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Results

Investigation of relapsed Burkitt lymphoma - towards improved treatment options and survival for childhood in high and low-income countries 31 May 2018

Unlike other childhood cancers genomic abnormalities are currently not used in the clinical management of aggressive Burkitt lymphoma (BL) and we cannot predict which children will or will not respond to therapy. There is huge disparity between outcome for children with BL in high- and low-income countries ( > 90% vs 50%) and BL remains a substantial global health challenge. For those patients who do not respond to front-line treatment or who relapse, outcome is dismal in both settings. There is, therefore, a clear clinical need to identify biomarkers and new therapeutic targets. Knowledge of the key genetic defects driving the pathogenesis of BL and disease progression is essential to develop rational targeted therapies suitable for both low- and high-income countries. In this project we will use cutting-edge next-generation sequencing approaches to fully characterise the genome complexity of patients with relapsed disease. Analysis of matched diagnostic and relapse samples from children diagnosed with BL in the UK and Malawi will enable the key abnormalities associated with disease progression to be identified. Our overall aim is to identify the specific abnormalities which could be targeted by novel drugs to improve survival for children diagnosed who are currently not cured by frontline treatment.

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

In Vitro Models for Complement Dysregulation 31 May 2018

Complement is an integral component of innate immunity, and its dysregulation is associated with diseases such as C3 glomerulopathy (C3G), atypical haemolytic-uremic syndrome (aHUS) and many chronic inflammatory diseases where self-tissues are inappropriately targeted and damaged. Complement factor H (fH) is an essential inhibitor of the alternative pathway of complement activation, it downregulates complement on self-tissues. In this project, I will produce an in vitro model of fH dysregulation using the factor H-blocking antibody, IIB6. I will purify the antibody from a pre-established hybridoma cell-line and determine its integrity using SDS-page and its binding ability with a fH western blot. Normal fH function will be tested in a fluid phase co-factor assay by incubating C3b, fH and factor I and testing for cleavage and inactivation of C3b. The ability of IIB6 to block inactivation of C3b in this pure protein system will be confirmed first, before spiking IIB6 into whole serum and assessing ‘fluid phase’ dysregulation of complement by western blot analysis of activation products. Finally, cell-surface inhibition of fH by IIB6 will be confirmed in a cell-based hemolysis assay, optimised for sensitivity. This assay can subsequently be used as a platform for testing complement therapeutics.

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

Telomere length inheritance 31 May 2018

We will establish what happens to telomere length in diploid cells that inherit abnormal length telomeres from one parent (equivalent to human beings inheriting abnormal telomere lengths from a mother or father). We will examine diploids created using haploid yeast strains containing null mutations causing long (L: rif1Delta or rif2Delta), short (S: yku70Delta or mre11Delta) or normal (N: no mutation) telomeres. We will passage the diploids cells for scores of generations to determine how telomere homeostasis is regulated in these cells. 9 types of diploids, derived from haploids with different length telomeres (NN, NS, NL, SN, SS, SL, LN, LS, LL), will be studied. Southern blots will be sued examine telomere length changes over 10 or more passages (each passage is approx. 30 cell divisions). The results will have implications for the inheritance of human telomere length syndromes.

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

The impact of patient mutations in Na/phosphate cotransporters to function and trafficking of the protein 31 May 2018

The renal transport system for inorganic phosphate (Pi), SLC34A1, is central to balancing Pi levels in the human body. Mutations in SLC34A1 have been identified in patients with isolated renal phosphate wasting, generalised proximal tubulopathies (renal Fanconi’s syndrome), renal stone formers and patients with nephrocalcinosis. The spectrum of phenotypes observed points to a complex interplay between the nature of the mutation and the genetic background of the patient. Intriguingly, some of the mutations show a dominant phenotype. The aim of this proposal is to investigate the molecular and cellular determinants for the dominant behaviour of certain SLC34A1 mutations. We have identified two patients with mutations in SLC34A1. The first patient carries a heterozygous SLC34A1 mutation Ile456Gln whilst the second is compound heterozygous for Arg512Cys and a deletion of Val91-Ala97. These mutations will be used to perform functional analyses in Xenopus oocytes and epithelial cell lines co-expressing wild-type and mutated transporters. Chimeric wt-mutant constructs will also be generated to exclude differences in intracellular processing of the individual units. Intracellular trafficking will be tested in renal epithelial cell lines using wild-type and mutated transporters with different fluorescent tags followed by confocal microscopy.

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

Measuring frailty in older rural South African population - Construction and validation of a Frailty Index 31 May 2018

Data from the HAALSI cohort from rural South Africa will be used to achieve 3 aims: To derive a Rockwood deficit-accumulation Frailty Index (FI) in this population To test whether the FI predicts mortality in the HAALSI population To compare results from the Fried frailty score and the FI A review of existing literature will inform the selection of a minimum of 30 variables for inclusion in the Frailty Index. Examples include (but are not limited to): disease diagnoses (e.g. angina, HIV), functional impairments (e.g. low gait speed, low grip strength), or biochemical/haematological derangements (e.g. low haemoglobin). Absence of a deficit scores zero; presence of a deficit scores 1. Cox proportional hazards models will be used to examine the association between the FI and time to death in the HAALSI data; unadjusted models and models adjusted for age and sex will be developed. Finally, the ability of the FI to predict 1 year mortality will be compared with the ability of the Fried phenotypic score to predict 1 year mortality in the HAALSI population. Receiver-operator characteristic curves will be developed for each score, and the c-statistic for each score compared.

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

Expression profiling of p53 transcriptional target genes as a predictor of cell fate following non-genotoxic activation of p53 by MDM2 inhibitors 31 May 2018

The purpose of the proposed project is to investigate the differences in p53-dependent gene expression between cells that undergo growth inhibition and senescence in response to p53 activation compared with those that undergo apoptosis. These alternative cell fates, which are cell type and context dependent, have important roles in a range of disease states and responses to therapeutic intervention, but the underlying mechanisms are poorly understood. We have identified a panel of cell lines that epitomise these alternative cell fate responses to p53 activation, which we will investigate by using MDM2-p53 binding antagonists to activate p53 directly and specifically, without DNA damage. In addition, we will use agents which demethylate DNA to test whether pro-apoptotic genes can be re-activated in those cell lines in which these genes appear to be silenced. Techniques used to investigate the downstream consequences of p53 activation will include flow cytometry, enzymatic apoptosis and senescence assays, Western immunoblotting and multiplex qRT-PCR gene expression profiling.

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

The Role of Sphingosine-1-Phosphate in Endothelial Integrity 31 May 2018

Sphingosine-1-phosphate (S1P) has been well established as a signalling lipid involved in the regulation of vascular permeability via binding of one of five G protein coupled receptors called S1PR1-S1PR5. This project aims to develop a model for measuring S1P control of vascular permeability, in order to demonstrate the usefulness of S1P as a therapeutic for reducing vascular permeability during organ transplantation. Previous work by this group have shown that both Human Microvascular Endothelial Cells (HMEC-1), and a positive control (Caco-2), grown to confluency on 0.4um transwells present a barrier to Evans Blue dye conjugated to albumin. This model will be manipulated by treating these cells with either S1P or agonists/antagonists of the different S1P receptors to show their effect on the ability of HMEC-1 to form a barrier to Evans Blue. This work will be supported by measuring the changes in electrical resistance across the endothelial barrier on these transwells following the aforementioned treatments, using an ohmmeter. Confluency of both cell types will be demonstrated using H & E staining. Together these results will demonstrate the ability of S1P to control endothelial permeability in vitro via the differing S1P receptors and therefore its potential for use as a therapeutic in organ transplantation.

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

Can ATR and Wee1 inhibitors sensitise cells to the PARP inhibitor, Rucaparib, by inhibiting homologous recombination repair? 31 May 2018

Ovarian cancer is the seventh most common cancer in women, and less than a third of women with ovarian cancer will survive beyond 5 years. This indicates that there is an urgent need for the development of new therapies. A new area of research is the DNA Damage Response (DDR). PARP is a key enzyme that promotes the repair of the most common form of endogenous DNA damage, oxidative stress, resulting from reactive oxygenating species. Most cancer cells have lost G1 cell cycle control, making them reliant on S and G2 checkpoints. The ATR/CHK1/Wee1 pathway signals DNA damage to arrest the cell proliferation cycle and promote repair. ATR promotes homologous recombination DNA repair (HRR) and PARP inhibition is synthetically lethal in cells defective in cells lacking HRR. PARP inhibitors are now licenced to treat HRR defective ovarian cancer but

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

Investigating the roles of Toxin/Antitoxin module in pathogenic Neisseria 04 Dec 2017

Pathogenic Neisseria species continue to cause harmful infections in humans. Neisseria meningitidis causes life threatening meningitis and septicaemia infections, particularly in infants, and Neisseria gonorrhoeae causes the sexually trasmitted infection gonorrhoea. There is an urgent need to further study these pathogens particularly N. gonorrhoeae as gonorrhoea cases are on the rise and it is increasingly in the news due to the sharp increase in cases with resistance to antibiotics, leading to the fear that gonorrhoea could soon become untreatable. We will investigate the role that toxin/antitoxin modules play in Neisseria biology. In other pathogens, these systems have been observed to include a toxin able to stall bacterial replication and an antitoxin that neutralises the toxin's activity. When under stress, the antitoxins are degraded leaving a free toxin to arrest bacterial growth. In this non-growing state bacteria are tolerant to antibiotic challenge. There is very little known about how the toxins of Neisseria function and what their role is in infections. This proposal will address this lack of knowledge by discovering the biological systems targeted by the toxins and assessing their effect on Neisseria metabolism.

Amount: £99,861
Funder: The Wellcome Trust
Recipient: University of Sussex

Newcastle Wellcome Trust Translational Partnership 30 Sep 2018

The partnership will help to engage our talented scientists in translational research by providing mentorship, support and addressing barriers in the early stages of the translational pathway, while creating an embedded and durable cultural awareness of translation in all of our scientists.

Amount: £800,000
Funder: The Wellcome Trust
Recipient: Newcastle University

Cell envelope synthesis in Gram positive bacteria: mechanisms, regulation and inhibition 28 Nov 2017

Cell wall synthesis is a highly conserved process in bacteria, and crucial as both a target for our best antibiotics and a source of innate immune signals of infection. The wall defines the shape of bacteria but it is sculpted with the help of conserved cytoskeletal proteins, including MreB, FtsZ and DivIVA. The aim of this project is to study the spatial regulation of wall synthesis, especially cylindrical elongation, in the model Gram positive bacterium Bacillus subtilis. Several factors in wall synthesis appear to be redundant and we will attempt to resolve the adaptive basis for this redundancy, as well as solving specific questions on the function of cell elongation factors. In another major lineage of Gram positive bacteria, the Actinobacteria, cell elongation is achieved by a completely different mechanism involving tip growth and branching. Little is known about the evolutionary pathway leading to these contrasting strategies. We have identified and will undertake comparative studies of an unusual group of Firmicutes that appear to exhibit branching tip growth like actinobacteria. The results will not only enrich our understanding of wall synthesis in general but will also provide insights that we hope to exploit in the search for new antibiotics.

Amount: £1,858,759
Funder: The Wellcome Trust
Recipient: Newcastle University

Recognition, activation and targeted degradation of protein kinases clients by the HSP90-molecular chaperone 10 Apr 2018

Many oncogenic protein kinases depend on interaction with the HSP90 molecular chaperone, mediated by the co-chaperone CDC37, for their cellular stability and oncogenic activity. Inhibition of HSP90's conformationally-coupled ATPase mechanism leads to the ubiqtuitylation and degradation of these protein kinase 'clients'. Consequently HSP90 is an important target for therapeutic intervention in cancer. Although there has been substantial progress in this field, important issues remain unresolved. In particular we wish to understand : How protein kinase clients are specifically and selectively recognised by the CDC37 co-chaperone, and recruited to HSP90 ? What structural and biochemical changes are elicited in the client protein by recruitment to HSP90 and by its conformationally-coupled ATPase cycle ? How dephosphorylation of CDC37 by the HSP90-targeted protein phosphatase PP5 regulates client protein release ? How protein kinase clients are targeted for proteasomal degradation when HSP90's ATPase is inhibited ? To address these questions we will use cryoelectron microscopy, X-ray crystallography, NMR spectroscopy, and a range of biochemical and biophysical approaches, to determine structures of key complexes along the pathway from initial client recognition to release or ubiquitylation, and define the structural and biochemical transitions that connect them.

Amount: £2,027,915
Funder: The Wellcome Trust
Recipient: University of Sussex

The effect of loss of RTN4IP1 on mitochondrial function. 31 May 2018

Mitochondria are complex cellular organelles that harness the process of oxidative phosphorylation (OXPHOS) to provide cellular energy, but defects in this process can cause mitochondrial diseases that are associated with a wide range of clinical symptoms, severity and age of onset. Recently, whole-exome sequencing identified pathogenic variants in RTN4IP1 in patients presenting with mitochondrial disorders. RTN4IP1 patient derived cells showed a complete loss of this protein, a mitochondrial respiratory chain Complex I assembly defect and reduction in mitoribosome formation. This project will utilise patient-derived fibroblasts harbouring pathogenic variants in the RTN4IP1 gene and the CRISPR/Cas9-mediated RTN4IP1 knockout cell lines to determine the precise role of this protein in mitochondrial function. First, we will examine cellular growth of RTN4IP1 patient and CRISPR/Cas9 knockout cell lines in galactose media forcing the utilisation of the OXPHOS system. Then, RTN4IP1 localisation within the organelle will be determined by mitochondrial sub-fractionation and Western blotting. In addition, the steady-state levels of OXPHOS and mitoribosomal proteins will be assessed in RTN4IP1-deficient cells. Finally, sucrose density gradient centrifugation will be used to assess a potential role of RTN4IP1 in the mitoribosome biogenesis. Key words: mitochondrial disease, RTN4IP1, OXPHOS, mitoribosome

Amount: £0
Funder: The Wellcome Trust
Recipient: Newcastle 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: £810,920
Funder: The Wellcome Trust
Recipient: University of Sussex

Unraveling genetic causes and risk factors for severe male infertility 28 Nov 2017

This research will significantly advance our molecular and clinical understanding of human spermatogenesis and severe male infertility. We will study the germline genomes of men with selected infertility syndromes as well as large-cohorts of men with non-obstructive azoospermia, aiming to identify pathogenic mutations in novel male infertility genes and non-coding genomic regions, including complex Y chromosomal abnormalities. In addition, we will use innovative flow cytometry and transcriptomics approaches to study normal and abnormal human spermatogenesis. Finally, we will study the consequences of assisted reproductive technologies for the genome of offspring, and look at the preservation of fertility in this offspring. Throughout this research, we will make use of unique material from infertile patients, their parents and their offspring born through ART. This will allow us study the role of de novo germline as well as somatic mutations as unappreciated causes of severe male infertility. The results of this research will be used to develop novel diagnostic procedures and improve the diagnostic yield in this largely unexplained patient cohort. In addition, this research will provide crucial biological information for the development of novel fertility procedures and provide improved methods to monitor the safety of these procedures.

Amount: £2,331,140
Funder: The Wellcome Trust
Recipient: Newcastle University

Open Access Award 2017/18 30 Sep 2018

Not available

Amount: £45,702
Funder: The Wellcome Trust
Recipient: University of Sussex

Open Access Award 2017/18 30 Sep 2018

Not available

Amount: £129,927
Funder: The Wellcome Trust
Recipient: Newcastle University

Microglia and type I interferon: protective and pathogenic mechanisms 23 May 2018

Viral encephalitis is a severe and largely untreatable manifestation of viral infection, with substantial rates of lifelong disability in survivors. The discovery, by myself and others, of rare monogenic diseases that predispose to viral encephalitis indicates that interferon-alpha/beta is an essential mediator of antiviral protection. Determining the underlying mechanism is a critical step towards developing therapeutic agonists of this pathway. Conversely, I and others have also discovered that exaggerated interferon-alpha/beta activity is linked to monogenic neuroinflammatory disease. Establishing causality is a clinical necessity, as therapeutic options are available to block interferon signalling. My proposal will definitively address the following questions: Does interferon protect brain cells against viral infection? Is prolonged interferon signalling damaging to brain cells? What is the specific role of brain-resident macrophages (microglia) in these processes? To address these questions, I exploit new models of human microglia from gene-edited and patient-derived pluripotent stem cells, together with a new knock-in mouse model. Key goals are to create fundamental knowledge about the action and regulation of interferon-alpha/beta in brain cells, and deliver a versatile and genetically-tractable human model in which to interrogate host determinants of viral neuropathogenesis. The skills I develop will underpin my future research programme in viral encephalitis.

Amount: £451,877
Funder: The Wellcome Trust
Recipient: Newcastle University

State-of-the-art proteomics for Newcastle University 05 Jul 2018

Proteomics is a powerful tool that is increasingly used by scientists in a wide range of biologically and medically important areas. Here, we are requesting funds for a cutting-edge liquid-chromatography mass spectrometry (LC-MS) system that will enable us to support Wellcome-funded researchers in Newcastle with access to state-of-the-art proteomics. We will utilise this instrument to enhance the research of a number of exceptionally successful clinically relevant research groups. In particular, we will perform quantitative proteomics to identify changes to the mitochondrial proteome in response to disease mutations, characterise immune populations during early human development, the role of mutations in inflammatory disease in humans, analyse molecular pathways and identify biomarkers in liver disease and fibrosis, and describe molecular mechanisms in bacterial cell biology and pathogenicity. Overall, this instrumentation will boost the research of Wellcome-funded researchers at Newcastle University.

Amount: £578,689
Funder: The Wellcome Trust
Recipient: Newcastle University

Vacation Scholarships 2018 - Newcastle University 16 Jul 2018

Vacation Scholarships 2018 - Newcastle University

Amount: £18,500
Funder: The Wellcome Trust
Recipient: Newcastle University