). Crucially, low affinity TCR:pMHC interactions contribute significantly to cancer vaccine failures. The biology of this interaction has been ignored by the vast majority of vaccine studies. This project takes a fundamentally different approach to therapeutic and prophylactic vaccines, by focusing on the details of the TCR:pMHC-II interaction. We aim to utilise our proven ability to generate high affinity TCR:pMHC-II interactions, with no loss of specificity, by targeting changes in the epitope flanking regions. This approach will illustrate how HLA-bespoke vaccines can be generated, and will be tested (using HLA-DR-transgenic mouse) in models of infection and cancer. The long term aim is to match superior vaccines to the individuals' HLA background, personalising treatment, and transforming vaccine design.

Amount: £1,839,908
Funder: The Wellcome Trust
Recipient: Cardiff University

Timestamping Integrative Approach to Understand Secondary Envelopment of Human Cytomegalovirus 28 Nov 2017

The mechanisms facilitating the assembly of Human cytomegalovirus (HCMV) in the cytoplasm of infected cells, a complex process termed ‘secondary envelopment’, are poorly understood. Our goal is to identify in-situ the identity, position, and interactions of all the essential proteins involved in this critical stage of the viral ‘lifecycle’. Despite decades of research, it has been difficult to dissect the complexity of secondary envelopment, as bulk assays only show ensemble averages of populations of viral particles. To study these intermediates that are formed when cytoplasmic capsids acquire tegument proteins and their envelope membrane, we will develop a novel approach that separates these intermediates in time and space. We will provide their spatio-temporal models by integrating complementary cutting-edge techniques and expertise within this collaboration, including flow-virometry, correlative (fluorescence and electron cryo) microscopy, crosslinking and ion-mobility mass spectrometry-based proteomics, and computational modelling. Specifically, we aim to: -Identify key players in tegument assembly on capsids/membranes. -Elucidate the order and spatial organisation of tegument assembly. -Validate the interactions in vivo and analyse capsid tegumentation in vitro. -Integrate the information into a spatiotemporal model. This will significantly improve our understanding of herpesvirus assembly in general, a crucial step towards identifying new therapeutic targets.

Amount: £673,700
Funder: The Wellcome Trust
Recipient: Birkbeck University of London

Brain Rhythms in Altered Vision After Stroke (BRAVAS) 08 Nov 2017

Stroke affects 152,000 people in the UK each year, and up to 80% experience visual impairment as a result. Post-stroke disorders such as hemispatial neglect (a loss of visual attention to one side of space) are notoriously difficult to treat, and are associated with limited functional recovery and reduced quality of life. In healthy adults, visual processing is modulated by neural oscillations which help to promote or suppress incoming visual information. Specific oscillatory frequencies are known to be disrupted in stroke, yet at present it is unknown how these oscillations are related to hemispatial neglect. I aim to develop a new intervention for neglect via 3 interlinked and interdisciplinary clinical projects: 1) to identify, using electroencephalography (EEG), the oscillatory markers of a temporary, induced improvement in neglect during a phasic alerting protocol, 2) to identify longer-term oscillatory markers of improvement from neglect using magnetoencephalography (MEG) at 1-3 months vs 6-12 months post-stroke, and 3) to compare two targeted interventions to modulate pathological oscillatory activity, using a biofeedback protocol vs non-invasive brain stimulation. This translational programme will bring together knowledge and expertise from cognitive neuroscience and clinical stroke rehabilitation to develop a novel intervention to treat visual impairment after stroke.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Glasgow

Influence of Sleep on Human Brain Structure 08 Nov 2017

Sleep is essential to brain functioning and its loss greatly impairs cognition, yet the brain mechanisms underlying the cognitive benefits of sleep remain largely unclear. During sleep, the brain’s functional networks break down, with different brain regions showing decoupled activities. I hypothesize that this decoupling of brain regions will facilitate the remodeling and optimization of brain structural networks, leading to improved brain functioning and cognitive performances after sleep. I will test my hypothesis in human participants by combining measures of brain structure, function, cognition, with brain stimulation during sleep. First, I will study how the structure of inter-regional connections change after sleep, whether these changes improve the network properties, and how these changes are reflected in the function of inter-regional communications. Then, I will study how the post-sleep changes in brain function correlate with brain activity in sleep, and whether these functional changes can be modulated by brain stimulation during sleep. Last, I will study how the post-sleep changes in brain structure differ across different inter-regional connections, and whether these structural changes can predict the selective influences of sleep on different cognitive performances. Overall, this project aims to explore how sleep benefits cognition by improving brain structure for higher functionality.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: Cardiff University

Stratification of bipolar disorder: harnessing clinical heterogeneity and genetics shared with other disorders 08 Nov 2017

The bipolar disorder diagnostic category, while clinically useful lacks biological precision/validity. There is consensus that this biological imprecision is impeding aetiological research and the development of new therapeutic interventions. BD overlaps with schizophrenia (SCZ) and Major depressive disorder (MDD) in its clinical presentation. It has a large polygenic component to it genetic aetiology which it partially shared with SCZ and MDD. This suggests the hypothesis that the clinical heterogeneity seen in BD may be due to underlying causal heterogeneity and the degree of clinical similarity between individuals diagnosed with BD, SCZ and MDD reflects overlapping risk alleles which selectively influence specific, shared clinical characteristics, rather than the global risk for the disorders. This study will use genome-wide and pathway-specific polygenic risk score methods to identify biologically valid stratifiers for BD, informed by psychopathological characteristics AND genetic liability. BD may be the extreme phenotypic expression of psychopathological dimensions distributed throughout the general population to explore this further, generalised latent variable modelling will be used to examine and compare the latent structure of the psychopathological phenotypes in BD cases with those found in the general population and LD score regression will test for genetic correlation

Amount: £310,234
Funder: The Wellcome Trust
Recipient: Cardiff University

What makes phleboviruses tick? Examining the molecular interactions of tick-borne phleboviruses with their arthropod vector. 21 Feb 2018

There is a fundamental lack of understanding regarding how tick-borne viruses replicate in ticks and how the tick innate immune system controls infection. My proposal will focus on tick-borne SFTS phlebovirus, its overarching goals are to understand how tick-borne viruses interact with ticks and tick cells and how this facilitates transmission to mammalian hosts. To achieve my goals, I will carry out in vitro and in vivo studies that can be divided into three specific aims: (i) to elucidate the basic molecular biology of tick-borne virus replication, (ii) to define the innate immune factors that control virus replication in the tick cell environment and (iii) to examine whether virions derived from tick or mammalian cells have similar biological properties and virulence? I will conduct in vitro experiments in tick cell lines to examine virus-vector interactions. Importantly, I will also establish unique tick colonies and infection capabilities for the UK. Through combined cell culture approaches and in vivo animal experiments I will investigate the replication of phleboviruses in the live tick for the first time. I will also explore the infectivity of virions derived from different sources and assess if tick-derived viruses are more virulent to mammals in animal inoculation studies.

Amount: £1,335,592
Funder: The Wellcome Trust
Recipient: University of Glasgow