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Results

Infants with intestinal failure. Establishing an ethical framework for an emerging therapy 23 Jan 2018

This project will establish a practical ethical framework for decision-making in neonatal intestinal failure (IF). It aims to identify circumstances in which active therapy might be ethically obligatory, circumstances in which it may only be ethically appropriate to recommend palliative care, and situations in which active treatment is ethically acceptable but not obligatory This will be achieved by combining empirical research with normative analysis and reasoning using a four stage process as described below: A critical interpretive review of empirical and theoretical literature will be carried out in order to acquire a thorough understanding of the clinical and ethical factors likely to be relevant. Qualitative methodology (semi-structured interviews with thematic analysis) will then be employed to develop a contextualised understanding of the problem as experienced and understood by a range of stakeholders including a healthcare professionals from different subspecialties, families and children. Coherence will then be sought between the empirical data and normative theory using reflexive balancing to reach defensible normative conclusions. Finally a draft guidance framework will be developed through a structured online consensus method (DELPHI) in order to gain consensus amongst professionals to develop a usable ethical framework for decision making in neonatal IF.

Amount: £327,300
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

A life-course approach to measuring capability for economic evaluation of health and social care interventions 01 Feb 2017

Health services face increasingly difficult decisions about what interventions to provide from available resources. These economic decisions currently concentrate on maximising health gain, but there is growing recognition that this is too narrow. An important alternative is to focus on generating capability wellbeing in the population. There are generic capability (ICECAP) measures for assessing the impact of health and care interventions for adults, older people and those at end of life, but not for younger people. Extending measurement of capability to children requires innovative step-changes in thinking (i) to a life-course approach that accepts differing values at different stages of life and (ii) to a dual focus on current wellbeing and future ‘well-becoming’, situating child measures in the context of development to adulthood. This research addresses these complex conceptual and empirical issues in a UK setting. In brief, key goals are to: (a) generate, value and validate new measures of capability wellbeing for children; (b) explore evidence on values during the life-course and generate an integrated framework for measuring capability wellbeing/well-becoming across the life-course; and (c) explore end of life assessment in children, given this life-stage does not typically directly follow childhood. Keywords: capability, children, economic evaluation, qualitative methods, life-course

Amount: £930,709
Funder: The Wellcome Trust
Recipient: University of Bristol

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

The role of cerebellar circuitry in movement control and real-time motor learning 28 Nov 2017

The cerebellum is known to play a critical role in ongoing sensorimotor behaviour and learning of novel associations, but these processes remain poorly understood. The aim of this proposal is therefore to provide an extensive characterisation of the cellular and circuit mechanisms involved in motor control and learning in the cerebellum. We will probe cerebellar processing in head-fixed behaving animals using whisker movement as a model sensorimotor behaviour. We will measure neuronal activity using a variety of functional imaging and electrophysiological methods, combined where appropriate with opto- and pharmaco-genetic perturbation of specific circuit elements. Throughout the data-gathering process, we will work with theoreticians to generate a comprehensive network model of whisker representation in the cerebellum. Three discrete but interconnected aims will be addressed: 1) What are the organisational principles governing control of whisker movement within the cerebellar cortex? 2) What are the functional characteristics of inputs and outputs to cerebellar cortex during active whisking? 3) What are the mechanisms of real-time motor learning in the cerebellum? Together, we will provide unique quantitative information about the function of cerebellum in voluntary movement, and reveal how learning-related changes influence the neural representation of a well-controlled motor behaviour.

Amount: £1,498,083
Funder: The Wellcome Trust
Recipient: University of Bristol

Micronutrients and Mood 30 Sep 2018

Depression and anxiety disorders are becoming increasingly common. There is some research suggesting that our diet, (what we eat) might make us more likely to become depressed and anxious. This type of research is called 'Nutritional Psychiatry' research. Many research studies have shown that people with depression and anxiety disorders do not have enough of certain 'micronutrients' either in their food, or in their blood. One example is magnesium, which is contained within green leafy vegetables, and is lacking in processed foods. It is possible that our society is not consuming enough magnesium, which could be increasing the number of people with depression and anxiety. However, it is difficult to say whether a low magnesium in depressed people was the cause of their depression. It may be because people with depression eat less healthily, or because people with other problems (alcohol use or long term illnesses) are more likely to get depressed. This research will aim to get around these difficulties by using our DNA or genetic code to look at whether genetic differences that result in having lower magnesium, are also linked to our risk of depression.

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

Causal analysis of maternal substance use during pregnancy and offspring neurodevelopmental outcomes 30 Sep 2018

Foetal alcohol syndrome (FAS) describes the symptoms of children born to mothers who used alcohol heavily in pregnancy. Intellectual disability, learning disorders and autism spectrum disorder (ASD) often occur at the same time as FAS. Lower levels of alcohol use during pregnancy may also be associated with ASD and learning disability in the child. Whether this is causal or not is unclear. I aim to further investigate whether alcohol use by mothers during pregnancy is causally associated with childhood ASD and learning disability. To do this I will use a variety of statistical techniques which may improve our understanding. These techniques include comparisons of pregnancies in the same family in which the mother did and did not drink, comparison of mother and father’s drinking behaviours and the use of genetic methods which help to determine causality. These analyses will be undertaken in several large population based birth cohorts. The project will help to expand our understanding of the non-genetic causes of ASD and learning/intellectual disability. If a causal association is found this would provide support for government policies that favour more cautious guidelines to alcohol consumption during pregnancy.

Amount: £0
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

Defining the factors that determine patient outcome following Staphylococcus aureus bacteraemia. 17 Jul 2018

Staphylococcus aureus is a major human pathogen, and of the types of infections it causes, bacteraemia is one of the most severe with mortality rates as high as 30%. With rates of bacteraemia increasing year on year, and antibiotic resistance making treatment more challenging, efforts are increasingly being focused on developing a vaccine. However, despite significant investment all attempts have failed, because we do not have a sufficiently detailed understanding of S. aureus’ pathogenicity. This proposal aims to address this deficit in understanding by applying a multi-stranded and multi-disciplinary research approach to large collections of clinical S. aureus isolates. Preliminary work modelling phenotypic, genomic and clinical data identified several novel bacterial features that significantly contribute to patient outcome following S. aureus bacteraemia. By adopting molecular, cellular, ‘omics and mathematical modelling approaches, this project will characterise these novel features and determine the contribution they make to the outcome of individual bacteraemic patients. In addition to transforming our understanding of S. aureus pathogenicity, the finding of this project has the potential to inform future S. aureus vaccine design approaches and identify bacterial targets for the development of novel therapeutic approaches.

Amount: £787,834
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

Drosophila as a model to study Immune Cell Signal Integration in vivo. 07 Jul 2015

Immune cells live in a complex environment and are constantly bombarded by multiple and often competing signals including wound induced damage signals, apoptotic corpses, and bacteria at sites of infection. To respond efficiently to any one of these cues it is not sufficient for these cells to simply possess the molecular machinery that allows detection of that cue; rather they must integrate the different signals and decide whether to prioritise one over another. We know little about how immune cells achieve this signal integration in vivo but this is key information if we are to design therapeutics to manipulate the decisions made by immune cells such that we can withdraw them from places where they are causing damage and direct them to places where they are needed. Using Drosophila as a model system to study immune cell migration my lab has demonstrated that embryonic macrophages actively migrate towards wounds as well as towards bacteria and apoptotic corpses in vivo. The aim of this application for fellowship renewal is to study how signal integration is achieved within a macrophage in vivo. How do these cells detect the early inflammatory cues coming from a wound? How do the same cells detect and engulf apoptotic corpses and bacteria in vivo and how are these signals integrated with inflammatory damage signals? We also want to understand how exposure to a given cue can prime a cells ability to respond to a subsequent signal and how this innate immune memory is operat ing in vivo.

Amount: £1,874,647
Funder: The Wellcome Trust
Recipient: University of Bristol

Ethics, Enhancement and Public Health. 27 Oct 2014

Health interventions are effective only if they confer an improvement: they are only effective if they enhance. However, enhancement is often assumed to be something beyond the nominally therapeutic borders of medicine, since enhancement typically involves improving health and functioning to a state that is better than normal. This makes it difficult to draw a clear line between therapy and enhancement. Because of this, the distinction between enhancement and the prevention of illness and diseas e is even more ambiguous, because therapies are at least administered to restore normality, whereas preventative health measures - much as enhancements - are defined by their being given to people in normal healthy states. Given the preventative role of public health medicine and policy, enhancement may have a connection to these which requires examination. The project therefore aims to answer two (bioethical) research questions, via conference presentations and the production of two original re search papers: 1: What is the relation between enhancement, illness prevention, and the aims of public health? 2: Is the status of an intervention as a therapy or an enhancement irrelevant to its legitimacy beyond a certain threshold of public utility? If so, what is it?

Amount: £5,337
Funder: The Wellcome Trust
Recipient: University of Bristol

Investigating post-translational modifications of Mitochondrial Fission Factor and their effects on mitochondrial dynamics 31 Jan 2017

Mitochondria exist as a cellular-wide, dynamic network, which changes according to the stress and energetic state of the cell. Mitochondria are constantly undergoing fusion and fission cycles, a means of quality control; healthy mitochondria fuse with the network, whereas those unable to maintain membrane potential are targeted for mitophagy. The major fission machinery consists of a transmembrane protein in the outer membrane of the mitochondria, mitochondrial fission factor (Mff), and dynamin-related protein 1 (Drp1), which is recruited to Mff from the cytosol to initiate fission. Drp1 is subject to extensive post-translational modifications (PTM), which alters its recruitment to mitochondria. Mff is also post-translationally modified, but little is known about the biological outcomes. We recently identified a SUMOylation site on Mff, and show that phosphorylation enhances SUMOylation. Our hypothesis is that these PTMs play critical roles in regulating physiological and pathophysiological fission that, among other things, may be involved in the aetiology of neurodegenerative diseases. Using phosphorylation, SUMOylation and ubiquitination deficient mutants, we will systemically investigate how these PTMs of Mff affect 1) Drp1 binding, 2) SUMOylation, 3) mitochondrial fission and morphology, 4) the reciprocal interactions between these modifications, and 5) their involvement in responses to cell stress in neurodegenerative disease.

Amount: £19,175
Funder: The Wellcome Trust
Recipient: University of Bristol

Investigation of long term memory consolidation as a preclinical indicator of Alzheimer’s disease 31 Jan 2017

Disease modifying treatments for Alzheimer’s disease (AD) are expected to be able to slow the progression of the disease, but not to provide any reversal of neurodegeneration. Hence, it is extremely important to be able to identify those at-risk of developing AD as early as possible, so that they can be treated before too much neurodegeneration has occurred, and symptoms are not significantly affecting a patient’s life. Subjective memory complaints (SMCs) have been proposed as potential very early signs of AD, however current clinical tests of AD, which only test short term memory up to approx. 30 minutes, are not sensitive enough to measure differences due to these SMCs. However, recent studies have identified a significant long term memory deficit in patients reporting SMCs and patients with mild cognitive impairment (MCI), when measured at 6 weeks. This project aims to provide a multi-modal investigation of this ‘accelerated forgetting’ phenotype and other potential predictors of AD, by means of novel tests of long term memory consolidation, prospective memory, magnetic resonance imaging, and electroencephalography. The ability of dopaminergic medication to reduce this long term memory deficit in patients with MCI and SMCs will also be investigated.

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

Investigating damage sensing, molecular priming and receptor recycling in Drosophila embryonic macrophages 31 Jan 2017

The use of model organisms is key to develop our understanding of dynamic immunological processes. Drosophila melanogaster embryonic macrophages carry out a diverse range of tasks, with many of the relevant molecules having human orthologues. Despite recent advances in immune cell biology, there are still many unknowns in the processes of damage signalling and apoptotic cell clearance, and how these areas link to the recent discovery of macrophage priming. As cell membrane receptors underpin the ultimate functionality of immune cells, their correct trafficking through the endosomal system must be key for the maintenance of macrophage activity. We wish to test some newly uncovered potential candidates in immune cell wound recruitment, as well as searching for priming ligands and observing how disruption to the endosomal system affects immune cell function. The tractable genetics of Drosophila will allow us to investigate potential candidates in both mutant and RNAi knockdown conditions. To do this, we will use in vivo live cell imaging of embryonic macrophages using fluorescent probes driven by the Gal4,UAS system. Live imaging immune cells - particularly their response to laser induced wounds - will enable us to gain a better understanding of the molecular mechanisms that underpin their diverse functions.

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

Interaction of the Irc5 chromatin remodeller and the replicative sliding clamp, PCNA 27 Apr 2017

Irc5 is a budding yeast chromatin remodeller that belongs to the same subfamily as the mammalian HELLS protein. Both have been implicated in the response to DNA damage and the HELLS protein is expressed abnormally or mutated in a number of cancers, yet their mechanism of action is not known. Recently, the N-terminus of Irc5 has been shown to interact directly with the replicative sliding clamp PCNA. Many other proteins involved in maintaining genome integrity interact with PCNA, several via a conserved PIP (PCNA-Interacting Peptide) box motif. A sequence similar to known PIP box motifs has been identified within the N-terminal domain of Irc5 and is the basis for this research. The first aim is to determine whether Irc5 interacts with PCNA via PCNA’s IDCL (inter-domain connecting loop), a region that PIP box proteins commonly bind. This will involve mutating two IDCL residues known to disrupt other PIP box- IDCL interactions, cloning, expressing and purifying the mutated protein and testing its ability to interact with Irc5 by pull-down assays. Secondly, Irc5- PCNA interactions will be disrupted in budding yeast using substitutions in the putative PIP-box of Irc5, to determine if Irc5- PCNA interactions impact genetic stability in vivo.

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

Effects of health warning labelling on alcohol consumers’ drinking behaviour and alcohol-related attitudes 27 Apr 2017

A recent European alcohol strategy indicated that there should be a review of alcohol product labelling. They identified that the inclusion of unit information, calorie information and health warnings should be added to labels to improve public health. This is particularly important as alcohol-related harms are not restricted to dependent individuals or binge drinkers. Alcohol labelling is a strategy by which alcohol-related information could be communicated to regular drinkers. However, an evidence base needs to be developed to inform public health researchers what information should be included and how it should be delivered. This study is part of a wider project that has collected information from the public and key alcohol stakeholders (e.g., clinicians, public health workers, local government licensing officials). The overarching aim is to develop a series of evidence based labels that have been shown to impact positively on drinker's behaviour. This study will objectively measure the impact of cancer health warnings on drinker alcohol-related behaviour and attitudes. Cancer warnings were chosen as the public survey identified that alcohol-cancer associated is poorly understood but would be likely to influence behaviour. A laboratory-based study will enable us to determine if this is the case.

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

Cerebellar inspired sensorimotor learning and control for robotics 14 Jul 2014

The aim of my research is to test how feedforward and feedback mechanisms operate in synchrony in the cerebellum not only to aid motor learning, but also to be able to adapt movement continuously. My PhD will involve two interlinked lines of research: one experimental; the other computational. The experimental part will be based on electrophysiological recordings in the cerebellum of rats. The purpose of my electrophysiological investigations will be to look at differences in the frequencies recorded in different cerebellar modules. These will involve both single spikes and local field potential activity.Furthermore, to be able to relate such activation frequencies to feedback/feedforward models, the recordings will involve actual motor activation in the animals. Therefore, the recordings will be conducted during behavioural tasks involving goal-directed movements and will include perturbations generated either by peripheral limb stimulation or by magnetic force field. The computational part of my PhD will involve expanding the Cerebellar Adaptive Filter Model into one which incorporates prediction learning mechanisms. This new model will be implemented into a robotic arm, and the results of the robot experiments will be compared to those of the animal experiments.

Amount: £150,057
Funder: The Wellcome Trust
Recipient: University of Bristol