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The Wellcome Trust

Results

The PE and PPE proteins of Mycobacterium tuberculosis and Mycobacterium bovis: exploring their potential as variable antigens. 13 Dec 2005

The PE and PPE proteins of Mycobacterium tuberculosis and Mycobacterium bovis are encoded by large, multigene families which account for approximately 10% of the genome. Although the function of these proteins remains unclear, they are widely speculated to represent a source of antigenic variation, and thus a means for these pathogens to evade host immune defences. The overall aim of the proposed study is to determine whether the PE/PPE proteins do indeed represent variable antigens. Specifically, I will test the hypothesis that the pattern of PE/PPE expression changes during the course of infection and that this in turn modulates the host immune response. After characterising PE/PPE expression profiles in vitro, I will use two experimental models: infection of mice with M. tuberculosis, and infection of cattle with the closely-related M. bovis to examine in vivo expression and T cell recognition. These models are well-established in the sponsoring and collaborating laboratories and there is evidence in both systems that the bacterial phenotype and the immune repertoire change over the course of infection. In parallel with this in vivo approach, I will investigate the control of PE and PPE expression by identification and characterization of relevant transcriptional regulators in M. tuberculosis.

Amount: £490,127
Funder: The Wellcome Trust
Recipient: Imperial College London

Quantifying the development of neural progenitor polarisation 27 Apr 2017

Apicobasal polarity plays a fundamental role in the defining functional features of neural progenitors during the early stages of embryonic development. The apical pole in neural progenitors is specialized for multiple rounds of progenitor divisions, resulting in brain growth, where as the basal pole forms the environment where neuronal differentiation will occur. However, it is not well understood how the apicobasal polarity of neural progenitors is established. During the project, we will test a hypothesis which suggests that apicobasal polarity is progressively generated and can be monitored by quantifying a Cdh2 protein gradient along the apicobasal axis in neural progenitors. A key goal will be to determine the distribution of the Cdh2 protein over time during neural progenitor polarization. To do this we will make three-dimensional time-lapse movies of developing neural primordium in zebrafish embryos that express a transgene Cdh2-GFP. The transgene containing GFP will make it possible to visualize the distribution of the Cdh2-protein during progenitor polarization. Quantification will be done using FIJI image analysis software.

Amount: £0
Funder: The Wellcome Trust
Recipient: King's College London

Making memories in the mushroom bodies. 23 May 2011

Kenyon cell (KC) output synapses in the mushroom body (MB) lobes are the postulated sites in the fly brain where aversive olfactory memories are stored as a result of reinforcing dopamine (DA) action. However, the connectivity between KCs and the relevant DA neurons of the PPL1 cluster remains to be determined. The proposed project will examine the innervation patterns of PPL1 neurons to the MB lobes. Single KCs and single PPL1 neurons will be labelled and their synaptic contacts imaged by S TED microscopy. This will shed light on the long-standing question of whether KC output synapses are tripartite structures. In a second aim, I will analyse DA modulation of synaptic weights at KC output synapses. Stimulating KCs via a patch pipette, and DA neurons by light-activated ion channels, will allow me to monitor changes in KC synaptic weights optically, using synaptopHluorin or synaptically localised calcium probes. I will next study the metaplastic regulation of KC output synaps es, i.e. the regulation of the relevant DA neurons by the neuropeptide dNPF, which is a critical factor signalling the animal's internal state of hunger. These results will resolve mechanisms underlying the motivational control of memory retrieval.

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

Cancer Care. 10 Apr 2013

We have unprecedented access to UCLs Cancer Institute and Cancer Hospital, allowing us to follow ground-breaking trials from the lab to the ward; intertwining life and death stories of people affected by cancer with those of the dedicated researchers working to find a cure. Following 4-5 cancer patients we will join them as they embark on clinical trials. One of many examples is Dr Martin Pule, who is running the cellular immunotherapy CHILDHOPE trial. Dr Pule is engineering chimeric artific ial receptors to create anti-CD19 CAR augmented donor leukocyte infusions to specifically target and destroy cancer cells in patients with B Cell Leukemias. Although Martin will explain the science to the patient, for the audience to fully understand the science it is imperative to use CGI to take them inside the engineering process at a molecular level. Similarly, UCLs combined PET/MRI scanner (unique in the UK) means tumours can be visualized in a way not previously available. But we need render these images in 3D to make them friendly to the viewing audience. The film will use the unique precinct provided by this highly integrated Hospital and Institute to interweave stories of various examples of cutting edge science being used to save or prolong lives, and in some cases cure patients of their cancers completely. CGI will be used to break down the jargon used by the clinicians, allowing the viewer to appreciate the complex and astounding biomedical technology being deployed deep inside these patients bodies.

Amount: £30,000
Funder: The Wellcome Trust
Recipient: True Vision Productions

A study of the interactions between proteins involved in chromosome segregation in Bacillus subtilis using the yeast-two-hybrid system 27 Apr 2017

During sporulation in the bacterium Bacillus subtilis, one of the sister chromosomes is translocated into the developing prespore. This mechanism is a useful model for studying chromosome segregation, a process which is vital in all organisms. The exact mechanism of chromosome segregation in sporulating B. subtilis is not fully understood. A protein complex, involving many proteins including Soj, Spo0J, MinD, MinJ, RacA, ComN and DivIVA, is known to anchor the origins of the sister chromosomes at opposite cell poles. We propose to test the direct interactions between members of this protein complex using yeast-two-hybrid assays. To begin with we will test interactions between the proteins Soj, Spo0J and MinD. Each of these are known to form dimers, and results from genetic and cell biology studies show that interactions between Soj-Spo0J and Soj-MinD are important for the anchoring of the chromosome origins to the cell poles. These latter interactions have not been shown directly and we aim to test these in this project. The project will hopefully move on to test further protein interactions in the complex, including those with RacA and ComN. Any interactions observed between these proteins will further our understanding of chromosome segregation in B. subtilis.

Amount: £0
Funder: The Wellcome Trust
Recipient: Newcastle University

Next generation engineered T-cell therapy for brain lymphoma 23 Nov 2015

Most patients with aggressive brain lymphoma die of their disease. T-cells are white-blood cells that are part of our immune system. T-cells can be imagined as "robots" moving through the body on a "seek-and-destroy" mission against virus infected cells. T-cells do not normally attack lymphoma cells, only infected cells. However, it is possible to genetically engineer T-cells taken from a patient's blood so they now recognize lymphoma cells. These engineered T-cells are called "CAR T-cells" and once they are injected back into the patient, they find and kill lymphoma cells. Dr Martin Pule at University College London will test a CAR T-cell treatment for aggressive brain lymphoma in a clinical study. While CAR T- cells may be good treatments for lymphoma outside the brain, treating brain lymphoma is harder: the brain is more difficult to reach than other parts of the body. Additionally, when CAR T-cells work quickly, they cause inflammation which the brain may not tolerate compared with other organs. The project plans to engineer CAR T-cells in an advanced way so the team can track them using a special MRI scanner and control how quickly they work with a drug. This will allow to safely and effectively develop this new treatment.

Amount: £2,733,673
Funder: The Wellcome Trust
Recipient: University College London

Mechanisms orienting chromosomes in mitosis and meiosis. 07 Jul 2015

The overall theme of my research is to understand molecular mechanisms of chromosome segregation. Altered chromosome number (aneuploidy) causes miscarriages, infertility and birth defects and is a characteristic of cancer. During mitosis, duplicated sister chromatids are pulled apart to produce identical daughter cells. Meiosis generates gametes through two consecutive segregation events: maternal and paternal chromosomes are separated in meiosis I and sister chromatids are segregated during mei osis II. Accordingly, sister kinetochores attach to microtubules from opposite poles in mitosis and meiosis II (bioriented), but to the same pole during meiosis I (monooriented). How these distinct orientations are specified and safeguarded remains poorly understood. We previously demonstrated that the chromosomal region surrounding the kinetochore, the pericentromere, plays multiple underappreciated roles in directing and monitoring chromosome segregation. I now propose to build on these discov eries and elucidate the molecular underpinnings of the interplay between pericentromeres and kinetochores to understand how chromosomes are oriented in mitosis and meiosis. We will use budding yeast to uncover fundamental mechanisms; to reveal conserved principles and vertebrate-specific regulation we will initiate studies on Xenopus oocytes. Specifically we aim to: (1) Determine how the pericentromere is functionally and geometrically organised to orient chromosomes; (2) Understand how the peri centromere acts as a signalling platform to monitor and regulate chromosome segregation; and (3) Reveal the adaptations to kinetochores which direct the specialized pattern of chromosome segregation during meiosis. Ultimately, we will gain an in-depth molecular knowledge of how kinetochores and pericentromeres confer directionality to chromosome movement in mitosis and meiosis.

Amount: £2,147,752
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Acentrosomal spindle formation in female meiosis. 28 Mar 2007

Accurate segregation of genetic material is essential for life. A bipolar spindle mediates this process in eukaryotes. Centrosomes, which nucleate microtubules, dictate spindle formation during mitosis. However, the formation of a bipolar spindle takes place without centrosomes in female meiosis in most animals. Despite its importance for human health and understanding basic cellular function, little is known about the molecular mechanism of this spindle formation in female meiosis in vivo. The long-term goal is to understand this acentrosomal spindle formation at the molecular level. I propose to study three key aspects of female meiotic spindle formation, namely, spindle pole organisation, chromosome-mediated spindle assembly and the regulatory network controlling spindle formation by applying genetics-led multidisciplinary approaches. Key goals include determining the assembly mechanism and function of the pole scaffold, establishing the molecular basis of multiple chromosome s organising a single spindle without centrosomes, and systematically identifying new proteins required for spindle formation to uncover their interactions. All together these studies will lead to understanding the regulatory network of acentrosomal spindle formation in female meiosis.

Amount: £1,447,263
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Medicine during the heroic age of Antarctic exploration. 08 Nov 2007

I plan to study: The doctors who accompanied expeditions during the Heroic Age of Antarctic exploration. This will include their careers before and after the expedition The drugs and equipment taken The diseases and injuries that occurred and their treatment. This will include psychological problems The research undertaken by the doctors. Some of this is physiological research on the expedition members and some was in other areas (eg bacteriology, parasitology) An exploration of the role of the doctor on these expeditions eg the doctor usually had responsibility for food and would have had to treat the dogs (on expeditions that took dogs) The other contributions of doctors to the expeditions eg Wilson as an artist, Atkinson s leadership after Scott s death and Mackay s participation on the first ascent of Mount Erebus and discovery of the South Magnetic Pole. Preliminary reading has identified some other related topics eg The history of hypothermia (why was it not recognised as a problem?) The uses of medicinal brandy The role of medical students (one medical officer was a medical student and there were at least 5 other students or ex-students as members of different expeditions)

Amount: £27,079
Funder: The Wellcome Trust
Recipient: Plymouth Hospital NHS Trust

Molecular mechanisms regulating the kinetochore-microtubule interaction in mitosis. 06 Dec 2011

To maintain their genetic integrity, eukaryotic cells must segregate their chromosomes properly to opposite poles during mitosis. The unravelling of the mechanisms that ensure high-fidelity chromosome segregation should improve our understanding of various human diseases such as cancers and congenital disorders (e.g. Down syndrome), which are characterized by chromosome instability and aneuploidy. Sister chromatid segregation during mitosis mainly depends on the forces generated by microtubules that attach to kinetochores. For proper chromosome segregation, kinetochores must interact with spindle microtubules efficiently and this interaction must develop correctly to achieve proper chromosome segregation in the subsequent anaphase. Our research goal is to discover and characterize the molecular mechanisms by which cells regulate these vital processes of kinetochore-microtubule interactions. We investigate the kinetochore-microtubule interactions in budding yeast because of the amenable genetics and detailed proteomic information in this organism. The basic principles of kinetochore-microtubule interactions are similar in yeast and vertebrate cells. Because of this conservation of basic mechanisms, it is likely that results from the yeast system will be of direct relevance to chromosome segregation mechanisms in human cells.

Amount: £3,848,259
Funder: The Wellcome Trust
Recipient: University of Dundee

Envy as Pathology: Body, Ethics, and Culture 30 Apr 2016

The work aims to investigate the singular place that envy holds among the negative emotions. Theorists of the eighteenth century appreciate the existence of all passions within human nature, both positive and negative ones, but find no ‘natural’ reason for envy as it is necessary neither to our safety, as anger can be, nor to our sense of worth, as resentment. Closely connected to this discourse of ‘unnaturalness’ is the association of envy to pathology. A long-established tradition that can be traced, in literature, as far back as Ovid’s Metamorphoses describes envy in pathological terms. These often include descriptions of ‘an unnatural’ ,’ inhuman’, ‘emaciated’ look and use of the terms ‘leaden’, ‘livor’ and paleness. In addition to the ill effects on the individual, the presence of envy within society is a major cause of concern for a culture that seeks to define moral sense and goodness. In light of the above the project aims to investigate the physiological reasoning behind the effects of envy on the individual, to determine the key terms that help form the pathological discourse of envy and, ultimately, to unveil the foundation of the representation of envy as a source of pathology within society.

Amount: £1,180
Funder: The Wellcome Trust
Recipient: No Organisation

Mechanisms directing homolog bi-orientation during meiosis I. 21 Apr 2009

Erroneous chromosome segregation in me1os1s results in gametes carrying an incorrect number of chromosomes. This can cause infertility, miscarriages, and birth defects such as Down's syndrome. To understand how these arise, a better understanding of how chromosomes are segregated is needed. Unique to meiosis is the segregation of maternal and paternal chromosomes or homologs towards opposite spindle poles. However, how homolog bi-orientation is achieved is unknown. The main goal of my study will be to elucidate the mechanism by which homologous chromosomes obtain bi-orientation during meiosis I. For this study I will use budding yeast, because its meiosis is relatively simple yet conserved. Specifically, the aims of my study are: 1) Establish the role of two kinetochore proteins Ctf19 and Mcm21 in ensuring proper segregation of homologous chromosomes during meiosis. 2) Identify proteins involved in homolog bi-orientation and determine their mechanism of action.

Amount: £142,336
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Spatial and temporal control of mitotic commitment 05 Apr 2016

We will use fission yeast to study the decision to divide and how it is re-wired following stresses. Cdk1-Cyclin B activation promotes polo kinase activity to further enhance Cdk1-Cyclin B activity. Events on the spindle pole body (SPB) are key to this feedback loop. Local activation on G2 SPBs is later enhanced to drive commitment to mitosis. Recruitment of protein phosphatase 1 (PP1) to the SPB scaffold protein Cut12 represses activation on late G2 SPBs. Abolition of PP1 recruitment defines an early, PP1 insensitive, portion of G2 (Stage1). We want to determine how the transition from Stage1 to Stage2 is set and what regulates PP1 recruitment within Stage2? Identification of Cut12 partners will be complemented by phosphorylation site studies to determine how the loop is later enhanced to promote mitosis. Mutations in a second SPB component, Sid4, supress Cut12 deficiencies and change the timing of division after heat stress. We will characterise these Sid4 functions and study how and why the configuration of mitotic commitment controls changes after heat stress. Sid2-Mob1 kinase regulates PP1 recruitment to Cut12 during Stage2 and is activated following oxidative but not heat stress, enabling us to compare the impacts of distinct stresses on switch re-configuration.

Amount: £1,754,813
Funder: The Wellcome Trust
Recipient: University of Manchester

The ribbon synapse in inner hair cells of the adult mouse cochlea. 07 Oct 2010

This project addresses the cellular mechanisms of synaptic transmission of information from adult sensory inner hair cells related to the dynamic range problem . It will use mouse models, but focussing on adult hair cells. JFA has recently developed a method for making whole cell recording relatively easily from adult cells and imaging their ribbon synapses, by leaving the cells in situ, in the temporal bone. There is no upper age limit to the cells which can be studied and so removes the tec hnical issues of extrapolating from early stage data, bridging the gap to ages where nerve fibre recordings are made. The project is designed to resolve cellular mechanisms of sound level segmentation that occurs between different subpopulations of fibres. Fast multiphoton laser scanning microscopy will be used to quantify a gradient of calcium and vesicle dynamics at multiple ribbon sites in the basal pole. The structural basis of this (planar) cell polarity will be studied in wild type and in mutant mice with PCP abnormalities and with ribbon synapse protein mutations. Mouse models of hearing loss will be used to obtain insights into age-related neural changes and to provide a deeper understanding of some audiological measures of presbyacusis.

Amount: £299,377
Funder: The Wellcome Trust
Recipient: University College London

Rate of degradation of Aurora kinases 27 Apr 2017

Aurora kinases regulate the segregation of chromatids and are key enzymes in mitosis. AurA assembles the spindle poles; AurB faciliates cytokinesis of the daughter cells. Their ubiquitin-mediated degradation regulates the transition from mitosis back to interphase and show different kinetic profiles: AurA degrades 5-fold faster than AurB. Previous unpublished data from the Lindon lab showed that a AurA1-133-AurB78-345 chimera tagged with GFP degraded with similar kinetics to full-length AurA. Therefore all of the information required for rapid degradation of AurA resides in the 1-133 region. We plan to construct various AurA-AurB chimeras and express them in dividing cells. We will carry out a quantitative analysis of degradation of these chimeras using single-cell fluorescence timelapse assays. We aim to identify the the minimal sequence within AurA1-133 required to specify accelerated degradation kinetics. We plan to compare this with other known regulatory sequences for ubiquitin-mediated degradation ('degrons') and to gain a better understanding of how AurA engages the destruction machinery to affect its degradation kinetics. This information can assist the design of new therapeutic tools, such as PROTACs, that harness ubiquitin-mediated degradation to destroy targets not druggable by conventional means.

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

Pathogenomics of Staphylococcus aureus: identification of novel virulence traits. 20 Nov 2012

Despite a wealth of recent work, the genetic attributes that determine the pathogenicity of Staphylococcus aureus remain poorly understood. Breakthroughs in genomic sequencing and in-vivo modelling have allowed development of a novel approach to identify genetic determinants of disease. Using a high-throughput model of systemic S. aureus infection in zebrafish embryos, I have screened closely related strains for differences in pathogenesis in the model. We have proved the principle of this a pproach as clear differences in pathogenesis can be determined between related strains and genomic comparison has revealed candidate genomic fingerprints associated with pathogenesis. These are currently being investigated to identify the constituents of the pathogenome. The proposed research allows us to scale up this project and screen prospectively collected hospital acquired methicillin-resistant S .aureus strains from across the country, to examine strain phenotype in the zebrafish model. A pplying whole genome sequence analysis, I will build a database of putative virulence determinants and subsequently test their role in pathogenesis. This will inform the use of a mammalian model of infection. The output from this model will have wide applications such as the proposal of new vaccine targets and the realisation of anti-staphylococcal therapies tailored to individual strains and therefore patients.

Amount: £222,695
Funder: The Wellcome Trust
Recipient: University of Sheffield

Recycling polarity mechanisms controlling stem cell polarity in consecutive divisions in the developing Drosophila central nervous system. 13 Nov 2012

Asymmetrically dividing Drosophila neuroblasts keep the cell polarity and division axis robustly oriented over many cell cycles. How positional information is generated to repeatedly polarise theses cells in an oriented manner between different cycles is unknown. As the mRNA of key asymmetry genes is apically localised, I aim to study if localised transcripts are polarity landmarks in neuroblasts. I further aim to study the level of mRNA localisation in these stem cells with the aim to identify centrosomally localised transcripts that I suspect to carry cell fate information. Cell fate information is also transmitted by differential segregation of cortex bound determinants from neuroblasts to differentiating daughter cells. How the mitotic cortex gets spatially organised into compartments that carry determinants remains unknown. I hypothesise that lateral diffusion barriers or a specific distribution of phospholipids organise membrane asymmetries in mitosis. Asymmetries of the me mbrane can also be detected in interphase at the basal neuroblast cell pole, evident with a specific structure overlying the last-born daughter cell. I plan to test if daughter cells send signals to the stem cell contributing to stem cell polarity to understand how the orientation of stem cell polarity is maintained from one cell cycle to the next.

Amount: £950,354
Funder: The Wellcome Trust
Recipient: University of Dundee

In vitro reconstitution of spindle bipolarity. 31 Oct 2012

The proposed study aims to answer the key question of what constitutes the mechanochemical core of the mitotic spindle using an in vitro reconstitution approach. Supported by microfluidics, mathematical modelling and experiments in Xenopus egg extracts, I will develop a novel experimental setup, consisting entirely of purified proteins, to test the central hypothesis of how a combination of spatially restricted microtubule nucleation and antagonistic motor activities generates symmetric bipolar spindles of appropriate size. To mimic the role of chromatin and locally promote microtubule formation, I will engineer different molecular gradients inducing microtubule polymerisation around functionalised glass beads, based on the Aurora B and the Ran pathways. Analysing the biophysical properties of these gradients will explain how high microtubule densities form in the proximity of chromosomes in vivo. Second, I will evaluate the role of the main microtubule crosslinking motors, the plus-en d-directed kinesin-5 and the minus-end-directed kinesin-14, in generating bipolar topology. By combining here, for the first time, the anti-parallel microtubule sorting potential of kinesin-5, the pole focussing ability of kinesin-14 and the continous turnover of locally generated microtubules, I will elucidate the relative contribution of each factor in ensuring a bipolar spindle-like state instead of mono- or multi-polar microtubule assemblies.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: Cancer Research UK

Public Engagement for the Thailand Major Overseas Programme 2015 – 2020 (supplement) 30 Sep 2017

The Wellcome Trust Thailand Major Overseas Programme’s central aim is to improve health and reduce the human disease burden in the developing world. Its strategic objectives are: The development of people and institutions: mentoring world-class clinicians and scientists Disseminating high-quality research evidence, locally and globally Strengthening governance, management and financial planning, thus building operational excellence in tackling tropical diseases Public engagement (PE) & outreach with the communities who host us, in turn inspiring and involving current and future generations in medical research This application pertains to the last strategic objective of the programme. The "must-do" engagement activities are part of the Thailand Major Overseas Programme core grant 2015 -2020. In April 2016, the programme received a PPE award (£673,180) to build a core PE team and to pilot some "smart-to-do" and "wise-to-do" activities in years 1 and 2 of the core grant and with a view of shaping the PE activities for years 3 to 5. The core PE team is led by Ass. Prof. Phaik Yeong Cheah, who is co-PI on this application. This application is for PE activities in years 3 to 5 based on learnings from our pilot projects and to grow further the PE capacity within the programme.

Amount: £454,843
Funder: The Wellcome Trust
Recipient: University of Oxford

Probing the role of outer membrane transport processes in host-­pathogen interactions using computational and single-­molecule biophysical approaches. 31 Jan 2017

The outer membrane (OM) of Gram-negative bacteria is a significant protective barrier. It is composed of an inner leaflet of phospholipids and an outer of lipopolysaccharide (LPS) with OM proteins (OMPs) that span the membrane. Recently OMPs have been shown to be inserted at discrete and non-uniform locations across the membrane, where they remain due to restricted lateral diffusion. These ‘islands’ are pushed to the poles by cell growth, with new material inserted at mid-cell. OM turnover during bacterial growth may have a role in immune system evasion. One key mechanism regulating human immune responses is the assembly of complement components on the OM nucleated by immunoglobulin binding. This process can lead to lysis of bacteria through insertion of pore complexes in the OM. Complex formation depends on localised clustering of antibodies, which is constrained by the location and molecular diffusion of antigens in the OM. In this project we will use computational and single-cell biophysical techniques to test our hypothesis that spatial confinement of LPS and OMPs near their insertion sites influences activation of the antibody-mediated complement pathway. We will test our hypothesis in Escherichia coli and Salmonella typhimurium, where immune evasion has a key role in pathogenesis.

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