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Results

Challenging Archives: Delivering research access, public engagement and the curatorial care of the Franko B Archive 16 Nov 2017

In consultation with the artist, this project will catalogue and conserve his unique, research-rich archive and make it accessible to meet established demands for research and public dissemination. The nature of the documentation, however, presents a set of particularly complex legal, ethical and practical challenges for archival and museological practice. These challenges, reflecting FB’s work, are interdisciplinary, and run parallel to those faced by other medical and LGBT+ collections containing similarly challenging material. As part of the project we will develop guidelines/methodology for curatorial care - and research access to - such material: an advisory committee of curators, academics, lawyers and regional medical humanities network representatives will support us and a case paper will be published at the end to serve as a model for other 'challenging' archives. FB is an artist whose extraordinary body-based performances have often involved blood-letting. His work, which explores the limits of the body, touching on pain, suffering and sexuality in contemporary culture, attracts considerable multi-disciplinary research interest, from art historians, artists and curators to medical humanities historians and anthropologists researching questions of the body as a site of connection between the social, bio-medical, political and affective forces that constitute contemporary life and well-being.

Amount: £136,049
Funder: The Wellcome Trust
Recipient: University of Bristol

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
Amount: £1,368,000
Funder: The Wellcome Trust
Recipient: University of Bristol

Biological and lifestyle predictors of outcomes in people with head and neck cancer 31 Jan 2017

Using data collected from a prospective clinical cohort of people with head and neck cancer (HNC)-Head and Neck 5000 (H&N5000), I will examine the potential value of baseline (pre-treatment) biological, clinical and lifestyle factors in predicting HNC prognosis at one year and three years post diagnosis. I will look at the association between tobacco and alcohol consumption and measures of outcome- overall survival, disease-free survival, metastasis, and second primary tumour (SPT) development. I will investigate whether behavioural change i.e. abstaining from, or reducing the consumption of alcohol and tobacco improves clinical and self-reported health outcomes in this population. To better understand how smoking and drinking behaviours may be influencing prognosis, I will analyse the methylation and metabolite profiles of baseline blood samples. I will explore whether there is an association between DNA methylation and metabolite levels and tobacco and alcohol consumption. Should I identify sites that are differentially methylated in smokers and drinkers, or metabolites that vary by smoking/drinking intake, I will evaluate whether they could potentially act as biomarkers for cancer progression and survival. I will look to develop a risk score that incorporates clinical, biological and lifestyle risk factors, which could be developed for use in clinical decision-making.

Amount: £0
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

The relationship between dendritic spikes and synaptic development 31 Jan 2017

Synaptic maturation and plasticity are essential for the establishment and refinement of neuronal circuits in the brain. Studies showing that dendritic excitability actively contributes to neuronal computation has redefined the classical concept of dendrites being passive electrical cables. Local NMDA-mediated dendritic spikes have been shown to alter synaptic plasticity and are associated with local rises in calcium concentration. Therefore, NMDA-mediated events are likely to influence the strength of the synapses, further underlying the importance of these receptors during synapse formation and information processing. However, these events have not been studied during brain development. Therefore, this research project aims to investigate the emergence of local dendritic NMDA-dependent spikes during development in vivo and in vitro in mice using electrophysiological techniques and calcium imaging. Our main goal is to understand whether these events drive synaptic formation and maturation or whether they require mature synapses to occur. We will both induce and block NMDA-spikes and observe the effects on synaptic maturation. Using sensory-deprived animals, the experience-dependency of these dendritic spikes will also be assessed. Furthermore, a knock-in mouse line of PSD95-eGFP, a major postsynaptic scaffolding protein, will be used to examine whether this protein is a marker for synaptic maturation.

Amount: £21,233
Funder: The Wellcome Trust
Recipient: University of Bristol

Genetics and urban environments in the development of autistic spectrum traits 31 Jan 2017

Cities are now home to more than half the world’s population and this number is expected to increase dramatically over the century. Previous research has shown that urban living is detrimental to mental health conditions such as autistic spectrum traits, so it is now more important than ever for us to understand the environmental causes of this increased risk and how our genetic background exacerbates or mitigates environmental influences. My PhD will use complementary methods to triangulate on these causes with data from UK and international population cohorts. The methods I will use include structural equation modelling of geocoded twin and DNA data, and Mendelian randomisation analyses to investigate causal influences. The results of my project may inform policy and health service provision for the next generation of urban planners.

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

The impact of stress on corticosteroid receptor binding to glucocorticoid target genes in the rat brain in relation to gene transcriptional responses and glucocorticoid hormone secretion 31 Jan 2017

My project concerns investigations on the action of stress-induced glucocorticoid hormones (GCs) in the rat brain. GCs play a critical role in an organism’s ability to adapt to external challenges and are crucial for maintaining health and wellbeing. Recently, the Reul lab demonstrated the enhanced binding of mineralocorticoid (MRs) and glucocorticoid (GRs) receptors to GC-responsive elements (GREs) within the GC-target genes Fkbp5 (FK506-binding immunophilin 51), Per1 (Period1), and Sgk1 (serum- and GC-inducible kinase 1)) in the rat hippocampus. My project will compare MR and GR to GRE binding within these genes in the hippocampus, neocortex, prefrontal cortex, amygdala, and hypothalamus, and pituitary under baseline and stress conditions and correlate these findings with the respective RNA levels generated under such conditions. In adrenalectomized (ADX) rats the separate and combined role and contribution of MRs and GRs to GRE-binding and transcriptional effects will be studied using pharmacological approaches. Bioinformatics analysis will be conducted on data sets generated by MR and GR ChIP-seq and RNA-seq on hippocampus of baseline and stressed rats. These analyses will involve comparison of MR/GR GRE-binding across the genome, comparison of these GRE-binding profiles with in silico generated data, and cross-correlational analysis if the ChIP-seq and RNA-seq data sets.

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

THE REGULATION OF AUTOPHAGY IN HUMAN IPSC-DERIVED MIDBRAIN DOPAMINERGIC NEURONS AND ITS COMPROMISE WITH AGING AND STRESS 31 Jan 2017

Autophagy is an intracellular lysosomal degradation pathway by which cytoplasmic cargoes are removed to maintain cellular homeostasis. This process is essential in neurons that need to cope with prolonged and sustained operational stress, and thus autophagy is known to protect against neurodegenerative diseases. I hypothesise that region-specific neuronal autophagy control pathways predispose particular subsets of neurons to loss during aging and stress. In this context, induced pluripotent stem cell (iPSC) technology has emerged as a powerful tool to study molecular processes in specific types of human neurons. We have described a new, improved iPSCs monolayer protocol to obtain midbrain dopaminergic neurons (mDANs) –the neurons lost in Parkinson’s disease (PD). During my PhD, I will characterise the spatiotemporal autophagy response in human mDANs using dynamic cell imaging. Using proteomics and transcriptomics approaches, I will fully characterise human iPSC-derived mDANs, and will focus specifically on how autophagy is controlled in these cells by midbrain-associated LMX1A/B transcription factors. Relevant data from our iPSC-neuronal models will be corroborated in human brain tissue of different ages. Armed with this background knowledge, I will then determine how mDAN autophagy pathways are affected by neurotoxic compounds and by ageing-associated stress to better understand mDAN loss in PD.

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

Differential activation of calcium targets at single synapses during plasticity 31 May 2018

Learning occurs through alterations of synaptic efficacy between neurons. There are many mechanisms of plasticity that contribute towards manipulation of synaptic efficacies. The classical case is the utilisation of calcium ions as a transducer of cell surface stimulation. Intracellular calcium binding complexes can lead to protein kinases and phosphatases such as CaMKII and calcineurin respectively. CaMKII has been associated with LTP formation whilst Calcineurin is linked to LTD. CaMKII is additionally linked to dendritic spine growth. It is thought that calcium's influx kinetics is the determinant of which opposing molecular pathway occurs. This project's aim is to investigate a neglected variable involved in calcium's intracellular binding, this is whether the spatial location of calcium binding proteins namely calcineurin and calmodulin. Using MCell to model a single dendritic spine and simulate precise alterations in the relative spatial positions of binding proteins; along with varying calcium influx kinetics will enable computation of the new variable of spatial location into already existing models of synaptic plasticity. Elucidating the exact mechanisms involved in learning will enable new approaches for treating certain learning disorders and dementias.

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

Neural Dynamics of Survival Circuits 30 Sep 2018

Insights gained into CNS mechanisms underlying emotional behaviours are important in the development of strategies to improve emotional disorders and animal welfare. Little is known about the way central ‘emotional’ circuits engage with the motor system to generate the highly characteristic responses essential for survival (i.e. fight, flight or freezing). My project will explore and characterize relationships between the cerebellum and key components of survival networks. Neural pathways between CBM and periaqueductal grey (PAG) will be identified using two techniques: neuronal tracers (e.g. retrogradely transported canine adenovirus, CAV-2), to map projections and the specific location of their origins. Electrophysiological mapping in an anaesthetised animal to identify direct or multisynaptic functional connections. Depending on the outcome of this initial step, neural pathways will be inactivated using DREADDs in awake freely moving animals (rodents) during fear behavioural (e.g. fear conditioning, predatory odour) paradigms. There is also scope to record single unit and population (LFP) activity from regions such as the Amygdala, PAG and CBM, to investigate the networks dynamics between these regions, and how different aspects of defensive behaviours might be encoded in the brain. The LFP signals will then be used to develop and test Dynamic Causal Models (DCM) of connectivity.

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

DISSECTING ACTIN-DEPENDENT CHROMOSOME COHESION IN MAMMALIAN OOCYTES 21 May 2018

When immature oocytes develop into eggs, a specialised form of cell division called meiosis segregates the chromosomes. Meiotic chromosome segregation errors are remarkably common and can give rise to aneuploidy, a leading cause of human embryo deaths and genetic disorders such as Down’s syndrome. I recently showed that accurate chromosome segregation in mammalian eggs critically relies on actin (Mogessie and Schuh, Science, 2017). I have now obtained data that suggest a previously unknown function of actin in chromosome cohesion, a mechanism that prevents untimely separation of chromosomes. It is known that loss of chromosome cohesion underlies aneuploidy in human and mouse oocytes. Actin-dependent chromosome linking is therefore a novel finding that deserves detailed investigation. Here, I will address actin-dependent cohesion in mouse oocytes by combining advanced microscopy techniques with drug-based loss-of-function assays. I will further dissect this novel mechanism by restricting loss-of-function assays to meiotic chromosomes and their kinetochores. Ultimately, I will examine whether actin can be used to bolster weakened cohesion and prevent aneuploidy in oocytes. Findings from this study will define a new ‘chromosome gluing’ mechanism that can potentially be repurposed to prevent aneuploidy in oocytes of fertility treatment patients.

Amount: £100,000
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

Understanding the Antecedents and Outcomes of Frequent Adolescent Cannabis Use 08 Nov 2017

As cannabis policy liberalises, frequency of use is expected to increase amongst adolescents. Frequent cannabis use during this period is associated with health-related harm, including increased risks for Common Mental Disorder (CMD). Early Life Stress (ELS) is a consistent correlate of adolescent cannabis use. However, we know little about the mechanisms underpinning the development of frequent cannabis use and the nature of the relationship between frequent adolescent cannabis use and subsequent CMD. I’ll use two large longitudinal datasets (ALSPAC and VAHCS) to: Explore how ELS is associated with frequent adolescent cannabis use Identify pathways between frequent adolescent cannabis use and adult CMD To address 1), ALSPAC data will be used to explore whether cumulative ELS increases likelihood of frequent adolescent cannabis use (Longitudinal Latent Class Analysis), and whether antisocial behaviour and mental health symptoms in adolescence mediate this relationship (Causal Mediation Models). For 2), VAHCS data will be used to ascertain whether post-adolescent employment and drug/alcohol abuse are on the causal pathway between frequent adolescent cannabis and adult CMD (Causal Mediation Models). The application of new statistical developments allows novel exploration of causal pathways between frequent cannabis use’s antecedents and outcomes, which has practical utility for informing intervention.

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

Applying ‘omics to understand and predict juvenile arthritis and its associated uveitis 30 Sep 2018

Juvenile idiopathic arthritis (JIA) is the most common rheumatological condition of childhood. Significant numbers of JIA patients (up to 30%) develop complications with their eyes (uveitis, JIA-U) and are at risk of blindness. We do not know why uveitis is so common in JIA, why only some children get uveitis or what causes more severe disease. Current research suggests our genes and our environment are involved but their exact contributions are unclear. This project will look at how genes related to similar autoimmune conditions may be involved in JIA and systematically assesses the evidence for environmental factors associated with JIA and JIA-U. This project will then look for genes specifically associated with JIA-U in a genome-wide association study. However, we know from similar diseases that having predisposing genes is insufficient alone to cause disease. Epigenetics studies how genes are switched on/off (our "epigenome") and helps explain how genes and the environment act together to cause disease. Thus, this project will also examine whether the epigenome mediates JIA and JIA-U disease risk. Finally, all of this information will be used to identify key elements of the epigenome of JIA patients and test whether changes to these can predict development of JIA-U.

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

Identification of deep vein thrombosis causative factors 31 May 2018

Thrombosis is defined by the abnormal formation of a clot within a blood vessel. Deep vein thrombosis (DVT), a subset of venous thromboembolism (VTE), commonly occurs within the deep veins of the legs. A variety of genetic and acquired risk factors have increased the prevalence of DVT during the past decade. Due to its somewhat asymptomatic nature, DVT can lead to complications in untreated individuals. While some research has been done on DVT, the direct causes of the disease are still relatively unknown. The purpose of this project is to identify the factors causally associated with DVT which may not have been identified through observational epidemiology. I will use an advanced causal analysis technique in genetic epidemiology called Mendelian randomization (MR) to determine what causes DVT. My first aim is to investigate what causes DVT using a hypothesis-free MR analysis. To do this I will use MR-Base - a database containing compiled GWAS summary data. I will then focus in more detail on a known cause of DVT (high BMI) and investigate what might mediate this causal effect. It is anticipated that the findings made during this project be a starting point for a prophylaxis against the outlined disease.

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

Foveal and peripheral contributions to controlling fixation duration 27 Apr 2017

Human vision relies on rapid gaze shifts to obtain high quality foveal information about the environment. Information is acquired during periods of stable fixation. During a period of stable fixation, several decision processes occur: (i) foveal analysis: the observer has to analyse (identify) the currently fixated object(s); (ii) target selection: the observer has to decide where to look next; and (iii) fixation control: the observer has to decide when to go there. In the current project, we aim to assess the role of foveal analysis and target selection on the control of fixation duration. Investigating this interaction is vital to understanding the processes which govern an observer’s active visual sampling of the environment. The critical question we will address is to what extent fixation duration is controlled by foveal analysis and target selection, when the difficulty of these two decision processes is carefully controlled.

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

Open access publishing costs 2014/15. 15 Sep 2014

Not available

Amount: £131,814
Funder: The Wellcome Trust
Recipient: University of Bristol