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Results

What are the molecular mechanisms regulating neuronal sensitivity to BDNF? 31 May 2018

Neurotrophins and their receptors play a key role in the maintenance and remodelling of the nervous system, and defects in trophic signalling are associated with mental illness as well as neurodegeneration. To date, the cellular mechanisms regulating neurotrophin receptor bioavailability are not fully understood. Here we focus on BDNF and its receptor, TrkB, which are widely expressed throughout the central nervous system. This project will investigate the role of two novel potential TrkB regulators that recently emerged from our screens. Candidates will be expressed in HEK-TrkB cells and primary cortical mouse neurons, and (i) TrkB receptor expression levels and (ii) downstream signalling events will be investigated using both Western blotting and immunofluorescence techniques. These experiments will address whether the candidates modulate TrkB availability and activity. A better understanding of the cellular mechanisms underlying TrkB regulation may highlight potential therapeutic targets to counteract TrkB degradation and restore sensitivity of vulnerable cells to the beneficial actions of BDNF.

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

The role of interferon response genes in an experimental model of Alzheimer's Disease 31 May 2018

Emerging evidence suggest that systemic infection can accelerate the onset and/or progression of cognitive decline in Alzheimer’s disease, but the underlying biological mechanism remain unknown. Exposure of AD mouse models to a real systemic infection results in exaggerated neuroinflammation and AD-like pathology and preliminary microarray analysis suggest this may be due to increased levels of type I or II interferon and/or it’s down-stream signalling pathways. Interferons are produced in response to viral and bacterial infections and well known to be associated with mood changes and depression. In this project we will test if these pro-inflammatory cytokines also play a role in progressing AD-like pathology. Brain tissue from AD mice exposed to a systemic bacterial infection has already been collected, with a control group treated with saline. The expression levels of interferons and their signalling pathways will be explored in this archived tissue and in primary neuronal cultures expressing human Tau. The in vitro cultures will allow us to test if exposure to interferon promotes spreading of tau pathology and if inhibition of the signalling pathways prevents progression of AD-like pathology. This could later be applied to in vivo AD disease models, taking into consideration behavioural changes.

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

Uncovering the Molecular Mechanisms of Asymmetric Cell Divisions in Mammalian Adult Epithelia 04 Dec 2017

Loss of asymmetric cell divisions (ACDs) regulation in the normal self-renewing stem cells is entwined with the growth and progression of poorly differentiated cancers. Yet, the molecular mechanisms controlling the execution of symmetric versus asymmetric divisions in adult epithelia are still unfolding. We recently demonstrated that KIF5/kinesin-1 is essential for mammary epithelial cell divisions and cytoarchitecture by governing the trafficking of the spindle orientation and apical polarity components, respectively. Whether KIF5/kinesin-1 couples spindle orientation and polarity machineries during mitosis to promote ACDs; and whether other mechanisms are involved remain open questions. Here, we will address these questions in mammary 3D organoids. We will use CRISPR/Cas9 gene editing to generate cells expressing AID-tagged endogenous KIF5/kinesin-1 to allow inducible and rapid degradation of the microtubule motor specifically during mitosis, for a precise evaluation of the role it plays in ACDs. We generated cells expressing GFP-tagged LGN –a key player in the spindle orientation machinery–to purify and analyse the LGN-containing complex by LC-MS/MS mass spectrometry and identify novel factors that participate to ACDs. These studies will elucidate the molecular mechanisms of ACDs in the mammary epithelia and provide rational for subsequent detailed investigations in vivo of their precise roles in development and homeostasis.

Amount: £100,000
Funder: The Wellcome Trust
Recipient: University of Southampton

Using a Drosophila model to determine how neuronal clock circuits couple visual inputs to sleep/wake rhythms 31 May 2018

An internal daily timekeeper, known as the circadian clock dictates a 24-hour cycle in behaviour and physiology. In organisms as diverse humans and the genetic model Drosophila melanogaster light perceived by the eyes signals to molecular clock cells in the brain to set their phase. A regular environmental light/dark cycle helps preserve synchrony among different bodily functions, while out-of-phase or abnormal patterns of light exposure can be disruptive to daily timekeeping and result in negative outcomes for both physical mental health and well-being. Given the similarity between the molecular clock circuits of the fruit fly Drosophila and those of mammals, genetic and molecular studies in Drosophila are likely to provide important insight in how visual organs contribute to the control of daily rhythms. To avoid the impact of the invertebrate-specific blue light photoreceptor CRYPTOCHROME, experiments in this proposal will make use of visual organ-detected red light to map light input pathways connecting the Drosophila visual organs to sleep/wake rhythms. In particular, histamine, a known signalling intermediate between the compound eyes and clock neurons, will be examined for its role in synchronizing cellular clocks and regulating intercellular clock signals .

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

Transformations: Encountering Gender and Science 16 Jun 2018

The Rethinking Sexology team’s historical research has uncovered important material on the relationship between medical authority and ‘patient’ experience and the development of diagnostic categories/treatment protocols. We propose a public engagement programme that invites young trans people (age 16-25) to explore this material, co-conduct new research, including an oral history project, and develop an ambitious programme of creative responses leading to a performance and exhibition in four relevant high-profile venues across the UK. The plan of action has been developed during an extensive consultation period with key stakeholders, in which ideas and methodologies have been fully tested. The programme is led by the Rethinking Sexology (RS) team who has an outstanding track record in field-leading engaged research and public engagement. The team’s experience will be complimented by collaborating with a uniquely qualified group of writers, performers and youth-facilitators, known for their pioneering and award-winning work with the trans community, with whom the RS team already has long-standing collaborative relationships. The programme will deliver a set of exceptionally innovative activities that will empower young people to: contribute to and enhance health and humanities research and public engagement practices; investigate clinical and diagnostic protocols and transform clinical dialogue; shape public debate through high-quality creative outputs (exhibition/performance) that promise to be intellectually, artistically and emotionally powerful and stimulating. The co-production model at the heart of the programme will feed systematically and continually into ongoing research activities, enabling the project to stand as a beacon of good practice in engaged research and public engagement.

Amount: £147,315
Funder: The Wellcome Trust
Recipient: University of Exeter

Understanding the formation of Pseudomonas aeruginosa biofilms in urinary catheters 31 May 2018

This proposal uses advanced microscopy and molecular techniques to examine the role of alginate in the attachment of Pseudomonas aeruginosa, and subsequent biofilm formation, on urinary catheters. There is an urgent clinical need for improved catheter management and the development of anti-biofilm materials, however approaches to date have failed and a lack of understanding of biofilm development may contribute to this. In this work, we intend using a simple laboratory model system to generate biofilms on urinary catheters, which can be tracked directly over time using episcopic differential interference contrast microscopy. Transposon mutants (obtained from the PA Two Allele Library) will be used and compared to the type strain, PAO1. In addition, Gibson Assembly will be used to generate knockout mutants for the same genes. The biofilm forming capability of each mutant and type (transposon vs knockout) will be assessed and compared. Transposon mutants have the potential to still produce peptides, with unknown form and function. Such peptides could affect biofilm development. In contrast, knockout mutants remove the target gene sequence. This project will provide information on general biofilm development, the role of alginate, and also indicate whether knockout mutants should be used for understanding the role of specific genes.

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

Do emotional stimuli grab attention in typical or anxious observers? 31 May 2018

An attentional bias (AB) towards emotional, and particularly threatening stimuli has been robustly demonstrated in anxious observers, with smaller biases in typical populations (Bar-Haim et al, 2007). Moreover, threat-related biases are suggested to occur even when observers are unaware of the threatening stimuli. A key paradigm used to measure AB is the visual probe (VP) paradigm, in both standard (aware), and backward masked presentations. Recent work (with typical populations) has highlighted the importance of controlling for low-level stimulus properties (e.g. luminance contrast), and using stringent measures of awareness (Hedger et al, 2016; Hedger, Adams & Garner, 2015a, 2015b) in order to properly interpret VP data. The current project aims to evaulate AB in anxious and typical observers in three variants of the VP task: a standard VP, and two VP methods that allow us to present threatening stimuli are outside of awareness: backward masking and continuous flash suppresion. Importantly, we will use careful stimulus controls to model the effects of low-level stimulus properties and stimulus awareness. The study will allow us to understand whether typical or anxious observers preferentially attend to threat stimuli during conscious and unconscious presentations. This has important applications for treatment development, such as attention bias modification.

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

Macromolecular Mechanisms of Microsporidia Infection Investigated by Cryo Electron Tomography 21 May 2018

Microsporidia are eukaryotic, intracellular parasites that infect most animals, including humans. They cause debilitating disease in immunocompromised individuals and are partly responsible for the global decline in honeybee populations. To infect a host cell, microsporidia employ a harpoon-like apparatus called polar tube (PT) that rapidly ejects from the spore, penetrates the membrane of a target tissue cell and transports the spore content (sporoplasm) into it. I propose to investigate the so-far unknown macromolecular architecture and mechanism of the PT using state-of-the-art cryo electron tomography (cryoET). The key goal is to examine the cellular machinery that facilitates PT release, sporoplasm transfer and target membrane penetration. This research will provide 3D molecular maps of the PT in action and thus detailed and dynamic understanding of the microsporidian infection pathway. The research will enrich our knowledge of fundamental cell biology, establish microsporidia as a eukaryotic model system for cryoET, inform new medical approaches to treat microsporidiosis and help fight the decline in honeybee populations. Seed Award funding will pave the way for my career as new independent group leader in the UK, with a high impact biomedical profile and will offer a plethora of opportunities to collaborate with academia and industry downstream.

Amount: £98,680
Funder: The Wellcome Trust
Recipient: University of Exeter

The development of insulin resistance and anabolic resistance during muscle disuse: what is the role of fuel integration? 08 Nov 2017

Skeletal muscle atrophy, which occurs during short-term disuse, is thought to be due to the development of anabolic resistance of protein metabolism and insulin resistance of glucose metabolism, although their cause is currently unknown. The primary research aim of this fellowship is to establish the role of muscle fuel availability and integration in disuse-induced insulin and anabolic resistance. In collaboration with the Medical School, I will perform two randomized, placebo-controlled studies in which young, healthy participants undergo 2 days of forearm immobilisation with placebo, Acipimox (to decrease plasma lipid availability), Formoterol (to stimulate glycolytic flux), or dietary branched-chain amino acid (BCAA) manipulation, to alter substrate availability. I will combine the arteriovenous-venous forearm balance technique, that I have recently established in Exeter, with stable isotope amino acid infusion and repeated forearm muscle biopsies to quantify muscle glucose, fatty acid, and BCAA balance, oxidation, and intermediary metabolism (including muscle protein synthesis), both fasted and during a hyperinsulinaemic-euglycaemic-hyperaminoacidaemic clamp. Two periods of research at the University of Texas Medical Branch will enable me to develop skills in mass spectrometry tracer analyses and develop a network of collaborators in the USA, both crucial for my future career investigating disuse-induced muscle atrophy.

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

Neurobiological mechanisms of emotional relief in adolescents with a history of sexual abuse 06 Dec 2017

Adolescents who experienced childhood sexual abuse (CSA) engage in non-suicidal self-injury (NSSI) more frequently than peers exposed to other forms of abuse or no abuse. NSSI serves an important function of relief from acute negative affect. Despite providing temporary relief from distress, NSSI is also linked to higher rates of suicide and hospitalisations and the effectiveness of current clinical interventions is limited. This may be attributed to a lack of understanding the neurobiological and behavioural mechanisms that underlie NSSI as a relief function in particular in youth who experienced CSA. To address this gap, the study aims (1) to model brain activity during distress and emotional relief (i.e., NSSI) in adolescents with and without a history of CSA using functional magnetic resonance imaging and (2) to examine if adolescents with CSA select actions to 'escape' an aversive context more quickly and often compared to non-abused peers. The ultimate goal of this translational research is to understand the neurobiological and behavioural mechanisms that confer vulnerability to NSSI following CSA (Stage 1) in order to develop effective intervention and prevention strategies to keep vulnerable teenagers safe (Stage 2) . Keywords: sexual abuse, non-suicidal self-harm, relief, functional magnetic resonance imaging, translational research

Amount: £230,048
Funder: The Wellcome Trust
Recipient: University of Exeter

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £58,344
Funder: The Wellcome Trust
Recipient: University of Exeter

Open Access Award 2017/18 30 Sep 2018

Not available

Amount: £7,956
Funder: The Wellcome Trust
Recipient: University of Southampton

Deciphering AMD by deep phenotyping and machine learning 10 Apr 2018

We will identify the structural changes leading to and associated with cell degeneration in the retina in patients with early age-related-macular-degeneration (AMD). This will pinpoint what makes AMD progress towards visual loss (late AMD). This will be achieved via machine learning, genotyping and high resolution phenotyping of early AMD patients using retrospective and prospective data. Patients will undergo state-of-the-art imaging of the major tissues; neurosensory retina, retinal pigment epithelium and choriocapillaris to identify the sequence of cell degeneration. We will control for genetic risk by genotyping to infer ancestry and to identify individuals with extreme polygenic risk scores. Thus accounting for confounder effects of cryptic genetic diversity. Machine learning will be utilized to generate a generalized model of AMD progression on a population basis, enabling us to assess individual deviation from normal ageing. Structural imaging biomarkers will be developed in already collected extensive imaging databases, and validated in a prospective cohort study. Biomarkers will: 1) detect conversion to late AMD earlier; 2) discriminate slow/fast progressors and 3) identify therapeutic targets. Results should improve clinical trial design by better characterizing study populations and result in novel therapies by identifying the underlying mechanisms of one of the largest unmet medical needs.

Amount: £3,980,169
Funder: The Wellcome Trust
Recipient: University of Southampton

Foundations for routine 3D X-ray histology 05 Jul 2018

Whilst 3D medical imaging is commonplace, microscopic tissue structure analysis (i.e. histology) remains overwhelmingly wedded to ~200-year-old practices of microscopic 2D examination of tissue sections. Building on our first demonstrated assessment of 3D microstructural detail in standard wax-embedded soft tissue (Scott et al., 2015, http://dx.doi.org/10.1371/journal.pone.0126230) we will develop the foundations for routine 3D X-ray histology by: Providing: Robust, non-destructive, high-throughput 3D microscopic imaging of routinely processed soft tissue samples at 5-10 µm resolution. Access to orders of magnitude more tissue structure data per sample (cf. optical sections). Tissue-level volumetric structure and connectivity insights (previously unavailable). Correlative 3D data supplementing other routine or specialist imaging (e.g. immunostaining, laser microdissection). Routes to novel medical and scientific discovery (Jones et al., 2016, http://dx.doi.org/10.1172/jci.insight.86375; Koo et al., 2018, in revision). Establishing: Hardware approaches to increased sample throughput. Standardised, automated workflows for image acquisition, calibration, CT reconstruction, data handling. Long-term roadmap for emerging X-ray technology improvements targeted for biomedical applications. Raising awareness/driving uptake through: Pilot studies (n~10 samples/study)/new applications validated by 2D histology and integrated with correlative imaging modalities. Biomedical case studies (n~100) at high statistical power. Data resources (n~100) for artificial intelligence and deep learning approaches in digital 3D histopathology.

Amount: £1,135,071
Funder: The Wellcome Trust
Recipient: University of Southampton

The filamentous phage assembly system as a therapeutic tool 04 Dec 2017

Antibiotic resistance is a growing healthcare concern worldwide. The rise in the number of resistant bacteria is not being matched with an increase in new antibiotics or treatments. Novel ideas harnessing modern technology therefore need to be applied to address this problem in a timely manner. In this work, a phage encoded assembly system will be assessed for its potential application as a "switch" to control bacterial proliferation. By genetic manipulation of cells and viruses, protein expression, purification and high-end electron microscopy, the structure of a virus-encoded machinery in its host bacterial cell membrane will be determined in different conformational states. Furthermore, pilot experiments will be carried out to express and purify individual protein components for downstream mechanistic and high-resolution structural studies. The knowledge gained will provide many further avenues for research on our quest to develop advanced bactericides and synthetic cell-based treatments, and will deepen our understanding of bacterial pathogenicity in crops and animals, including humans. Funding for this proposal will also open up a multitude of downstream opportunities for collaboration with academia and industry, and importantly will provide me with the means to launch the crucial next stage of my career as an independent investigator.

Amount: £99,386
Funder: The Wellcome Trust
Recipient: University of Exeter

A Healthy Interest: diets, exercise, and ideal bodies in England and Holland, 1650-1800. 08 May 2018

My thesis will analyse diet and exercise advice and practices to investigate attitudes to ‘healthy bodies’ in Dutch and English printed medical literature, physician’s casebooks, patient-physician correspondence, and recipe books between 1650 and 1800. With modern concerns around increasing obesity rates and an ever-growing body of dietary advice in both medical and popular literature, a study of diets and exercise in the past can help us understand where our current ideas and ideals concerning body and health originate. The key goals of this project are to locate the health values and practices that were being promoted at this time; to assess to what extent dietary advice and ideals reached lay society; to analyse to what extent patients followed advice and made dietary and exercise considerations part of their ‘lifestyle’; and to examine attitudes to ‘healthy’ or ‘unhealthy’ bodies and bodily ideals in late seventeenth and eighteenth-century Dutch and English society. Examining manuscript and printed sources in a geographically comparative study will provide a rich and in-depth understanding of contemporary ‘health cultures’ and bodily ideals. In so doing the thesis will analyse how far we can identify the development of a modern ‘health culture’ in this period.

Amount: £99,441
Funder: The Wellcome Trust
Recipient: University of Exeter

Care, the great human tradition: A multi-disciplinary collaborative exploration of family care across time and culture 27 Jun 2018

There are 7 million family carers in the UK and their unpaid work has been valued at more than £132 billion per year. The demand for family care, however, is rapidly exceeding supply and carers experience serious physical and mental health problems as a result of their role. Novel approaches to supporting family carers are urgently required to ensure the sustainability of family care into the future. Archaeological, anthropological, and historical accounts of care may help carers to contextualise their role, enhancing wellbeing through connection with positive accounts of care across time and cultures. The aims of this project are to (1) bring scholars from archaeology, anthropology, and history together with contemporary care researchers, carers, and partner organisations, to develop the Collaboration for Applied Archaeological, Anthropological, and Historical Research and Engagement (CARE) Network and, (2) undertake scoping research for a large Collaborative Award application. The Collaborative Award will be used to develop a comprehensive account of family care across time and cultures, and create an evidence-based intervention for contemporary carers that can be delivered by a range of arts, education, and outreach organisations.

Amount: £29,050
Funder: The Wellcome Trust
Recipient: University of Exeter

Decolonising madness? Transcultural psychiatry, international order and the birth of a global psyche 07 Mar 2018

Are mental illnesses and the core concepts in the psychiatric toolkit universal and identical across cultures, ethnic groups and 'civilisations'? This research will offer the first substantial historical analysis of the roots of the current global mental health movement and transcultural psychiatry. It challenges the idea that the concept of a global psyche is a recent development, and aims to demonstrate that it emerged in the aftermath of WWII and during decolonisation, when Western psychiatry endeavored to leave behind its colonial legacies, and lay the foundation for a new union of Western and non-Western concepts of mental illness and healing. In this period, leading psychiatrists across the globe set about identifying and debating the universal psychological characteristics and psychopathological mechanisms shared among all cultures. My research will explore this psychiatric, social and cultural search for a new definition of 'common humanity', and analyse the core medical-historical forces behind it. The International Pilot Study of Schizophrenia will serve as a case study. The project will involve the scoping of archives in Europe, Africa, Asia and the US, the employment of four research assistants, organisation of an international conference, and the creation of a network of researchers and practitioners in global psychiatry.

Amount: £28,155
Funder: The Wellcome Trust
Recipient: University of Exeter

University of Southampton MSc Global Health 11 Jul 2018

In an increasingly interdependent world, complex health problems require solutions that transcend geographic boundaries and draw on international and multidisciplinary collaboration to develop innovative responses. The MSc in Global Health within the School of Social Science at Southampton University is a multi-disciplinary programme designed to equip students with the necessary skills to understand and respond to global health challenges. Taught by research-active academic experts from multidisciplinary backgrounds, it includes core modules which provide students with a comprehensive understanding of key issues and concepts in transnational health. In addition the course has a strong quantitative component, which provides students with a robust understanding of statistical and epidemiological methods. A further feature is that students are able to choose from a range of optional modules offered by the Schools of Social Science (which includes social statistics, demography and gerontology), Geography and Law, as well as the Faculties of Medicine and Health Sciences in order to tailor their programme to meet their specific needs and interest. While not exclusively designed for those planning a research career, a significant proportion of former students have successfully chosen or continued on this path and currently work for academic institutions or research departments within governmental bodies.

Amount: £84,405
Funder: The Wellcome Trust
Recipient: University of Southampton