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Results

East London Genes & Health: human knockouts in a population genomic medicine cohort of British-South Asians 10 Apr 2018

East London Genes & Health is a long term programme for population genomic medicine research in British-South Asian adults. Unique features include high rates of health deprivation, especially diabetes, cardiovascular disease and mental health; high rates of consanguinity (including human knockouts, rare predicted loss of function variants occurring as homozygotes); local excellence in e-health record access/analysis; and recall for further research by genotype/phenotype. In this proposal we wish to continue and expand successful East London Genes & Health recruitment and commence a new site Bradford Genes & Health - to reach 100,000 volunteers; add value to the Genes & Health resource through SNP array genotyping all samples; and by sequencing and analysing consanguineous individuals. This will then enable us as a collaborative team to ask detailed research questions about adult-human knockouts. Specifically we will perform population based analyses of naturally occurring adult-human knockouts to better understand their population genetics, and (with Deciphering Developmental Disorders) recessive disease; contribute to and establish The Human Knockout Project, a worldwide database of population-based studies of human knockouts; perform blood -omics to study major perturbations of biological systems including downstream networks; and deeply study individuals with knockouts and other variants in reported Mendelian disease genes.

Amount: £4,142,778
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

Design of Small Molecule Inhibitors of the Pro-Survival Protein Mcl-1 31 May 2018

Apoptosis is a highly conserved and controlled process, with the Bcl-2 family of proteins playing an important role as key regulators. The family consists of both pro- and anti-apoptotic proteins and there is a careful balance within a cell controlling its fate. High levels of the anti-apoptotic proteins are often observed in cancer and not only contribute to the development of the tumour but also confer resistance to current therapies including chemotherapy and radiation treatment. In particular over-expression of myeloid cell leukemia-1 (Mcl-1) is one of the most common forms of genetic abnormality in cancer. In addition Mcl-1 has been shown to be essential for some tumours survival, resulting in a genetic vulnerability of the cancer cells which can be exploited by the design of Mcl-1 specific inhibitors. As a single agent, an inhibitor would target tumours that rely on Mcl-1 for survival and in combination with other therapies it is expected to overcome Mcl-1 mediated resistance. We have recently identified a small molecule capable of modulating the interaction between Mcl-1/Noxa. In this proposal we now seek to improve the binding affinity and selectivity of the compound through synthesising a small library of analogues.

Encountering genes: Postwar genetic counselling in the UK and Ireland 23 Jul 2018

The proposed project uses genetic counselling as a focused vantage point for understanding how genetics has been communicated, experienced and given meaning. Genetic counsellors are medical professionals who, today, help parents and patients interpret the results of genetic tests and make decisions about treatment and reproduction. Counselling encounters involve highly technical information about risk, are potentially highly emotional, and can powerfully impact intimate practices of family life, medical treatment and lifestyle. Genetic counselling has a seven-decade history in the UK and Ireland—countries that are especially important for their exceptional politics of healthcare, and the range of international collaborations forged by genetic practitioners. In tracing this history, the project has five aims: to chart the making of genetic counselling within the NHS; to produce a sustained history of the genetic counselling encounter; to examine how the profession accommodated and shaped practitioner and patient identities; to trace how efforts to contest genetic medicine changed ethical standards; to explore how genomics is refashioning counselling roles and practices. This will be the first sustained study of emotion in the history of genetic medicine, the first in-depth social history of genetic medicine in the postwar UK and Ireland.

Amount: £314,967
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

Supramolecular peptide nanotechnology for antimicrobial therapies 04 Dec 2017

Antimicrobials remain the main means to treat and control bacterial infections, but their efficacy is now compromised due to overuse in humans, animals, agriculture, with bacteria developing resistance that renders certain antibiotics ineffective. Infections due multi-drug resistant (MDR) bacteria have emerged as one of the most significant global threats to human and animal health in the 21st century. Thus, the development of new antibiotics, or better ways to deliver existing antibiotics more effectively, is an urgent priority. Polymyxins are "old" antibiotics that have re-emerged as the last resort for treating infections caused by MDR Gram-negative bacteria. There are two polymyxins in clinical use, polymyxin B and polymyxin E (colistin), but their low stability, unpredictable pharmacokinetics and nephrotoxicity still raise significant concerns. We hypothesize that nano-engineered carriers will be able to restore and/or enhance the efficacy of polymyxins against MDR Gram-negative bacteria by improving their pharmacokinetic profiles, compared to standard mono and dual antimicrobial formulations, whilst minimizing the risks of adverse systemic effects. We will develop and optimize novel self-assembled nanocarriers for the controlled delivery of polymyxins and assess their potential to treat more effectively bacterial-related infections. This data will make the basis for future grant applications under the AMR initiatives.

Amount: £99,986
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

Making microbes complex: parasites, epidemics and the intellectual origins of disease ecology. 30 Nov 2015

Two-day symposium and workshop on the intellectual origins of modern ideas of disease ecology at the School of History Queen Mary University of London, 7-9 July 2016. Building on the work of J. Andrew Mendelsohn, Warwick Anderson, and others, the aim is to bring into view the neglected contributions of medical researchers who advanced a more dynamic view of health and disease in the early and middle decades of the 20th century, while providing a forum for the reinterrogation of the question posed by Mendelsohn in 1998: namely, ‘where did the modern, ecological understanding of infectious disease come from?’

Amount: £5,000
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

Right to health and technology assessment in courts: an empirical analysis 30 Nov 2015

Judicial claims for the provision of high-cost drugs funded by the public health system have been growing in Brazil, as has the economic costs on the government’s budget of complying with the court orders. Claimants’ rate of success is high as courts tend to accept that treatments must be publicly funded whenever they can offer any health benefit to an individual patient, ignoring cost considerations and relying on weak scientific evidence. In 2011 a new body – CONITEC – was established to make decisions on the incorporation of healthtechnologies in the public health system more transparent, accountable and scientifically rigorous. Our hypothesis is that judicial claims will be significantly less successful if the claimed treatment was assessed by CONITEC and, based on the assessment, there was a decision not to publicly fund it. To test thishypothesis we will compare patients’ rate of success in claims for treatments assessed by CONITEC before and after the assessment, and in claims for these treatments as opposed to those for other non-assessed treatments during the same period.

Amount: £10,000
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

Institutional Strategic Support Fund Phase2 FY2014/16 27 Oct 2014

ISSF Small Grants Fund The Life Sciences Institute (LSI) Small Grants Fund is an early stage fund designed to support pilot projects aimed at the identification and early support of promising ideas for the future development of larger proposals and initiatives. ISSF Proof of Concept Fund Sitting alongside QMUL’s established Proof of Concept Fund, this LSI Fund is aimed at supporting work that is intended to develop new life science ideas, technologies or processes from a pilot or early-stage exploration to the next stage of a more comprehensive commercial plan. Early Career Stage Researchers Bridging Fund Support for researchers early in their careers (ECRs) is essential to ensuring that they are able to take full advantage of opportunities to develop and succeed. Critical points typically occur in transition periods, when funding rounds for fellowships, major grants and permanent positions may not coincide with contract end-points. The LSI ECR Bridging Fund is aimed at addressing this need and will support periods of funding for up to four months for the salary costs of four leading ECRs working within the relevant research areas of the LSI. Some matching funding commitment is required from the home School or Institute of the ECR – equal to 30% of the ISSF funding. Funding: Implementation The ISSF/QMUL award supports three posts that are critical to the progress of the Life Sciences Initiative and the development of the proposed Life Sciences Institute: A Programme Director (who will focus primarily on external engagement work) A Programme Manager (who will mainly provide professional services management support for the Initiative) A 0.5 fte Programme Officer (who will provide administrative support for the Initiative). Funding: Public engagement Public engagement is a key element of our Life Sciences Initiative and is embedded across all aspects of it. Our Centre for Public Engagement [http://www.qmul.ac.uk/publicengagement/] (CPE) leads on this work and the ISSF award supports a dedicated community engagement post, support for training and collaborative projects, and a programme of outreach through the Centre of the Cell, focussed on life sciences work. The Community Engagement Officer will liaise regularly with local community groups, and engage sections of the community not accessed easily through existing links, with the aim of raising the voice of community partners within our planning for, and delivery of, research for the life sciences

Amount: £600,000
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

Music, Emotions, and Well-Being: Historical and Scientific Perspectives. 22 Apr 2013

Music is commonly treated as an emotional stimulant that can calm, console or energise. That music can and frequently does contribute to an individual's sense of well-being is commonly accepted. This relationship between music, the emotions and well-being has been studied from two different perspectives. Firstly, it has been the subject of historical investigations problematising what emotions are and exploring historically variant practices of using music as an emotional tool. Secondly, psycho logists and, increasingly, neurologists have produced exciting results by measuring music's effects on the emotions in physiological terms; these appear, however, to be universal and thus a-historical. We aim to bring these two seemingly incompatible views of music's emotional effects together to search for research strategies that can incorporate ideas of cultural conditioning into scientific research methods. As such, the symposium addresses both the role and potential of music in well-being, but it also raises the bar for medical humanities by investigating how its research areas can impact on research questions and strategies beyond the humanities. Delegates will present their views from the fields of neurology, psychology, music therapy, history and musicology. The symposium will be based on pre-circulated papers to allow maximum discussion time.

Amount: £5,000
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

Biomedical Vacation Scholarship 24 Jun 2013

Not available

Amount: £1,520
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

Evolutionary Predictions In Colorectal Cancer (EPICC) 05 Jul 2016

We aim to make prognosticating cancer like forecasting the weather. Weather forecasting combines detailed measurement of the current atmospheric state with a mechanistic understanding of atmospheric evolution that can be ‘played forward’ using a mathematical model to give accurate predictions. In oncology, we have the capability to make detailed measurements of the current state of a cancer, but critically lack a mechanistic understanding about how tumours will evolve over time. The shortfall in knowledge presents a major hurdle to accurate prognostication and is the focus of our proposal. We will perform a uniquely high-resolution molecular analysis of human colorectal cancers, and via mathematical modelling of these data, derive an unprecedented quantitative understanding of the ‘evolutionary laws’ that underpin colorectal carcinogenesis. We will evaluate the prognostic value of these laws, and then use them to construct and test models that mechanistically forecast disease evolution. The proposal builds upon our previous work demonstrating the predictability of cancer genomic alterations (Williams et al., Nature Genetics, 2016) as a direct consequence of physical constraints on tumour evolution (Sottoriva et al., Nature Genetics, 2015). This research will represent a major step towards the replacement of correlation-based prognostication with a new paradigm of accurate mechanistic forecasting.

Amount: £1,317,862
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

Open access block grant 2016/17 30 Sep 2016

Not available

Amount: £41,742
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

"Restless Tides of Electrical Being": Epilepsy Research, Neuroscience, and Subjectivity in Post-War Britain 10 May 2016

My project will critically examine experimental epilepsy research in Britain in the two decades following the end of the Second World War. In particular, I will investigate how interactions between neuroscientific concepts of the brain and psychological concepts of the mind shaped the material practices, technologies, and procedures used to understand and treat epilepsy during this period. As well as examining the roles of experimenters and clinicians, I will explore how patients and human subjects interpreted and influenced the research programmes in which they participated. I will focus on three particular programmes within a comparative framework: the neurosurgical programme of Murray Falconer at the Maudsley Hospital, London, in which temporal lobectomies were used to treat 'intractable' cases of epilepsy; the electroencephalographic research of William Grey Walter at the Burden Neurological Institute, Bristol, where EEG technologies were used to reveal the electrical mechanisms behind seizures; and the pharmaceutical initiatives of the Epilepsy Society in Chalfont St. Peter, in which patients were enrolled in trials of cutting-edge anti-seizure medications. By comparing and contrasting these programmes, I will assess claims made in recent sociological literature regarding the 'colonisation' of ideas of consciousness, the emotions, and subjectivity by the neurosciences in the late twentieth-century.

Amount: £88,530
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

East London Genes & Health: 2016-7 Public Engagement Plan 31 Dec 2015

Parental relatedness (e.g. cousin marriage) is common in certain UK ethnic groups including the health disadvantaged British-Bangladeshi and British-Pakistani communities. Recent studies indicate that outbred human genomes contain ~100 genuine complete loss of function (LoF) variants. Consanguineous (parental and/or historic) individuals carry genomic regions identical-by-descent (autozygous), thus rare frequency variants occur as homozygous genotypes. Our knowledge of human gene function an d genome annotation remains incomplete. Characterisation and deep-phenotyping of healthy adult individuals enriched for naturally occurring homozygous knockout alleles will provide invaluable knowledge of human biology. We propose a large-scale community based exome sequencing programme of consanguineous individuals (25,000) of whom a subset (3,000) with genotypes of interest will be later recalled. We will focus on East London populations whose recruitment and recall will be coordinated arou nd our Whitechapel site. We will recall sequenced individuals possessing autozygous variants of biomedical importance (predicted complete LoF, coding, and regulatory) for deep-phenotyping and experimental medicine studies. Our proposal complements existing rare disease sequencing programmes, national sequencing studies (UK10K, DDD), and other UK BioResources (Cambridge and NIHR BioResources, TwinsUK and UK BioBank). We will substantially engage East London communities and increase our existing p ublic engagement activities around genetics and genomics.

Amount: £18,448
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

The effects of neo-adjuvant chemotherapy on myeloid cells in high-grade serous ovarian cancer metastases. 02 Mar 2016

Many tumours have abundant macrophage populations. Tumour-associated macrophages (TAMs) frequently have tumour promoting roles and high levels are associated with poor clinical outcome. In mouse cancer models chemotherapy appears to increase TAM density. Furthermore, macrophage depletion improves response to chemotherapy in breast cancer models. The host lab has studied the effects of neo-adjuvant chemotherapy (NACT) on T-cell responses in high-grade serous ovarian cancer (HGSOC) patients and shown potential enhancement of the host anti-tumour immune response following NACT. However, we do not know the effect of chemotherapy on TAMs in these patients. We hypothesise that targeting the recruitment, polarization and effector function of TAMs may improve HGSOC response to chemotherapy as well as having independent anti-cancer activity. We will characterise TAMs in HGSOC pre and post NACT using human samples and mouse models. Anticipating significant heterogeneity of TAM populations we will employ single-cell and whole myeloid population RNA-sequencing to define the major macrophage populations in HGSOC pre and post NACT. These results will be validated using flow cytometry and immunohistochemistry. We will test the effects of chemotherapy and macrophage-targeting agents on TAM populations and tumour response in mouse HGSOC models. Our aim is that these results will translate to clinical trial.

Amount: £313,427
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

Understanding the rise of HIV-associated Hodgkin Lymphoma despite HAART: the role of immune dysregulation 19 Nov 2015

HIV-associated Hodgkin Lymphoma (HIV-HL) is the second commonest non AIDS-defining HIV-associated malignancy and incidence is rising despite highly active antiretroviral therapy (HAART). Although intensive chemotherapy cures 80%, treatment toxicity is significant and prognosis for the remaining 20% poor. There is an urgent need for more effective, less toxic therapy, especially in poor nations where safe chemotherapy delivery is difficult. CD4+T cells coordinate the anti-tumor response but some are manipulated into supporting the lymphoma. Low HIV-HL incidence at low CD4 counts suggests CD4+T support is essential to HL survival. Additionally, low HIV-HL incidence at high CD4 counts (when immunosurveillance is strong) highlights their important anti-tumor role. Our preliminary data supports our hypothesis that the peak of HIV-HL at intermediate CD4 counts despite HAART relates to compromised immunosurveillance and a requirement for CD4+T support. Drawing on our group’s experience we will study a large cohort formed through international collaboration and aim to test this hypothesis and functionally characterise mechanisms involved. By targeting mechanisms protecting malignant cells we can increase effectiveness of current therapies and reduce dosage. Furthermore, this project may explain the rise of HIV-HL despite HAART and identify mechanisms limiting cell survival ex vivo which hold back study of this disease.

Amount: £243,245
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

The relationship between innate immune cell function and bacterial infections in severe acute malnutrition 22 Feb 2017

Severe acute malnutrition (SAM) underlies one million deaths in children under 5 years old annually. Immunodeficiency is implicated in SAM mortality because deaths are predominantly due to infections and infectious mortality persists after nutritional rehabilitation; however, we know very little about how malnutrition affects immune cell function. This fellowship will characterise the relationship between bacterial infections and the anti-bacterial functions of monocytes and dendritic cells (DC) using blood samples collected from children admitted to hospital with SAM (n=200) and track this relationship during hospitalisation and over 48 weeks of community-based nutritional rehabilitation (n=100). I will evaluate both the capacity of monocytes and DC to bind and respond to bacteria in vitro, and how pro-inflammatory mediators in plasma, which are elevated in SAM, affect healthy monocyte and DC. These assays will generate a detailed profile of monocyte and DC function in each child which I will use to determine whether innate immune function is: 1) compromised relative to adequately-nourished controls (n=200); 2) associated with bacterial morbidity and mortality; and, 3) restored by treatment. Understanding the relationship between innate immune cell dysfunction and bacterial mortality in children with SAM could identify new immunotherapeutic targets to improve clinical outcomes in this high-risk population.

Amount: £1,159,877
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

PPE: The impact of cotrimoxazole on healthy birth and growth in rural Zimbabwe. 07 Jul 2015

The goal of this proposal is to evaluate the impact of cotrimoxazole, integrated with a package of nutrition interventions early in the lifecourse, on healthy birth and growth in rural Zimbabwe. Stunting is highly prevalent, begins in utero and causes increased mortality and reduced long-term productivity. Current nutrition-specific interventions have only a marginal impact. New approaches targeting mechanistic pathways early in the life-cycle are needed. We will use cotrimoxazole to test the hy pothesis that inflammation is a common mechanism underlying preterm birth, intrauterine growth restriction and postnatal stunting. We hypothesize that inflammation is driven predominantly by clinical and subclinical infections, abnormal micobiota composition and environmental enteric dysfunction, all of which will be impacted by cotrimoxazole. The specific questions are: 1) Does antenatal cotrimoxazole improve fetal growth and reduce prematurity? 2) Does postnatal cotrimoxazole improve li near growth? 3) Through what mechanistic pathways does cotrimoxazole operate? We will conduct a randomised clinical trial of cotrimoxazole, integrated with a package of evidence-based nutrition interventions, in two phases. First, women will receive a lipid-based nutrient supplement (LiNS) and nutrition education during pregnancy and will be randomised to daily cotrimoxazole or placebo, with a primary outcome of birth weight. Second, breastfeeding women will continue to receive LiNS and nut rition education; their infants will be randomised to daily cotrimoxazole or placebo, with a primary outcome of height-for-age Z-score at 6 months. Finally, we will investigate the impact of cotrimoxazole on underlying biological pathways to better understand its mechanism of action.

Amount: £40,000
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

Twentieth century disease ecologies: an intellectual history of emergence, 1920-1970 - Extension. 31 Mar 2015

Although the origins of the modern ecological understanding of infectious diseases has been examined by other scholars, for the most part these studies have focussed on specific groups of scientists and/or disciplinary settings. Moreover, preliminary studies of the subject are divided as to the extent to which these ecological perspectives were already present in medical micribiology as opposed to being importation from biology and molecular genetics. There is a need therefore for a comprehensiv e, monograph-length study that surveys the history of ecological perspectives across a range of disciplines from bacteriological epidemiology, to evolutionary biology, parasitology, animal ecology and immunology, and across a broader group of scientific researchers. In particular, this study will build on the preliminary surveys of this field by Anderson, King, Mendelsohn, and Tilley (see bibliography) by tracing the intellectual influences and professional associations between scientists at the forefront of research into epidemic diseases in the interwar and post-war periods. At the same time it will examine the connections between these scientists and key public health institutions, such as the Rockefeller Foundation and the Hooper Foundation, and the effect that post-war debates around the eradication of infectious diseases and environmental politics had on these nascent ecological perspectives

Amount: £51,748
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

Neuron 'Pod' for Centre of the Cell. 14 Mar 2012

Not available

Amount: £1,100,000
Funder: The Wellcome Trust
Recipient: Queen Mary University of London