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Paul Hamlyn Foundation
The Wellcome Trust
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University of East Anglia
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Results

Cancer chemotherapy as a driver for antibiotic resistance evolution 06 Sep 2018

Antibiotic resistance is one of the most urgent challenges in healthcare. The overuse and misuse of antibiotics has driven the evolution and spread of antibiotic resistance in bacteria, reducing the effectiveness of antibiotics that are currently available. Understanding how antibiotic resistance evolves and is selected for is crucial for developing strategies to counter this threat. Growing evidence shows that many therapeutic drugs commonly used in healthcare also have antibacterial effects, including several classes of cancer chemotherapy drug. Bacteria can become resistant to chemotherapy drugs through the same mechanisms used to develop resistance to antibiotics, and bacteria can carry chemotherapy resistance genes alongside antibiotic resistance genes on mobile genetic elements (MGEs) such as plasmids. This suggests that exposure to chemotherapy drugs contributes to the evolution and spread of antibiotic resistance. This study will interrogate cancer genome data and cancer patient gut metagenome data to assess the occurrence of chemotherapy resistance genes in bacteria from cancer patients, use experimental evolution under chemotherapy drug exposure to determine the ability of chemotherapy drugs to select for reduced susceptibility to antibiotics, and use a novel Hi-C method to determine the degree to which chemotherapy drugs promote the spread of MGEs that carry antibiotic resistance genes.

Amount: £99,985
Funder: The Wellcome Trust
Recipient: University of East Anglia

Understanding ligand recognition in a mammalian membrane transporter 31 May 2018

GltPh is an homotrimeric aspartate transporter from the thermophile Pyrococcus horikoshii. This archaeal homolog of mammalian glutamate transporters belongs to the SLC1 transporter family, which also includes the human Excitatory Amino Acid Transporters (EAAT). The EAATs have been implicated in various neurological diseases including epilepsy and Alzheimer's disease. Crystal structures suggest large scale conformational changes and recent Electron Paramagnetic Resonance (EPR) spectroscopic studies have suggested a heterogeneous mixture of distances and have therefore remained inconclusive with respect to conformational changes associated with substrate transport. To dissect the underlying conformations, which contribute to the EPR spectra, we aim to purify and spin-label this transporter. Mutations have been designed to block the transporter in specific conformations. In silico predictions of further mutations for EPR experiments will be performed to identify suitable variants and subsequent spin labelling will be performed. The overall aim is to obtain a complete set of EPR results in various intermediate conformations of the transport cycle, both in detergent and reconstituted into proteolipsomes. In other studies, preliminary data indicate that the conformational stability of GltPh also depends on the status of ligand binding. We aim to extend our EPR studies to also address this ligand-dependant conformational stability.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of East Anglia

Identification and characterization of novel peptides in snake venom that pharmacologically modulate the human P2X4 receptor 31 May 2018

P2X receptors are ligand-gated ion channels activated by extracellular ATP. The human genome encodes seven receptors (P2X1-7) of which the P2X4 receptor has emerged as a promising drug target for the treatment of neuropathic pain and hypertension. However, progress in this area has been severely hampered by a paucity of selective small molecule modulators of P2X4. This project will seek to identify and characterise novel snake venom peptides that can pharmacologically manipulate the activity of the human P2X4 receptor.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of East Anglia

Cellular plasticity in the avian primitive streak - a differential analysis 31 May 2018

During gastrulation, mesoderm cells undergo ingression through the primitive streak followed by migration and further specification. Our aim is to investigate how these closely linked processes become integrated by developmental signalling pathways. We showed previously that BMP2 and Wnt3a converge on Smad1 to alter cardiac progenitor cell (CPC) migration in the early chick gastrula; interestingly, ectopically located cells remained cardiogenic. In contrast, paraxial mesoderm progenitors (PMPs) at the mid-gastrula stage responded to elevated BMP2 by changing fate without changing their migration. We have used RNAseq to uncouple the differential responses of early and late mesoderm progenitors to the same signalling network: BMP2/Wnt3a/Smad1. CPC and PMP cells were exposed to BMP2, Wnt3a, or constitutively-active Smad1. RNAseq analysis identified candidate genes that were up- or downregulated in response to all treatments. We have identified, some developmental regulators alongside more specific signal transducers and several novel genes. The summer studentship will contribute to the ongoing validation of these candidate genes. Following confirmation of differential expression by RT-qPRC, the key goal will be to undertake gene expression analysis using whole mount in situ hybridisation in early gastrula stage embryos. The outcome from these experiments will underpin our future functional in vivo analyses.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of East Anglia

Understanding how antibiotic-induced microbiota disturbances affect breast cancer progression 31 May 2018

Breast cancer (BC) is the biggest cancer killer for UK women, with ~12,000 deaths/annum. Critically, incidence has risen by 20% over the last 20 years, and treatment for BC, particularly metastatic disease, remains challenging. Recently, the gut-tumour axis has emerged as an important modulator of anti-cancer immune responses, which is correlated with the ability of gut microbes (i.e. the microbiota) to impact mucosal and systemic immunity. Whilst previous studies have focussed on how specific microbes augment immune checkpoint drugs in non-BC cancers, there remains an important open question; what are the consequences for disruption of the microbiota (e.g. antibiotics) on primary and metastatic BC? Clinically this is highly pertinent as previous population studies have correlated antibiotic usage with increased incidence of BC, and BC patients also receive antibiotics throughout treatment. Our preliminary data shows in disease relevant mouse models that a harsh cocktail of antibiotics (which severely disrupts the microbiota) promotes primary tumour growth, and metastatic spread, and that this correlates with immune readouts known to correlate with poor BC prognoses. This summer studentship will examine how clinically-relevant antibiotic regimes (which generate less severe microbiota disturbances) impact BC progression, and tumour immune surveillance.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of East Anglia

Challenges to the 'Mental Deficiency System': The National Association for Mental Health's role in Legislative Change and the Development of Community Care 1946-1967 15 Nov 2016

From its formation in 1946 the National Association for Mental Health (NAMH) was a key stakeholder in ‘mental deficiency’ services. It provided professional training, experimental hostels, and advice to the government and public. An examination of its activities is crucial to understanding post-war developments in services. However, academic commentaries commonly give NAMH little role. Instead they focus on three other stakeholders (Welshman and Walmsley 2006): The National Council for Civil Liberties (NCCL) attacked the workings of the Mental Deficiency Acts, psychologists showed patient’s abilities were higher than claimed, and the National Association for Parents of Backward Children (NAPBC – now Mencap) gradually influenced policy and practice. The recent opening of the MIND archive offers the first opportunity to develop a rigorous account of NAMH’s role, including its significant relationships with all of these groups. NAMH had a close relationship with NAPBC from its formation. Leading psychologists who critiqued mental deficiency services worked with NAMH. And all these groups engaged closely with NCCL’s campaigning. These groups were involved in two particular areas: legislative change and developing community care. This project’s key objective is to understand NAMH’s role in these areas in the context of its relationship to these other important stakeholders.

Amount: £24,976
Funder: The Wellcome Trust
Recipient: University of East Anglia

Early sleep and circadian markers of Alzheimer’s disease: The impact of APOE-ε4 on circadian rhythm and sleep-wake homeostasis in humans 12 May 2017

Sleep abnormalities are common in neurodegenerative disorders, and can be present long time before the clinical onset of the disease. This is true for Alzheimer’s disease (AD) as well, where the APOE-epsilon4 allele, a genetic predisposing factor for AD, has been recently correlated with impaired sleep in healthy adults. These data suggest a mechanistic contribution of sleep to neurodegeneration supported by its essential role in energetic restoration, neural plasticity and beta-amyloid clearance from the brain. Less is known as to how the circadian system and sleep-wake homeostasis are affected in AD and might interact in modulating or driving the onset and progression of disease, in particular in at-genetic-risk of AD (APOE) healthy participants. We plan to investigate for the first time the impact of the APOE genotype on the circadian system and the sleep-wake-homeostat and the way they interact in defining sleep and waking cognition in everyday life and under sleep laboratory conditions where we will experimentally modulate sleep pressure. This will help understand biological mechanisms linking cognitive deficits and sleep impairment in high-risk population for neurodegeneration, which in turn will pave the way for future intervention studies to improve sleep function and potentially delay disease onset.

Amount: £97,673
Funder: The Wellcome Trust
Recipient: University of East Anglia

Vacation Scholarships 2017 - University of East Anglia 16 Jun 2017

Vacation Scholarships 2017 - University of East Anglia

Amount: £6,000
Funder: The Wellcome Trust
Recipient: University of East Anglia

Exploiting MALDI Imaging Mass Spectrometry to understand effects of plant extracts in a human model for atopic dermatitis 27 Apr 2017

The first aim of this project is to analyse microarray and MALDI-IMS data obtained from an atopic dermatitis (AD) ex-vivo skin model produced in my supervisor's lab by cytokine treatment. A comparison between altered gene expression shown in microarrays will be compared with altered protein expression shown in the MALDI-IMS data. The cytokine treated ex-vivo skin explants treated with resveratrol will also be compared with published proteomic data for AD and psoriasis, as well as comparing cytokine and resveratrol treated skin explants with published data. Once this has been done three key proteins will be identified for further study. The expression of these key proteins will be confirmed in the cytokine and resveratrol treated skin explants through qRT-PCR and immunocytochemistry. Gene expression of the key proteins will involve RNA extraction and the use of qRT-PCR. Immunostaining of the key proteins of skin extract cryo-sections will also be carried out. Serial section will also be stained for specific keratinocyte proliferation markers. In this project, I will gain the key skills of bioinformatic analysis, techniques in skin explant culture, qRT-PCR, immunocytochemistry and Western blotting. I will also be gaining an understanding of the specific localisation of key proteins involved in AD patients.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of East Anglia

IDENTIFICATION OF THE GINSENOSIDE BINDING POCKET ON THE P2X7 RECEPTOR: TOWARDS THE DEVELOPMENT OF AGENTS TO ENHANCE MICROBIAL KILLING 27 Apr 2017

The emergence of resistant prevalent bacteria as Mycobacterium tuberculosis, is boosting the development of novel strategies different to direct anti-microbial killing (antibiotics). An attractive approach is stimulating the immune system response to pathogens exploiting the existing pathways to deal with infection. This needs understanding of the mechanisms, for the development of novel modulators capable of boosting immune responses. P2X7 ion channels regulate immune responses, and activation on infected macrophages with ATP induces killing of Mycobacterium tuberculosis. Ginsenosides, known for their key role in the beneficial effects of immune system stimulation by ginseng, have been demonstrated by our collaborator, Dr Leanne Stokes, to be positive allosteric modulators of the P2X7 channel. Her research has shown the potential of enhancing P2X7 response with ginsenosides to increase microbial killing in macrophages. In this project, we will reveal the location and structural details of the binding pocket in P2X7 specific for ginsenosides of the protopanaxadiol series (Rb1, Rd, Rh2, and CK). We will use protein-ligand docking calculations on human P2X7 to predict the binding location and mode of the ligands, and molecular dynamics simulations to assess the dynamic stability of the complexes. This project will complement further NMR studies on P2X7/ginsenoside interactions.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of East Anglia

Investigating the cognitive benefits of a combined flavanol plus n-3 fatty acid intervention in older adults: The CANN Study 27 Apr 2017

My vacation studentship will be embedded in the ongoing CANN trial (Cognitive Ageing Nutrition and Neurogenesis), which is a 1y RCT which aims to assess the impact of a combined dietary intervention on cognitive function in patients with mild cognitive impairment. It is a double-blind, parallel RCT in 240 participants (≥ 55y). Samples/data will be available from n=75 completed participants by July 2017. The primary outcome is number of false positives in a computerised picture recognition task, which is particularly sensitive to hippocampal integrity, with a key secondary outcome being MRI assessed hippocampal structure/function. My project will focus on cardiovascular biomarkers and will have the following key training and research goals Provide me with training in: The design and implementation of human RCT, Critique of the published literature, Biological sample, handling and processing, and blood biomarkers analysis, The assessment of peripheral- and cerebro-vascular function, using techniques such as pulse wave velocity (PWV) and arterial spin labelling (by MRI) Research: Investigate the impact of intervention on the plasma lipid, glucose and insulin profile and vascular function and relate these to cognitive outcomes.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of East Anglia

Limits to habitability under climate change 30 Sep 2016

We propose to develop improved indicators of habitability, survivability and heat-related tipping points, and to assess the effects of climate change on future population exposures, understand regional vulnerabilities to heat exposure estimates, and quantify uncertainty in the outcome measures. We will undertake further analyses using an ensemble of 20 climate models selected to reflect the full range of uncertainty, comparing global temperature changes of 1.5° C, 2°C, 2.5°C and 3°C. Different RCPs, including those consistent with the commitments in Paris, and policies for deeper cuts in emissions, will be included. We will calculate impacts of different global mitigation policies on thermal stress (combining temperature and humidity analysis) and aim to identify if there are thresholds within the global temperature range where habitability is undermined on a substantial scale in low, middle and high income countries. We would also aim to include an analysis of the times/locations in the recent decade where the proposed ‘limits of habitability’ have been breached and if possible what that has meant for local populations so that our model analysis is grounded in data. The results will be disseminated to the UNFCCC, the IPCC 1.5°C impact assessment, national climate change negotiators, WHO, ILO, UNDP, WMO, IOM and other national and international stakeholders as well as published in the peer reviewed literature. We would aim to undertake this work within a year of the grant award.

Amount: £99,520
Funder: The Wellcome Trust
Recipient: University of East Anglia

‘Molecules to Modulate Insulin Production?' 01 Sep 2016

The Pathfinder project led by Dr Zoë Waller at University of East Anglia aims to investigate the biological properties of molecules with the potential to alter insulin gene expression. Over 400 million people worldwide are diagnosed with diabetes, a major cause of blindness, kidney failure, heart attacks, stroke and lower-limb amputation. Despite current treatments, the WHO projects that diabetes will be the 7th leading cause of death in 2030, thus there is the need for alternative treatment options. The insulin minisatellite region resides in the promoter of the gene coding for insulin, which regulates how the gene is read. The region consists of a tandem repeat DNA sequence capable of forming alternative DNA secondary structures. Mutations or shortening in the length within this sequence have been linked to the development of both type-1 (insulin dependent) and type-2 (noninsulin-dependent) diabetes. We predict we can alter insulin expression specifically by targeting this region. We have identified hit compounds which can target this DNA. This project will explore the biological capabilities of these molecules, their effects on insulin gene expression in cells and determine any potential liabilities for future therapeutic development. The potential impact of this could provide alternative treatment options for diabetes.

Amount: £100,406
Funder: The Wellcome Trust
Recipient: University of East Anglia

MIND’s Campaigning for People with Learning Disabilities 1970-1983 25 Nov 2015

Present government policy and professional practice for people with learning disabilities has its origins in the deinstitutionalisation processes, civil rights concerns and social integrationist philosophies of the 1970s and 80s. However, we know little about how these issues were mobilised. The MIND archive at the Wellcome Trust offers a unique resource for developing a rigorous historical account of this mobilisation. MIND prominently campaigned to change government policy and professional practice for learning disabled people during the 1970s and early 80s. However, academic commentaries on MIND’s activity during this time have focussed virtually solely on its mental illness campaigning (e.g. Crossley 2007, Jones 1997, Toms 2013). Drawing on published and unpublished material, this project will help correct this skewed representation. But, more importantly, it will enable the first detailed reconstruction of a leading organisation’s attempt to found the transformation of policy and practice for people with learning disabilities on citizenship rights and a philosophy of social integration. The project’s key goal will be to historically reconstruct how, why and with what consequences MIND developed this strategy. Results will be of relevance to multiple audiences: Outputs will be produced that are accessible for people with learning disabilities, academics, practitioners and policy makers.

Amount: £26,000
Funder: The Wellcome Trust
Recipient: University of East Anglia

Modulating properties of antibodies using unnatural amino acids 15 Aug 2016

Recent advances in molecular biology and genetics have greatly enhanced the production of proteins with unnatural amino acids having diverse chemical properties. Proteins from several classes are now being modified using unnatural amino acids that can add to or alter the natural properties of the protein. Antibodies, with their wide range of applications through molecular biology to medicine, present an attractive class of proteins whose properties may be modulated using unnatural amino acids. In Aim 1 of this project, we propose to develop photoactive antibodies, i.e., antibodies whose binding to their corresponding antigen can be controlled using light. Such antibodies could be used as research tools to study antibody-mediated processes, and also have the potential to be developed into novel antibody-based photoactive therapeutics. In Aim 2 of this project, we propose to develop antibody-based optical switches, i.e. non-fluorescent antibodies that become fluorescent upon binding to target antigens. These switches would overcome a major limitation of current antibody-based detection methods, where immobilisation of antigen or antibody to a surface is required. Such optical switches are expected to have applications in cancer diagnosis, and in detection of viruses and bacteria.

Amount: £99,921
Funder: The Wellcome Trust
Recipient: University of East Anglia

The regulation of microRNAs in cartilage by circadian rhythms 01 Apr 2016

Osteoarthritis (OA) is a degenerative joint disease and a leading cause of disability in the UK. There is currently no pharmaceutical cure for OA and pain relief is rapidly inadequate. The role of both microRNAs (miRs) and the circadian rhythm in OA have recently come to the fore, and a clear involvement for both areas in cartilage homeostasis has been identified. However, there are no data on the control of miRs in cartilage by circadian rhythms. This proposal aims to: (i) measure expression of cartilage-relevant miRs in synchronised chondrocyte cell cultures to identify those expressed in a circadian fashion; (ii) validate CLOCK as a direct target of miR-455, predicted by bioinformatics. This will provide initial data on the role of the circadian rhythm in miR expression in cartilage and inform on novel therapeutic strategies in OA.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University of East Anglia

Biomedical Vacation Scholarship. 22 Jun 2015

Not available

Amount: £14,000
Funder: The Wellcome Trust
Recipient: University of East Anglia

From Genes to Disease: Investigating the Role Of ECM1 Variants in the Pathogenesis of Inflammatory Bowel Disease. 25 Jun 2014

Inflammatory bowel disease affects 1:250 people in the UK. It is a chronic condition associated with significant morbidity. It comprises two principle forms; Crohns Disease and Ulcerative Colitis (UC). Genome wide association scanning has identified gene variants involved in maintenance of the intestinal epithelial barrier as being associated with UC including ECM1. In yeast models ECM1 binds and inhibits matrix metalloproteinase 9 (MMP9), a protease involved in tissue remodelling which has been implicated in colitis pathogenesis. I propose to investigate the function of ECM1 and its variants and to define the interaction between ECM1 and MMP9 within a disease appropriate model. The hypothesis is that ECM1 variants cause functional attenuation reducing the inhibitory effect on MMP9 leading to increased tissue breakdown and thereby a dysfunctional intestinal epithelial barrier. My research objectives are: 1. To determine the conditions under which ECM1 and MMP9 associate i n human colonic epithelial cells 2. To determine the requirement for ECM1 in maintaining epithelial cell barrier integrity. 3. To determine the impact of ECM1 variants on ECM1 function This may allow us to stratify patients susceptibility to IBD and highlight potential therapeutic targets.

Amount: £145,051
Funder: The Wellcome Trust
Recipient: University of East Anglia