- Total grants
- Total funders
- Total recipients
- Earliest award date
- 22 Nov 2005
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Panel Sponsorship for one-day conference, 'A Life As A Lens: Using Individuals in Wider Historical Research'. 29 Aug 2014
We are organising a one-day conference for 12 September 2014 called, 'A Life As A Lens: Using Individuals in Wider Historical Research', aimed primarily at early career researches. This conference is due to have a special panel dedicated to the history of medicine. The conference will explore the methodological issues involved in research that is based on an individual or group of individuals, bringing together historians working across all periods, regions and concentrations. Rather than pa pers which focus on individuals in and of themselves, the conference will explore how historians use individuals and the sources related to them. Papers will concentrate on the challenges within this form of historical research. Can individuals truly function as representatives of wider groups, or as 'lens' through which to view broader issues, events, and ideas? Or do they obscure the past by providing a personalised or subjective picture? Among other topics, speakers will explore the role o f 'Great Men' narratives in history of medicine scholarship; the roles of resident hospital artists; and the 1960s cultural shift in 'diagnosing' child abuse as reflected through the paediatrician Henry Kempe.
Application of Traditional Medicine for improving the possibility of accessinghealth and social care for people living with HIV/AIDS in Vietnam. 08 Jun 2009
Investigation of Hanta virus infection in humans 20 May 2011
The workshop will be based on a real-life case study, concerning an outbreak of Hanta virus. This infects deer mice in the USA, and is usually harmless, but a mutant form of the virus has now infected field mice. 26 people in the USA died from an unknown viral infection, and DNA technology later showed that their deaths were caused by the mutant form of Hanta virus that passed from field mice to humans. In the workshop, students will be given this case study to solve for themselves, using restriction enzymes, micropipettes and gel electrophoresis. These techniques are not normally available to us in a sixth form college.
Conservation survey costs 31 Aug 2010
This professional survey is needed to inform our bid to conserve and catalogue the materials in five of our most important collections relevant to the history of modern genetics. The assessment will look at the current condition and storage of the materials, and make costed recommendations in terms of re-housing, repair and cleaning. The conservator will take into account the need to make these materials accessible, particularly through digitisation. This report is essential for the bid to give an accurate picture of the work needing done. The collections on which our bid is based contain very diverse material with a range of conservation challenges. There are, for instance, printed items which have suffered extensively from being kept in damp and unheated conditions in a chicken shed; glass negatives; press cuttings on acidic paper; manuscript items in need of refoldering and reboxing; bound volumes in need of binding work; films which need extensive work to assess their storage and preservation requirements. These factors mean that it is not straightforward to identify and cost the various conservation activities required, and that a survey by a professional conservator is necessary. If we do not assess the scale of the task properly, there is the danger that long-term access through cataloguing and digitisation of these collections will not be sustainable because the materials themselves cannot be handled and consulted. Caroline Scharfenberg, who has provided the attached quotation, is a highly experienced private conservator who is based at Edinburgh University Library.
"3rd Annual History of Science, Technology and Medicine Postgraduate Workshop" to be held at the University of Leeds on 22-24 June 2010 19 May 2010
The workshop, which will last three days, aims to improve the academic skills and network of postgraduates through discussion of their work and specific training sessions with senior scholars. On day one there will be presentations by nine PhD students - three each from the Universities of Leeds, Cambridge and Aarhus - split into three sessions, each consisting of three twenty minute presentations followed by a one hour panel discussion. During the discussion, senior faculty members will prepare questions that critically engage with the doctoral research of the presenters, and other PhD students may pose questions to the panel. On day two, the postgraduate speakers and other students from the School of Humanities in Leeds are invited to attend a series of four sessions examining methods for improving doctoral - research and developing an academic career. Throughout both days, students will have the opportunity to ask questions about their own research and how they can improve their methodological and theoretical frameworks. On day three, the Leeds Research and Humanities Centre will host the Tyndall Correspondence Symposium which is part of an international project coordinated from York University Canada. Papers will focus on the life and research of the scientific naturalist John Tyndall.
The ability of cells to generate complex gene expression patterns is fundamental to multicellular life. While global mRNA levels can now be routinely determined using ‘omics technologies, a major gap in our knowledge is how a cell produces these mRNA levels with the correct temporal dynamics. In addition, the fate of individual mRNAs represents another variable that is rarely globally considered. Therefore, the overarching question addressed in this proposal is: How are global mRNA accumulation dynamics and translatability harmonised with developmental timing to control cell fate decisions? We will exploit the rapid development and tractability of Drosophila to address this question in a developing embryo. We will model the dynamics of mRNA synthesis, processing and degradation across early embryogenesis and integrate these data with the export efficiency and translatability of mRNAs. For individual mRNAs the dynamics will be validated in vivo using live imaging and modeled to give single cell spatiotemporal resolution. For key developmental genes we will perturb mRNA production rates and translatability to determine the effect on protein function and the accuracy and robustness of dorsal-ventral patterning. Overall our data will reveal how dynamic regulation at every step in the gene expression pathway drives developmental patterning.
The Drosophila embryo undergoes a series of pattern-forming events that shape its body plan during embryogenesis. A bone morphogenetic protein (BMP) signalling gradient is crucial for accurate dorsal patterning. However, it is poorly understood how gene expression timing contributes to the patterning of specific cell fates. This project aims to determine how the dynamics of mRNA accumulation and translational efficiency influence cell fate decisions. We will use the Drosophila embryo as a model and focus on amnioserosa and epidermal cell fates, which are specified by BMP signalling. I will combine live imaging and single molecule fluorescent in situ hybridization to characterize the mRNA accumulation dynamics and mRNA processing efficiency for key BMP target genes, pannier, u-shaped and hindsight. The experimental approaches will provide single cell resolution data and reveal changes relative to the cell’s position within the expression domain. The translation timing of the pannier, u-shaped and hindsight mRNAs will also be visualised using live imaging. The effect on cell fate and robustness of dorsal patterning will be determined following perturbation of the dynamics of mRNA accumulation and translation. Our results will provide new insights into the regulation of gene expression, with imprecise regulation leading to developmental defects and disease.
Characterising the spatial determinants of antimalarial resistance in P. falciparum malaria 31 Jan 2017
At present artemisinin-based combination therapies (ACT) are recommended for the treatment of uncomplicated malaria and are hoped to limit possible development of antimalarial resistance. Recent observations of ACT resistance in Southeast Asia however indicates that the emergence of clinical resistance is occurring, indicating that parasites may be developing resistance to both components of the ACT. It is thus imperative that a course of action for balancing both the longevity of antimalarial efficacy and the immediate public health impact is identified. We aim to develop a spatial individual stochastic model of malaria transmission that incorporates both the epidemiological and within host process in order to better understand the drivers of ACT resistance emergence. Through this endeavour we aim to identify strategies at regional levels within Southeast Asia in order to slow the speed of ACT resistance. Finally we will predict and map the potential future burden of ACT resistance within Southeast Asia.
Genome wide association studies demonstrate that amyotrophic lateral sclerosis (ALS) has a large genetic contribution and a gender bias in risk. However, these studies also indicate that we still have much to learn about the genetic causes of ALS. To explain this missing component we hypothesise that endogenous non-LTR retrotransposons, which are known to be active in the human genome, result in novel insertions that can act as germline predisposition variants or new de novo mutations. These non-LTR retrotransposons include LINE-1, Alu- and SINE-VNTR-Alu (SVA) elements. We are currently identifying novel somatic insertions in DNA from both motor neurons and lymphocytes of individuals who have died of ALS using a technique termed retrotransposon capture sequencing. This data is now available to validate, data-mine and address the functional consequences of such insertions. Particular focus will be given to insertions on the X chromosome which might in part explain the gender bias. The proposal is therefore to determine if: a) Increased or novel retrotransposition events have occurred in the motor neurons of individuals with ALS which would correlate with neurodegeneration of these neurons. b) Specific germline insertions are a predisposing factor for ALS.
Successful cell division relies on faithful chromosome segregation. Central to this process is sister chromatid cohesion by cohesin that topologically entraps sister chromatids. Cohesin shows increased association with chromosomal regions surrounding the centromere, called pericentromeres. Pericentromeric cohesin is crucial during both meiosis and mitosis. In meiosis I, when homologous chromosomes segregate, pericentromeric cohesion is protected from separase-dependent cleavage ensuring that sister chromatids stay together until they segregate in meiosis II. In mitosis and meiosis II, pericentromeric cohesin facilitates chromosome biorientation by establishing preferred kinetochore geometry for capture by microtubules. How exactly pericentromeric cohesion facilitates chromosome biorientation is unknown. It was proposed that pericentromeric cohesin establishes intramolecular linkages allowing the pericentromere to adopt a cruciform structure. This would facilitate a back-to-back geometry of kinetochores and would promote kinetochore capture by microtubules from opposite spindle poles. This project aims to characterise the conformation of the pericentromere in budding yeast. I will examine how the conformation of pericentromeric chromatin responds to the presence and absence of tension that is exerted on chromosomes during biorientation. The research will extend to mitotic and meiotic cells, with wild type and cohesin-deficient backgrounds. Ultimately, this will further our understanding on how kinetochore geometry facilitates accurate chromosome segregation.
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG repeat in the huntingtin gene, HTT. The disease has characteristic motor and cognitive symptoms resulting initially from degeneration of the medium spiny neurons (MSNs) in the striatum. There are currently no disease-modifying treatments. The length of the CAG repeat is inversely correlated with age at motor onset but other factors influence onset including genetic variation elsewhere in the genome. A recent GWAS (GeM-HD) identified genetic variation in or near DNA repair genes as modifiers of age at onset. We hypothesise that DNA repair processes trigger post-mitotic CAG repeat expansion in MSNs leading to their degeneration. The work here aims to establish a cellular model of CAG repeat expansion which we can use to assess the effects of the DNA repair genes (and their variants) implicated by the GeM-HD GWAS. CRISPR technology will be used to knock-out or introduce the relevant genetic variation into HD-iPSC lines. Functional assays will then be conducted to assess cell viability. Characterising how these genetic variants affect cells harbouring the expanded CAG repeat will better define appropriate targets in the DNA repair pathway for further exploitation in therapeutic development.
Single-cell genomics is a fantastic tool for studying developmental biology: it allows unbiased and large-scale study of gene expression at the correct resolution for cell fate decision making. New fluidics systems provide the capability to study tens of thousands of cells simultaneously - as many as there are in the young embryo. For my PhD, I will analyse scRNA-seq data generated on this platform, studying mouse gastrulation between E6.5 and E8. I will be able to study this process at both an exceptional cell-level resolution (thanks to the fluidics) and at an unprecedented time resolution, at 0.1 day intervals. My focus will be on identification of lineage specification, and how cells make their fate choices. I will need to develop new methods to account for the large numbers of cells assayed, the numerous lineage decisions made, and heterogeneity of speeds of development across and between embryos. I hope to produce a map of lineage specification from epiblast (E6.5) cells through to every cell type present at E8. This work will provide a developmental atlas through gastrulation, and general inferences on cell fate decisions may provide insight for cellular reprogramming and regenerative medicine.
Integrating genomic, transcriptomic, metabolomic and behavioural data from 12 strains of C. elegans to understand gene/environment interactions under different dietary regimens 31 Jan 2017
C. elegans can grow on a range of different bacterial diets. It has already been shown that it changes its behaviour depending on the available food. Its lifespan also depends on its diet. Autophagy has been shown to mediate the increase in lifespan when the nematode is grown on certain foods. However, the mechanisms by which the environment leads to a change in beheviour and life history traits remain largely unknown. With this project, we would like to use high-throughput sequencing and metabolomics to build a quantitative and comprehensive map of the underlying molecular networks activated in a specific dietary environment. Furthermore, we would like to harness the genetic diversity of C. elegans to study the genetic basis of its phenotype as well as the interaction of its genome and environment in the determination of its behaviour and lifespan. For this purpose, we plan to extend the latest statistical techniques to integrate all layers of genomic and phenotypic data. Many of the genes involved in metabolism are conserved between humans and nematodes. Therefore, we expect that the findings will be relevant to human physiology.
Functional proteomic analysis of novel antiviral restriction factors in primary leukocytes 31 Jan 2017
This project aims to identify and characterise novel antiviral restriction factors (ARFs) that play key roles in preventing infection of primary leukocytes. ARFs may function by preventing viral entry or exit at the cell surface, or replication at various intracellular stages. I will focus on the subset of plasma membrane (PM) ARFs, which will be identified by two properties: interferon (IFN) induction and virally-induced downregulation. For this I will employ tandem mass tag-based MS3 mass spectrometry, enabling quantitation of PM proteins in primary leukocytes. Key Goals: 1. Use IFNs and infection with two important human pathogens, human cytomegalovirus and HIV as a functional screen to identify novel cell surface ARFs 2. Investigate how these ARFs inhibit viral infection, and how are they targeted for destruction by viruses. The use of IFN as part of the functional screen will additionally enable exploration of the difference in effects between IFNalpha, beta and lambda at the PM, a subject which is currently surprisingly poorly understood. This will provide important insights into human immunity in its own right. Understanding how viruses interacts with and targets ARFs for destruction will have important implications for therapy.
The Ketone Diet and Embryological Development; Examining the cellular variations in brain and spinal cord precursor cells in a ketogenic supplemented cell culture model 27 Apr 2017
The ketone diet (KD) replaces glucose for ketone bodies as the primary brain fuel by reducing carbohydrate and increasing fat and protein intake. The diet is growing in popularity and many women of childbearing age are choosing the ketone diet for greater long-term weight loss results. Some data suggests that KD during pregnancy results in foetal anatomical abnormalities, predicting organ dysfunction post-natally. This study will evaluate the potential cellular effects of beta-hydroxybutyrate (ketogenic) supplementation on neural precursors and their subsequent lineage potentials during central nervous system (CNS) formation in a C57B6 mouse cell culture model. Vimentin and nestin are present on all neural precursors. Upon differentiation to astrocytes, these proteins are down-regulated in exchange for increased expression of brain lipid binding protein (BLBP) which is strictly expressed on mature astrocytes. The study will examine expression of these and other biomarkers in an effort to observe abnormalities and understand the mechanisms behind ketosis induced alterations in CNS cell growth. The final goal is to determine if KD during embryological development exerts an effect on cell lineage and phenotype. Results will provide information to educate women and health professionals considering KD.
Optimisation of novel small molecule antivirals. 27 Apr 2017
Respiratory syncytial virus (RSV) causes severe bronchiolitis in susceptible populations, particularly babies and the elderly and is responsible for one-third of acute lower respiratory tract infection related deaths in infants less than one year of age. There is currently no vaccine. This project will use open source cheminformatics and bioinformatics hosted at Elixir UK, together with HEp2 and HepG2 model cell assays of a set of novel inhibitors that have been found to be effective against the virus to improve their solubility, toxicity and distribution profile to lung tissue and stability in the body. Inhibition of host protein DDX3 that the virus is obliged to use prevents the expression of viral proteins and reduces severity of RSV in our pre-clinical studies. Closely structurally related inhibitors are active against very serious infections including dengue and West Nile virus. They have potential to become broad-spectrum antivirals and hence of relevance to hospitals in the UK as well as to global health. We will: 1. Identify antiviral - protein transporter partnerships. 2. Identify and acquire commercial inhibitors of these transporters. 3. Use these inhibitors to test the hypothesis that the antivirals are transported by these proteins in suitable liver and lung cell models.
Use of tDCS in traumatic brain injury patients to modulate brain network and cognitive function 27 Apr 2017
Good cognitive control requires efficient brain network activity. The posterior cingulate cortex (PCC) is an important node within the Default Mode Network (DMN). The DMN shows deactivation on functional MRI (fMRI) during tasks requiring externally directed attention. Abnormal activation of this area is observed in TBI patients, and is related to poor cognitive function >. However, this area is not homogenous in its function, with the dorsal PCC thought to be involved in coordinating task-relevant changes in brain network activity >. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique. TDCS can modulate cognitive function and has also been seen to modulate brain network activity >. There have been no studies of its effects on brain network activity in TBI patients. This study will test whether tDCS can improve cognitive control in TBI patients and whether it does so by brain network function, specifically whether it differentially modulates activity within the PCC. Key goals - To test the hypothesis that: 1)tDCS in TBI patients can modulate cognitive function 2)tDCS in TBI patients can modulate brain network function 3)The modulations in brain network function are related to any modulates in cognitive function
Internal daily timekeeping systems known as circadian clocks are used by all types of organisms to regulate their metabolism. For example, the clock-controlled scheduling of food intake and use affects health and longevity in both mammals and insects. Time-restricted or nutrient-restricted feeding improves the health of both mice and fruit flies (Panda, Science 2016). The period gene, which plays a key role in the circadian clocks of animals, provides a link between daily timekeeping and metabolic health. Flies lacking the period gene store less glycogen and triglycerides in spite of ingesting more food and are, therefore, more sensitive to starvation. I propose to test where and how the period gene provides this metabolic function. In particular, I will ask whether its role in starvation resistance is due to its control of sleep/wake rhythms or its function in periperhal clocks of metabolic tissues such as the fat body. Moreover, Dr Wijnen's laboratory recently showed that the period gene is induced at colder temperatures (Goda et al., Proc Biosci 2014) and I will test whether period-mediated starvation resistance is found preferentially at colder temperatures.
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.
Hepatic fibrosis is a chronic liver disease associated with the accumulation of scar tissue caused by the excessive deposition of extracellular matrix (ECM) proteins. The Activation of hepatic stellate cells (HSCs) is the initiating event in liver fibrosis, and as such uncovering the molecular determinants behind this activation is of great importance in understanding the disease. The expression of UCHL1, a deubiquitinase enzyme, is dramatically elevated upon hepatic stellate cell (HSC) activation and is involved in the regulation of HSC proliferation, however the precise targets of UCHL1 in this context is unclear. UCLH1 has recently been identified as a HIF1 alpha deubiquitinase which causes increased HIF1 activity under normoxic and hypoxic conditions by disrupting the degradation of HIF1 alpha. Preliminary data has suggested that HIF1a levels are elevated in activated HSCs and this activation is dependent on UCHL1. This project aims to build on these findings with the following aims - 1. Examine relationship between UCHL1 and HIF1 exploring the contribution to the fibrotic phenotype. 2. Examine effects of elevated UCHL1 and HIF1 on cellular proliferation. 3. Analyse markers of fibrosis and HIF activity.