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Results

What makes phleboviruses tick? Examining the molecular interactions of tick-borne phleboviruses with their arthropod vector. 21 Feb 2018

There is a fundamental lack of understanding regarding how tick-borne viruses replicate in ticks and how the tick innate immune system controls infection. My proposal will focus on tick-borne SFTS phlebovirus, its overarching goals are to understand how tick-borne viruses interact with ticks and tick cells and how this facilitates transmission to mammalian hosts. To achieve my goals, I will carry out in vitro and in vivo studies that can be divided into three specific aims: (i) to elucidate the basic molecular biology of tick-borne virus replication, (ii) to define the innate immune factors that control virus replication in the tick cell environment and (iii) to examine whether virions derived from tick or mammalian cells have similar biological properties and virulence? I will conduct in vitro experiments in tick cell lines to examine virus-vector interactions. Importantly, I will also establish unique tick colonies and infection capabilities for the UK. Through combined cell culture approaches and in vivo animal experiments I will investigate the replication of phleboviruses in the live tick for the first time. I will also explore the infectivity of virions derived from different sources and assess if tick-derived viruses are more virulent to mammals in animal inoculation studies.

Amount: £1,335,592
Funder: The Wellcome Trust
Recipient: University of Glasgow

Tuft Cell Activation and Intestinal Immunity 17 Jul 2018

Immunity to nematode parasites requires sequential activation of innate and adaptive immunity in a concerted Type 2 response dependent on the cytokines IL-4, IL-13 and IL-25. Our work, and that of others, has identified a novel epithelial cell type that is critical to initiation of this response, known as tuft (or brush) cells. Most significantly, tuft cells are a major source of IL-25 during gastro-intestinal nematode infection, which induces IL-13 production from innate lymphoid cell type 2 (ILC2s), to activate further innate and adaptive cell populations. They also express high levels of the enzymes that produce acetylcholine and lipid mediators implicated in immunity. Tuft cells are found in other mucosal locations, including the lungs, and are highly conserved across the Mammalia, including in ruminants where intestinal nematodes are a major problem. A fascinating aspect is their expression of taste receptors suggesting that they may chemically ‘sense’ the presence of nematodes. In this proposal we seek to (i) determine the immune effector functions of tuft cell mediators; (ii) identify molecules from parasites that may activate tuft cells; and (iii) establish whether tuft cell functions are conserved in ruminants and may lead to new strategies for control of nematode infection in sheep.

Amount: £1,203,739
Funder: The Wellcome Trust
Recipient: University of Glasgow

Recognition, activation and targeted degradation of protein kinases clients by the HSP90-molecular chaperone 10 Apr 2018

Many oncogenic protein kinases depend on interaction with the HSP90 molecular chaperone, mediated by the co-chaperone CDC37, for their cellular stability and oncogenic activity. Inhibition of HSP90's conformationally-coupled ATPase mechanism leads to the ubiqtuitylation and degradation of these protein kinase 'clients'. Consequently HSP90 is an important target for therapeutic intervention in cancer. Although there has been substantial progress in this field, important issues remain unresolved. In particular we wish to understand : How protein kinase clients are specifically and selectively recognised by the CDC37 co-chaperone, and recruited to HSP90 ? What structural and biochemical changes are elicited in the client protein by recruitment to HSP90 and by its conformationally-coupled ATPase cycle ? How dephosphorylation of CDC37 by the HSP90-targeted protein phosphatase PP5 regulates client protein release ? How protein kinase clients are targeted for proteasomal degradation when HSP90's ATPase is inhibited ? To address these questions we will use cryoelectron microscopy, X-ray crystallography, NMR spectroscopy, and a range of biochemical and biophysical approaches, to determine structures of key complexes along the pathway from initial client recognition to release or ubiquitylation, and define the structural and biochemical transitions that connect them.

Amount: £2,027,915
Funder: The Wellcome Trust
Recipient: University of Sussex

Dissecting the transcription regulatory network in malaria parasites at early transmission stages. 01 Jun 2016

During the progress through its complex life cycle, the malaria parasite requires strict control of gene expression, but the mechanisms controlling this process remain poorly understood and unexplored for therapeutic purposes. A group of apicomplexa-specific putative transcription factors with AP2 DNA binding domain(s) (apiAP2) has been identified as major regulators of the parasite transcriptome at multiple stages. However role of the majority of the members of the family and their targets are unknown. My recent work identified that a network of at least four interacting apiAP2 proteins controls gene expression during the major bottleneck of Plasmodium life cycle – ookinete formation. Here I propose to analyse this network identifying the key apiAP2 proteins involved and their targets, binding partners and interactions with the epigenetic landscape. The resulting comprehensive model of transcription regulation at the critical stage of parasite transmission would provide valuable insights into the key aspects of parasite biology (potentially resulting in new drug targets) and generate the tools for further investigation of transcription regulation across the parasite life cycle.

Amount: £1,007,878
Funder: The Wellcome Trust
Recipient: University of Glasgow

Nursing, Reproduction, and Writing: Naomi Mitchison’s Science Fiction as Activism 29 Feb 2016

This study will explore the ways in which the experiences of the Scottish writer Naomi Mitchison (1897-1999) as both a geneticist and a nurse shaped her science fiction, her political writing, and her activism in favour of women’s reproductive rights. Through archival research and literary analysis, informed by science fiction studies, this project will explore Mitchison’s importance to twentieth-century medical humanities. The outcomes of the project will be a conference presentation and a peer-reviewed journal article, with potential for future projects.

Amount: £1,534
Funder: The Wellcome Trust
Recipient: University of Glasgow

The Gaelic language and medical provision in the 19th-century Scottish Highlands 31 Jan 2016

This proposal examines communication between monoglot Gaelic-speakers and members of the medical profession (not all of whom were Gaelic-speakers) in the 19th-century Scottish Highlands, considering the ways in which Gaelic was, and was not, accommodated in the emerging health care system and how this impacted upon patient care. This will involve carrying out work in Highland Archive, Inverness, focusing on the records of the Inverness District Asylum, the Northern Infirmary and Inverness Parochial Board. The aim is to build on work already undertaken on contemporary published reports, as well as preliminary archival work, and to establish a fine-grained picture of language usage between patients and medical staff and thereby to: identify the provision made for Gaelic-speaking patients by those tasked with overseeing the administration of health care provision in 19th-century Inverness and its environs establish Gaelic-speaking staff : patient ratios by drawing on both patient & staff records and the Censuses of 1881 and 1891 identify the extent to which the language of communication was perceived as being problematic by staff or patients identify occasions when communications between patients and medical staff was impeded or affected by a language barrier and the impact of this on patient care

Amount: £1,297
Funder: The Wellcome Trust
Recipient: University of Glasgow

Pan-genome copy number variation analysis in Leishmania and possible association with origins of replication 01 Apr 2016

Genome replication is central to the propagation of life. Although DNA replication machinery arose prior to emergence of the three domains of cellular life, pronounced differences have since evolved in execution of this process. While all bacterial and many archaeal genomes are replicated from a single origin of replication, until recently it was believed that eukaryotic chromosomes are replicated from multiple origins. We have recently performed origin mapping in two Leishmania species, revealing only one origin per chromosome and providing the first example of a eukaryotic microbe that displays prokaryote-like replication dynamics. Chromosome origin singularity in Leishmania raises questions about the dynamics of genome replication, in particular because the genome of this parasite displays pervasive plasticity, including genome-wide gene and chromosome copy number variation (CNV). We hypothesise that the organisation of genome plasticity will relate to the sites of replication initiation, specifically, we suggest that CNV will display predictable patterns in the genome in relation to the origins. We will therefore map CNV relative to origins and, in so doing, test if the unprecedented strategy for Leishmania replication intersects with genome plasticity and if specific genes and gene families are affected.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University of Glasgow

Expression and purification of ApolipoproteinE4 - A potential target for Alzheimer's disease therapeutics 01 Apr 2016

The purpose of my project will be to express and purify the human recombinant ApoE4 isoform as the basis for conducting subsequent structural analysis and small molecule screening in an early-stage drug discovery project. In the first instance, I will attempt to reproduce previously published data with so-called "structural correctors" that convert the morphology of the "bad" ApoE4 isoform into the more benign "good" ApoE3 isoform. More specifically my aims will be: 1. Small-scale expression tests of human ApoE4 cDNA in various standard strains of bacteria (E. coli) 2. Large-scale (2-5L) expression of ApoE4 under optimal conditions identified in Step 1. 3. Isolation and purification of ApoE4 using affinity, size and/or ion exchange chromatography and fast-protein liquid chromatography (FPLC) Stretch objectives (if all goes well) include: 4. Crystallography trials and thereafter X-ray crystallography 5. Development of an ApoE4 strucutural conformation assay using a previously-published fluorescence resonance energy transfer (FRET) assay

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University of Sussex

Can Exercise Attenuate the Effect of Acute Exposure to Urban Lighting on Behaviour and Brain? 01 Apr 2016

There is an increased prevalence of obesity and cardiometabolic disease in human shift-workers that might be partly mediated by disruption of circadian rhythms. Studies in both humans and animals have reported that disruption of circadian rhythms affects glucose homeostasis, and increases body weight. Circadian disruption (CD) is classically associated with shiftwork, but a more chronic form of disruption induced by the irregular lifestyle and artificial light of the urban environment could similarly disrupt rhythmicity and affect metabolic health. Inflammation and activation of microglia in the hypothalamus is thought to contribute to the pathogenesis of obesity, and upregulation of inflammatory signalling was also associated with CR induced by dim light at night. The aim of this study is to investigate the effects of chronic dim light at night on body weight, food intake and markers of glial plasticity in the hypothalamus.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University of Glasgow

Endgame Strategies for the Elimination of Canine Rabies 09 Feb 2015

My goals are to develop a framework for integrating viral sequences, transmission histories and spatiotemporal incidence data and to investigate the dynamics of rabies across scales and implications for control and elimination. I will explore: 1) Genetic variation generated during transmission. Ultradeep pyrosequencing of amplicons from samples of rabid animals with known transmission histories will be used to quantify genetic variation generated and transmitted between consecutive infections. 2) Determinants of transmission. The influence of physical geography, population structure, demography and vaccination effort on transmission will be investigated using transmission histories of rabid animals in populations where density and structure have been precisely measured. Transmission trees will be constructed and statistical techniques developed to combine these withviral genetic data to refine epidemiological inference, particularly for incompletely observed epidemics. 3) The scaling of transmission processes from local to landscape-level dynamics. A hierarchical suite of models will be parameterized from spatiotemporal data to explore disease spread and persistence across landscapes. 4) Applications for disease control. These models will be used to investigate vaccination design and implementation, including spatial extent, outbreak response and containment. Within a state-space framework, analogues will be fitted to surveillance data from large-scale control programs to evaluate their impacts.

Amount: £120,208
Funder: The Wellcome Trust
Recipient: University of Glasgow

Is the skin the site of a human reservoir in African trypanosomiasis? 07 Aug 2015

The aim of this project is to examine the role of natural genetic variation in both the human host and parasite in determining the outcome of infection with either T.b. gambiense or T.b. rhodesiense. There is now a body of data, which shows there is variation in the factors that: (a) prevent initial host infection; and (b) determine disease severity. However, we have a relatively limited knowledge of the mechanisms involved and how genetic variation affects disease outcome. This proposal will ex ploit natural genetic variation to identify the key features and molecules involved using a combination of host association of candidate genes, parasite population genomics and molecular analysis of trypanolytic complexes present in serum. In addition, the proposal will create a large genomic sequence resource of >140 parasite strains together with a biobank of the parasites strains for those working in other areas. Thus, by dissecting some of the key components of both host and parasite which are determinants of infection and disease outcome, a series of pathways and molecules will be identified which could be the targets of novel interventions aimed at preventing or controlling the disease

Amount: £108,531
Funder: The Wellcome Trust
Recipient: University of Glasgow

Heterogeneity of sympathetic stimulation as a mechanism of ventricular arrhythmias following myocardial infarction. 13 Nov 2014

Patients surviving myocardial infarction (MI) are at high risk of sudden cardiac death due to ventricular arrhythmias. Preventative therapies for this condition are limited and our knowledge of the underlying mechanisms is incomplete. This application investigates the novel concept that heterogeneous sympathetic remodelling interacts with cellular and tissue-level changes to cause ventricular arrhythmia following MI. We hypothesize that such remodelling: (i) causes local myocardial foci of near- synchronous diastolic Ca2+ release which trigger ectopic beats and (ii) creates a vulnerable pro-arrhythmic substrate that interacts with a critically timed ectopic beat to produce sustained arrhythmias. This project is unique in that it will examine how both the critically-timed trigger and vulnerable substrate may arise by a single mechanism and this innovative approach will yield important mechanistic findings which will be critical to the development of improved risk stratification tools and new treatment strategies to prevent sudden death.

Amount: £921,103
Funder: The Wellcome Trust
Recipient: University of Glasgow

Brain algorithmics: reverse engineering dynamic information processing in brain networks from MEG time series. 07 Jul 2015

Information processing is a pervasive assumption of the most influential models in cognitive neuroscience. For example, in predictive coding, predictions imply explicit knowledge of the detailed information propagated down the visual hierarchy. Likewise, categorical decisions imply the successful match of sequentially accrued, sensorily coded information (the evidence) with memorized information serving as decision criteria (categorical knowledge). Consequently, one of the most pressing developments in cognitive neuroimaging is the development of a brain algorithmics, to reverse engineer the actual information that brain networks dynamically process between stimulus onset and behaviour. The cornerstone of brain algorithmics is the existence of rigorous methods to reverse engineer from brain data the dynamic processing of fine-grained information. Groundbreaking progress in visual neuroscience followed Hubel and Wiesels seminal research on the receptive fields of simple and complex cells. Key to this success was their insight to dissect thevisual input into fine-grained information components and measure how brain cells responded to each. From themapping between information components and cell responses, they inferred the information processing function of the cells. Extending this approach to visual cognition is challenging because stimuli aretypically highdimensional. I have developed methods that dissect these stimuli into fine-grained components. Much like Hubel and Wiesel, I can now quantify where, when and how MEG network nodes code and transfer these information components. Consequently, I aim to apply this unique interpretive framework to understand the information processing functions underpinning visual categorisations. Specifically, I will study how different tasks (i.e. face detection, identity recognition, categorisation of gender, age, emotion, social traits) applied to the same face modulate the dynamic processing of information in brain networks across the lifespan. My approach will provide an unmatched level of interpretation of the coding of brain signals, the function of network nodes and of the information flow.

Amount: £1,310,585
Funder: The Wellcome Trust
Recipient: University of Glasgow

Open access publishing costs 2014/15. 15 Sep 2014

Not available

Amount: £83,288
Funder: The Wellcome Trust
Recipient: University of Glasgow

Encountering R.D. Laing's Archive: Mental Health, Care and Creativity. 10 Feb 2014

2014 marks an exceptionally significant year in the history of mental health in Glasgow, being the bicentenary of institutional care, and this conference seeks to open up conversations about these issues through the lens of one of Glasgow's most famous psychiatrists, R.D. Laing. These events aim to bring together a number of individuals from across different academic disciplines, professions and communities to share reflections on the changing nature of institutional care. Using the 'Laing Archi ve' as a pivot this event seeks to promote the collections and to set future agendas for working with the 'archive'. A number of interconnecting events at the University of Glasgow are proposed. The first, held in the Special Collections, seeks to bring together a number of participants from across different backgrounds (artists, writers, service users, therapists) to explore materials held in the Laing collection and to generate creative output. The second will bring together leading academi cs from across institutional backgrounds to share, reflect and generate new discussions about mental health care in Scotland and beyond. Finally, the 1972 US Tour Showreel by Peter Robinson will be screened in order to generate further conversations about mental health, the arts and institutional landscapes.

Amount: £4,085
Funder: The Wellcome Trust
Recipient: University of Glasgow

Biomedical Vacation Scholarship 23 Jun 2014

Not available

Amount: £9,000
Funder: The Wellcome Trust
Recipient: University of Sussex

Biomedical Vacation Scholarship 23 Jun 2014

Not available

Amount: £21,500
Funder: The Wellcome Trust
Recipient: University of Glasgow

Wellcome Trust Centre for Molecular Parasitology. 15 Jul 2014

Modern approaches to parasitological research are multidisciplinary requiring many and varied expertise that a Centre best employs and exploits. Based upon polyomics and extensive bioinformatic/modelling platforms coupled with cutting edge imaging and novel, in house molecular parasitological methodologies the WTCMP will continue to play a leading role in tropical disease research. Primarily focussing on the molecular and cell biology of apicomplexan and trypanosomatid parasites, we address the major problems caused by parasitic infection in the tropics in a setting continuously strengthened by responsive investment in infrastructure and recruitment of promising group leaders. Translation is principally envisaged to be discovery and development of drug targets and vaccine candidates. WTCMP will continue to provide excellent training at pre-and post-graduate levels, mentoring across the career spectrum. WTCMP will accelerate the development of activities and partnerships in disease ende mic regions (DER) notably via the Wellcome Trust Liverpool Glasgow Centre for Global Health (WTLGCGH) initiative providing access to any relevant Glasgow expertise whilst allowing WTCMP-centred clinical engagement. Polyomics (particularly metabolomics) and modelling will be central to DER engagement allowing integration of our interactions with DER into a unified approach. WTCMP outreach will continue to inform the public of our activities and the problems we address.

Amount: £7,878,934
Funder: The Wellcome Trust
Recipient: University of Glasgow