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Results

Active Inference and Optimal Decision-Making 30 Sep 2018

Depression is strongly associated with a decline in cognitive function, and is seen in a high number of elderly individuals. It has been suggested that there is a strong epidemiological link between a personal history of depression and an increased risk of developing Alzheimer’s disease in later life. The key aim of this project is to use models of learning and decision-making to better link behavioural characteristics of these two psychiatric illnesses to their brain circuit substrates. We aim to reveal model-based behaviours and brain circuits that are shared with depression and different dementia profiles, including Alzheimer’s disease. We will use an adapted version of a pre-existing video game environment to examine activation of the dopaminergic midbrain, using fMRI. We will look specifically at reward prediction errors, and precision, i.e. the degree of confidence in the action an individual takes. By describing these behaviours using computational models, we hope to provide more accurate descriptions of human behaviour, the causes of such behaviours, and the specific brain regions and neural circuits that these behaviours are linked to. This may lead to earlier diagnosis of such psychiatric illnesses; therefore patients can undergo treatments earlier on in the disease progression.

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

Fighting global worming: understanding parasites using evolutionary genomics 04 Dec 2017

Roundworms (Nematoda) and flatworms (Platyhelminthes) are among the most species-rich animal groups. They include free-living animals, but also parasites with a dramatic impact. Worm infections (helminthiasis) ruin farm animals and plants, and infect more than half of the worldwide human population decreasing birth outcome, cognitive development, and school and work performance. Understanding their biology is imperative to fight these organisms with a huge socioeconomic importance. This is a pilot study to apply evolutionary genomics to the origins of parasitism and drug targets detection. Genomes compared under the light of their evolutionary relationships will define differential genetic content (gene gains and losses) between parasites and non-parasites. This will provide new insights on how harmless organisms became parasitic at genome level, but will also detect new targets to fight these diseases. Parasite-specific gains will constitute ideal drug targets, providing high specificity; gene losses will indicate deficiencies in the parasites physiology that can be also attacked. The application of evolutionary biology to discover drug targets is highly original, building on the emerging field of evolutionary medicine, and has never been applied to macroscopic parasites. This project will be the basis of future research and collaborations to further develop drugs to target these diseases.

Amount: £99,870
Funder: The Wellcome Trust
Recipient: University of Bristol

The causal map of the human phenome 18 Oct 2017

This fellowship is focused on maximally exploiting GWAS summary data and 2SMR methodology. I will: 1. Create a computational framework that can construct and represent the causal map of the measured human phenome. Using existing (MR-Base) and upcoming (e.g. GoDMC, UK Biobank) data sources I will construct a graph of pairwise causal relationships between thousands of traits. Each causal relationship will be assessed using all available 2SMR and sensitivity methods to ensure transparency and highest standards for hypothesis-driven causal inference. 2. Exploit the graph to improve a) reliability of causal estimates by empirically assessing pleiotrpy; b) statistical power by exploiting outliers in the data to search for putative novel associations, and using graph traversal algorithms to find links for which direct associations are underpowered; c) interpretability by deconvolving the mediating relationships between arbitrary numbers of traits. 3. Use the causal graph as a tool for phenomic modelling. Example 1: linking molecular phenotypes to new or existing drug targets will enable the prediction of the efficacy and safety of developing interventions. Example 2: using MR against fitness related traits to obtain selection coefficients for each phenotype, I will construct models of human evolution, investigating the cost of complexity and evolutionary trajectories.

Amount: £809,240
Funder: The Wellcome Trust
Recipient: University of Bristol

An investigation of the causal pathways from childhood conduct problems to poor health outcomes and criminal behaviour in adulthood 08 Nov 2017

Conduct problems (CPs) are common across childhood and adolescence and there is increasing evidence from prospective, longitudinal studies that they may impact on a wide range of adverse outcomes in adulthood including antisocial behaviour and offending, psychiatric disorders, and poor physical health. However, there is little empirical evidence regarding processes underlying the strong associations observed. Additionally, less is known about the long-term consequences of CPs in low- and middle-income countries. Using two population-based birth cohorts in the UK and Brazil, the aims of this proposal are to: 1) Examine how different patterns of CPs across childhood and adolescence relate to adverse outcomes in adulthood (criminal behaviour, psychiatric disorders, cardiovascular disease risk). 2) Test three hypothesised explanations for the associations observed, comprising: a) Exposure to ongoing adversity across the life-course; b) Shared genetic and early-life environmental risk factors; c) Potential "snares" in young adulthood (i.e. mediators of the association between CPs and adverse outcomes). The overarching goal of this research is to identify a short-list of potential intervention targets to reduce the risk of negative consequences arising from childhood CPs. Therefore, I will also conduct a feasibility study to examine the potential of modifying the intervention targets identified from the research.

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

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £124,716
Funder: The Wellcome Trust
Recipient: University of Bristol

Opening up the Children of the Nineties: making the administrative archive of the ALSPAC (Avon Longitudinal Study of Parents and Children) population study,1990-2005, available to researchers and the wider public. 19 Nov 2014

The Avon Longitudinal Study of Parents And Children (ALSPAC) is an internationThe preservation and cataloguing of the archive of ALSPAC will be of great impThe aim of this project is to build on the scoping study funded by the WellcomKey goals of the project will be to: - Create a detailed catalogue of the wide range of administrative records contai- Digitise and provide access to the ALSPAC newsletters sent to participants - Produce a website with digital content, linked to the online Archive Catalogue- Ensure the physical and digital archive is preserved to enable the long term access for researchers and the wider public.

Amount: £95,394
Funder: The Wellcome Trust
Recipient: University of Bristol

Approaches to diagnosing dementia syndrome in general practice: Determining the value of gestalt judgment, clinical history and tests. 24 Jun 2015

I will investigate whether an evaluation in general practice can have comparable test accuracy to a specialist opinion for diagnosing dementia in symptomatic elderly people. Objective 1: I will systematically review the test accuracy of general practitioners gestalt clinical judgment for the diagnosis of dementia in symptomatic primary care patients and, if indicated, perform a meta-analysis. My hypothesis is that the utility of the gestalt clinical judgment of general practitioners in diagn osing dementia is better than chance but inferior to specialist assessment. Objective 2: I will conduct an empirical, prospective, diagnostic test accuracy (DTA) study comparing GP gut feeling , blood tests, neuroimaging, index collection of cognitive tests suitable for GPs and specialist assessment to a reference consensus expert panel diagnosis. I will identify the most useful components of a diagnostic evaluation in general practice. My hypothesis is that a combination of brief cognitive tests adds diagnostic value to a GP's gestalt judgment. Objective 3: I will conduct exploratory qualitative research to evaluate the feasibility and acceptability of GP diagnosis of dementia for patients and clinicians, based on the set of tests that I identify as most useful.

Amount: £321,248
Funder: The Wellcome Trust
Recipient: University of Bristol

Balancing Best Interests in Medical Ethics and Law (BABEL). 18 Sep 2015

This project asks: How are the best interests of incapacitated patients interpreted and applied in judicial decision-making? The aim is to establish whether or to what extent bioethical understandings of best interests are captured in law, and vice versa. This will involve exploring the (bio)ethical values associated with the best interests standard and the values captured in judges' use(s) of this standard and the weighting(s) these acquire in the judicial balancing exercise. The project examin es decisions to treat or not treat a range of incapacitated patients, focusing on particular areas of bioethical controversy (e.g. sterilisation, vaccination, dementia care, and the withdrawal of life-sustaining treatment). In addition to combined legal and bioethical analysis, which will be published, the project will prepare the way for a programme of research on best interests, by supporting networking and the preparation of bids. The programme will ask: How should the best interests of incap acitated patients be interpreted and applied in medico-legal decision-making? The programme will utilise integrated empirical bioethics methodologies and thus encompass documentary analysis, normative arguments and empirical enquiry. A Seed Award would provide vital support to the formation of the proposed programme.

Amount: £49,995
Funder: The Wellcome Trust
Recipient: University of Bristol

Immune cell signal integration in vivo. 03 Oct 2013

We will use Drosophila embryonic hemocytes as a model to study cell migration and chemotaxis in vivo. We will initially investigate the dynamic interplay between microtubules and actin in migratory cells as well as further investigating the role of microtubules during contact inhibition and in the maintanence of polarity in hemocytes. In addition to elucidating their cytoskeletal regulation we will explore what external cues direct hemocyte migrations and how their contact inhibitory behaviour is regulated. To this end we will carry out a genome wide-RNAi screen allowing us to identify novel genes required for normal hemocyte dispersal during development as well as their rapid chemotaxis towards epithelial wounds. In addition we will carry out a microarray approach to probe the transcriptome of discrete populations of hemocytes at different developmental timepoints in order to understand the process of hemocyte maturation and specification during development. Finally we also plan t o continue our initial studies using Drosophila embryos as a model system for following bacterial infection in real time. We will test the in vivo function of genes previously identified in RNAi screens in vitro as being important for the recognition, engulfment and degradation of bacteria by S2 cells in culture.

Amount: £116,240
Funder: The Wellcome Trust
Recipient: University of Bristol

Institutional Strategic Support Fund FY2013/14 14 Oct 2013

Playing a key role in developing a biomedical research strategy for the University of Bristol. Identifying and enabling the necessary interactions and providing funding to support interdisciplinary workshops and pilot projects. Identifying and nurturing the next generation of talented clinical and non-clinical health researchers from inside and outside Bristol and supporting our research community with prestigious Elizabeth Blackwell Fellowships. Ensuring our research is continually grounded by real clinical, social and public health needs, working with Bristol Health Partners, industry and other partners to deliver adoptable solutions. Establishing an open and lively dialogue with patients and the public, and involving them in the future of our health research. Providing expertise in developing partnerships, as well as access to information, potential collaborators, and research resources.

Amount: £750,000
Funder: The Wellcome Trust
Recipient: University of Bristol

A Device for the removal of circulating autophagic vesicles in patients with sickle cell disease 13 Jan 2016

Sickle Cell Disease(SCD) is the commonest inherited genetic disorder in the UK with 14,000 patients and over 300 affected children born annually. There are three disease modifying treatments available, hydroxyurea, blood transfusion and stem cell transplant. Of these, transfusion is the mainstay of preventative treatment. However, there are frequent clinical situations where transfusion would be recommended but blood is not available in sufficient quantity on a regular basis or not available at all. Ninety percent of patients with SCD worldwide live in the developing world where there is no safe and freely available access to blood. Consequently, there is a need for a novel therapy that does not require donated red cells. Professor David Anstee proposes a novel technology to address this need. Recent work in his laboratory at NHS Blood and Transplant in Bristol has shown that a critical step in the formation of normal red blood cells involves the removal of membranous vesicles containing waste products from immature red cells when the cells pass through the spleen. Patients with SCD lose the function of their spleen very early in life and as a consequence vesicles cannot be removed and remain in their blood. The vesicles that are retained in the peripheral circulation likely contribute to the pathology of SCD. Professor Anstee and colleagues are developing a device to selectively remove these vesicles from the blood of patients with SCD and anticipate that patients undergoing this treatment will enjoy a dramatic improvement in their quality of life.

Amount: £100,800
Funder: The Wellcome Trust
Recipient: University of Bristol

University of Bristol - Molecular, Genetic and Lifecourse Epidemiology 30 Sep 2016

Molecular, Genetic and Lifecourse Epidemiology

Amount: £118,751
Funder: The Wellcome Trust
Recipient: University of Bristol

University of Bristol - Molecular, Genetic and Lifecourse Epidemiology 30 Sep 2016

Molecular, Genetic and Lifecourse Epidemiology

Amount: £118,751
Funder: The Wellcome Trust
Recipient: University of Bristol

The influence of presynaptic mitochondria on synapse formation, stabilization and elimination in 30 Sep 2016

Mitochondria are found at many presynaptic terminals and are known to influence synaptic function. However, we do not know how and when mitochondria are recruited to synapses and whether that recruitment influences synaptic longevity. Long-term stabilisation of a newlyformed synapse represents a novel, persistent means of communication in the brain, and has been proposed to underlie memory or learning. Therefore, we wish to test the hypothesis that targeted trafficking and retention of mitochondria at a presynaptic terminal is required to establish an enduring, functional synapse in the central nervous system. To do this, we will use live cell imaging of axons, which have been transfected/transduced with fluorescent markers for mitochondria and presynaptic terminals. Our goal is to track mitochondrial recruitment to synapses as they turn over. Longitudinal in vitro and intravital imaging of neurons will be used to establish the timecourse of mitochondrial recruitment and its relationship with synaptic stabilisation. Finally, optogenetic control of mitochondrial anchoring will be used to control synaptic mitochondrial retention and thereby influence synapse stability to demonstrate their inter-dependence. In this way, the importance of a stable pool of synaptic mitochondria for synaptic turnover will be demonstrated, with potential implications for learning, cognition and neurodegenerative disease.

Amount: £32,996
Funder: The Wellcome Trust
Recipient: University of Bristol

Structure and Mechanism of Key Nonsense-Mediated mRNA Decay Factor Complexes 10 Apr 2018

Nonsense-mediated mRNA decay (NMD) is an essential eukaryotic surveillance mechanism to eliminate aberrant and potentially harmful mRNAs that contain a premature termination codon (PTC). The discrimination of a PTC from a correct stop codon during active translation is key, but the underlying molecular mechanisms remain elusive. We recently discovered a role for the NMD factor UPF3B in delay of translation termination in vitro, mediated by new interactions of UPF3B with ribosome, release factors and UPF1. This puts UPF3B at centre stage of the events at the terminating ribosome. To validate our discovery and to discover novel interactions of NMD factors, I will establish in vivo cross-linking/mass spectrometry. I will explore the impact of disease-conferring mutations in NMD factors UPF3B and SMG1 kinase on functionally important protein-protein interactions, and characterise novel functions of UPF1 and UPF3B at near-atomic resolution in an integrative approach, combining biochemistry, biophysics, electron cryo-microscopy and crystallography or NMR. This highly interdisciplinary research aims at a step-change in our molecular-level understanding of the role of the individual NMD factors in a paramount step of human translational control; a vital prerequisite for the development of new intervention strategies to treat NMD-related disease.

Amount: £1,514,695
Funder: The Wellcome Trust
Recipient: University of Bristol

Designing modular protein scaffolds to study growth factors’ synergy: how splitting modular synthetic proteins into self-assembling parts affects overall expression and structure 31 May 2018

Growth factors control the fate of stem cells but it is still unclear how their organization and synergy contributes to cell proliferation and differentiation. To study these effects, molecules that can precisely display multiple growth factors need to be developed. Modular proteins, formed by repetitive units, can be designed to have very complex structures and their length can usually be changed easily. In this project I aim to express a modular protein, which has been computationally designed, in E. coli both as a whole protein and as self-assembling peptide blocks. I will use split inteins to allow multiple peptide fragments to join and bond to produce the desired modular protein. The aim of this research is to investigate how using self assembling blocks of peptides affects the yield of the final modular protein product when expressed in E. coli and to find whether or not expressing a modular protein in the form of self assembling blocks changes its structure compared to expressing the same protein as one polypeptide chain initially. These results will help understand how to better produce modular proteins to display growth factors and study effects of signal organization on cell response.

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

Father involvement and child development in the context of maternal postnatal depression 23 Jul 2018

Key goal: Children of postnatally depressed mothers are at high risk of adverse developmental outcomes, however, many adapt successfully. One potential protective mechanism is sensitive and involved fathering. The overall aim is to gain unprecedented insights into the nature of fathering and the impact it has on child development in the context of maternal postnatal depression using interdisciplinary methodology. Specific goals: 1. Gain in-depth sociological insights into the nature of father involvement and parenting in the context of maternal postnatal depression. HOW: gathering rich qualitative data using three complementary approaches (in-depth individual interviews, couples’ interviews and semi-structured diaries) with families participating in the intergenerational birth cohort ALSPAC-Generation2. 2. Examine behavioural manifestation of father involvement and parenting through detailed examination of father-child interactions in families with depressed and non-depressed mothers. HOW: recording 200 father-child pairs at home using novel wearable cameras with ALSPAC-Generation2 families. 3. Quantify the role of father involvement and parenting in the association between maternal postnatal depression and child development. HOW: using data from UK-based birth cohorts the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Millennium Cohort Study (MCS). This will provide the evidence-base to develop interventions that modify specific behaviours and target individual needs.

Amount: £281,578
Funder: The Wellcome Trust
Recipient: University of Bristol

MSc by Research Population Health Sciences (Bioethics) 11 Jul 2018

Established in 1996, the Centre for Ethics in Medicine has a longstanding record of providing excellent postgraduate education in healthcare ethics and law/bioethics, through PhD, taught Masters and research Masters courses. Our current MSc by Research (MScR), which is designed to equip students for future bioethics research, offers students the opportunity to develop their own research in a structured and supported environment. It provides a distinctive opportunity in UK higher education to engage in a research-focussed bioethics Masters’ degree, which supports the acquisition of topic knowledge, skills and research experience essential for progression to PhD study but rarely provided in PGT programmes. We seek to provide an immersive experience, with MScR students joining our thriving research community. Beyond core training and research activities, and auditing other relevant teaching and training, students attend and present at the Centre research seminar series, and participate in Centre conferences and workshops. Significantly, our MScR students are also closely supported by Centre staff to develop funding applications for doctoral study. We specifically aim to grow this programme into a national feeder programme for research careers in bioethics, including as a feeder into our own PhD programmes, to develop the next generation of talented bioethics researchers.

Amount: £68,728
Funder: The Wellcome Trust
Recipient: University of Bristol