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Results

A temporary exhibition on cancer: Exploring understandings of and relationships with cancer 18 Jun 2018

The temporary exhibition on cancer aims to showcase how understandings and experiences of cancer have changed over time including addressing the medical, social and ethical complexities associated with current research developments. This includes an examination of the impact of developments in scientific research such as genomic medicine on perceptions of what cancer is, how it is managed and what it might look like in the future. The researcher embedded in the project team will conduct the research and development that would shape the overarching narrative, content and interpretation strategy and learning outcomes of the exhibition; with the option of focusing on a key area identified during the development process, for example, exploring challenges and opportunities associated with generating and interpreting genomic data. This would include interviews with those affected by cancer as well as experts in the field of cancer research including scientists, data specialists and healthcare practitioners. The researcher will also develop a public participation project which would take the form of a public consultation exercise centred on the contemporary patient experience, with the objective of generating public dialogue and policy recommendations for relevant organisations.

Amount: £19,425
Funder: The Wellcome Trust
Recipient: University of Leeds

Functional characterization of a novel KMT2D-related developmental disorder 31 May 2018

The proposed research uses standard molecular biology, protein purification and biophysical structural analysis methods in a focused series of experiments that comprise a complete 6-week project. This builds on existing molecular genetics studies that have identified novel missense mutations in KMT2D (also known as MLL2) as the cause of a unique phenotype (renal tubular dysgenesis, choanal atresia and athelia). Previous studies have identified KMT2D mutations as a major cause of Kabuki syndrome, a comparatively common autosomal dominant congenital mental retardation syndrome. The missense mutations occur in a central region of the KMT2D protein (2841-3876) that does not have variants associated with Kabuki syndrome. This central region contains a series of coiled-coil domains that are likely to mediate protein-protein interactions. However, the effect of the missense mutations on KMT2D structure and interactions is completely unknown. This project will determine the structure-function relationships between KMT2D and a unique phenotype that are likely to be caused by altered protein-protein interactions, as well as describing the broader genotype-phenotype correlations in this important gene. The approach described in the proposal is the only tractable way to understand possible structure-function relationships, given the large size of the gene and encoded protein.

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

Grb2-mediated regulation of miRNA maturation in the basal state. 30 Sep 2018

Cancers develop as a result of many interacting factors. Two such factors are cell stress and microRNA (miRNA) expression. Cell stress causes fluctuations in protein levels, which can perturb the proper functioning of the cell. miRNAs silence specific genes, and therefore can induce changes within the cell which cause them to become cancerous. However, little is known about how miRNA expression is altered. I aim to investigate a novel mechanism of miRNA regulation, which may be perturbed by cell stress. I will determine how the levels and activity of key components in miRNA biogenesis are altered in cells expressing different proteins and which have been subject to different stress conditions, using a range of in vitro, cell-based and biophysical approaches. I will also perform several screens to identify key microRNAs regulated by this mechanism, and how their expression changes with cell stress. This work will reveal new avenues for cancer therapy and help us to target cancer with a fresh perspective.

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

Brain regulation of feeding behaviour through mitochondria fission 21 May 2018

Obesity causes brain insulin resistance and prevents the brain from regulating metabolic responses, maintaining energy balance and controlling the nutritional status of an individual. Restoring the brain’s ability to modulate metabolic functions could be an important intervention to prevent the negative outcomes of obesity and diabetes. The Dorsal Vagal Complex (DVC) in the brainstem senses insulin to regulate glucose metabolism, food intake and body weight in rodents. Three days of high-fat diet feeding is sufficient to completely disrupt the insulin response in the DVC, thus causing an increase in blood glucose levels and excessive eating. Recently, I discovered that increased mitochondria fission and ER stress in the DVC can cause insulin resistance and affect the ability of the DVC to regulate blood glucose levels. I aim to understand whether increased mitochondria fission in the DVC can affect food intake and body weight in rats. Using in vivo and in vitro experiments, I aim to uncover the mechanism by which changes in mitochondria shape and size affect DVC insulin sensing and eating habits in rodents. This project could lead the way for the development of novel approaches that target the brain to regulate food intake and body weight in obese subjects.

Amount: £99,948
Funder: The Wellcome Trust
Recipient: University of Leeds
Amount: £148,505
Funder: The Wellcome Trust
Recipient: University of Leeds

Suicide Voices: Narratives of Trauma in the Globalised Workplace. 17 Sep 2015

This project examines the 'epidemic' of suicides within the globalised workplace during the 2000s and asks why work or conditions of work can push some individuals to take their own lives. It aims to bring a critical humanities perspective based on a close reading of suicide testimonies in their social, cultural and economic contexts, to bear on emerging public health research on the rise of economic suicides internationally. The project investigates what suicidal individuals' own testimonies ca n tell us about the social conditions that motivate self-killing in work and therefore provides a critical alternative to current epidemiological approaches to suicide in public health. Building on an emerging collaboration between humanities and public health researchers in the UK and France, the project breaks new ground in its interdisciplinary, methodological and international scope. It has three main goals: 1. To create a new interdisciplinary and transnational research network that expand s and deepens our understanding of the workplace suicide crisis internationally. 2. To publish two peer-reviewed articles that draw on the projects findings and target both English and French-speaking academic audiences. 3. To develop a joint funding application (with Prof Martin McKee) for the Wellcome Trust's Senior Investigator Awards.

Amount: £46,548
Funder: The Wellcome Trust
Recipient: University of Leeds

Biological NMR for Challenging Biomedical Problems. 25 Jun 2014

Funds are requested to purchase a new generation of NMR console and cryogenically cooled probe for our outdated 750MHz NMR Spectrometer (funded in 2001 by WT) which has reached the end of its useful lifetime. Our current instrument is inefficient, unreliable and incapable of modern NMR experiments. These purchases will transform NMR capability in the Astbury Centre for challenging biomedical projects that require the sensitivity, artefact suppression and stability only possible with modern elect ronics. For 443k of WT funds, and University investment of 647k, the new equipment will enable cutting edge biological NMR techniques, including: 1) analysis of protein dynamics (via relaxation experiments); 2) structural characterization of 'invisible', lowly-populated protein conformations (via relaxation dispersion experiments); 3) characterization of large supramolecular assemblies and membrane proteins (via multidimensional methyl NMR); 4) time-efficient structural calculations of small (20kDa) proteins (structure in 1 week); 5) real-time kinetic measurements of folding and enzymatic activity (via rapid acquisition techniques); 6) analysis of unstable samples (via fast techniques allowing data acquisition up to 100 time faster) and materials available only at low concentration (10-100 uM); 7) analysis of samples in biological buffers (up to 1M salt) 8) time-efficient ligand screening (via rapid data acquisition and sample changer).

Amount: £443,015
Funder: The Wellcome Trust
Recipient: University of Leeds

Multifunctional imaging of living cells for biomedical sciences. 25 Jun 2014

The goal of this research is to develop and use a new confocal microscope, and exploit its much improved sensitivity and spectral capabilities, as well as its ability to perform fluorescence correlation spectroscopy to open up new areas of research. The new confocal microscope will be placed in our central Bio-imaging facility, which supports over 60 different research groups across the Faculties of Biological Sciences (FBS), and Medicine and Health (FMH), of whom the Wellcome Trust funds (o r has funded in the past) a substantial number. The research includes a diverse range of applications including medical engineering (WELMEC: Prof. Eileen Ingham), neuroscience (Nikita Gamper and others in FBS and Medicine), viruses and infection (Mark Harris, Nicola Stonehouse and others) and basic cell biology research underpinning health (Michelle Peckham, Colin Johnson, Rao Sivaprasadarao and others), the main applicants of this proposal. In addition, the new microscope will support the r esearch of many others including those undertaking cardiovascular research (David Beech and many others in FMH and FBS) and research into protein aggregation diseases (Sheena Radford and others in FBS).

Amount: £192,763
Funder: The Wellcome Trust
Recipient: University of Leeds

Harnessing the molecular-scale resolution of DNA-PAINT to study the structural basis of electrical signals of the healthy and arrhythmic hearts 12 May 2017

Single molecule localisation microscopy (SMLM) has revolutionised our understanding of signalling microdomains in many biological systems. Among such molecular systems, are arrays of gap junction (GJ) channels paving the fundamental electrical signalling pathways of the heart. Conventional SMLMs are yet, limited by resolution, unable to visualise individual GJ channels within their native tissue environment. One of the newest SMLM techniques, called DNA-PAINT, promises resolution of ~ 5 nm, sufficient to resolve single proteins within tightly packed arrays or clusters and to visually observe their interactions with other molecules. However, by design, this technique is not suitable for imaging complex tissues like the myocardium. This project aims to implement three possible modifications to the DNA-PAINT protocol to enable in situ optical mapping of GJ isoforms at an unprecedented single-channel-level resolution. DNA-PAINT will be further harnessed to quantify the changes in the phosphorylation states of GJ channels within the ventricular cardiac tissue exhibiting pathological electrical disturbances known as arrhythmias. Both the improved DNA-PAINT protocol and the pilot measurements on GJ remodelling will seed a larger investigation pioneering a direct, in situ correlation of the GJ nanostructure and the disturbed electrical patterns within hearts undergoing life-threatening arrhythmias.

Amount: £96,118
Funder: The Wellcome Trust
Recipient: University of Leeds

An investigation into the impact of Carbazamine on postural stability 27 Apr 2017

Gamma knife®(GK) is a stereotactic radiosurgery that can be used to treat trigeminal neuralgia(TN), without the need for pharmacological medication, and has been shown to result in patients being pain free without medication from as early as 6 months after surgery (Loescher et al, 2012). TN is a serious health issue that causes short, reoccurring sessions of intense, sharp facial pain, which has been compared to the feeling of an electric shock (Headache Classification Subcommittee of the International Headache Society, 2013). The cost effectiveness of GK has yet to be fully elucidated. Qualitative work has evaluated the effects of the drug of choice, Carbamazepine, used to treat TN, and found that patients report motor and cognitive difficulties (Zakrzewska et al, 2017). However, a more objective, quantitative investigation into the effects of Carbamazepine and GK treatment on patients with TN would allow for standardised assessment of risks and benefits and therefore make cost-effectiveness discussions more informed. This study will investigate the effects of different treatment regimens on manual dexterity tasks, where participants use a handheld stylus to interact with visual stimuli and postural stability tasks, where participants are exposed to a cognitive load and their gross motor control is measured.

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

Determining the mechanism of β-barrel assembly machinery (BAM) in bacterial outer membranes 14 Jul 2014

Outer membrane proteins (OMPs) in Gram negative bacteria are critical for bacterial survival and virulence 1 . However how these beta-barrels fold in the membrane is not well understood. The in vivo folding of most substrate OMPs relies on the function of the beta -barrel assembly complex (BAM)2, of which the key component is BamA 3, itself a beta-barrel. Here we propose to use a panoply of structural and biophysical methods to dissect the functionality of BamA and the mechanism of OMP folding. Our key aims are: 1) To investigate the hypothesis that BamA functions by lateral gating. Using a combination of disulphide linking and FRET we will determine whether lateral gating is necessary for the folding of different OMPs, and how it may function. 2) To determine how BamA function is affected by liposome size and membrane crowding, by utilising a varied subset of lipid types and comparison of substrate OMPs in folding assays. 3) To determine the importance, and role of the beta -signal of OMPs in the interaction with BamA by dynamic force spectroscopy measurements. The question of how OMPs fold represents a fundamental gap in structural biology understanding. In addition, the OMPs of Gram negative bacteria are key to their pathogenicity, therefore understanding the mechanism of BAM may present new possibilities for drug targets.

Amount: £149,973
Funder: The Wellcome Trust
Recipient: University of Leeds

Structural and functional studies in indanomycin biosynthesis 14 Jul 2014

Polyketides represent a broad and diverse class of natural products which includes many pharmaceutically-relevant compounds. Historically, identification of novel polyketides relied on natural screening methods; however, rational engineering of polyketide synthases (PKS) represents a powerful tool to create libraries of ‘unNatural’ products to be screened for novel therapeutic properties. The project’s key goals are 1) Elucidating the structure of the indanomycin PKS, starting with the first subunit, IdmL By elucidating the structure of indanomycin PKS, we will increase our understanding of the interfaces between the functional domains and the rules governing the successful rearrangement of polyketide assembly lines. 2) Engineering mutant and chimeric IdmL for the production of novel polyketides By employing synthetic biology approaches, we will investigate the potential for engineering the indanomycin gene cluster to produce novel polyketides. 3) Characterising the structure and function of the post-PKS cyclase IdmH To expand a synthetic biologist’s toolkit of natural product modifying enzymes, we aim to elucidate the structure and reaction mechanism of this novel enzyme. These goals will increase our knowledge of the assembly of the PKS complexes as well as the chemistry involved in the generation of mature polyketide and bring us closer to rational engineering of these systems.

Amount: £149,973
Funder: The Wellcome Trust
Recipient: University of Leeds

The Endless Possibilities of Rejuvenation: Hormones, Electricity and Cosmetics, c.1870-2000. 14 Apr 2014

This grant will enable initial archival scoping, mapping out the content and nature of primary historical sources relating to the history of rejuvenation treatments and therapies from the late-nineteenth century onwards. The project will focus on three key episodes in the history of rejuvenation: the use of chemical hormone treatments, the advent of domestic electrotherapy for physiological rejuvenation, and the relationship between trends in cosmetics and anti-ageing. The emphasis of the projec t will be on establishing how rejuvenation treatments were devised, manufactured, marketed and, most importantly, used. Two key historiographical themes - the gendered nature of the ageing process, and the domestication of everyday medical technologies - will underpin the three case studies of hormones, electrotherapy and cosmetics. There is much archival material held at the Wellcome Library and the Boots Archive relating to these themes, and this grant will support a thorough survey of these s ources. This research will lay the groundwork for further funding applications designed to fully realise the project in the form of a monograph, although this grant will of itself lead to a research article addressing one of the key questions as outlined in this application.

Amount: £1,745
Funder: The Wellcome Trust
Recipient: University of Leeds

Biomedical Vacation Scholarship 23 Jun 2014

Not available

Amount: £12,000
Funder: The Wellcome Trust
Recipient: University of Leeds

Generation, optimisation, validation and implementation of bacterial whole-cell biosensors for the detection of novel antibiotics 15 Jul 2013

Antibiotics remain our primary means of treating bacterial infection. Unfortunately, these agents are increasingly being rendered ineffective by theemergence of antibiotic resistance, and the problem is compounded by the dearth of new antibiotics being discovered. Given the failure of rational/synthetic approaches to antibacterial discovery, drug developers are beginning to revisit the screening of natural products from microorganisms in an attempt to identify new antibiotics. This project will address some of the major deficiencies associated with current natural product screening methodologies, particularly the failure to detect antibiotics at low concentrations or in complex mixtures. This will be achieved through generation of bacterial whole-cell biosensors that produce a quantifiable output when exposed to inhibitors of a target pathway. The O'Neill laboratory has recently created first generation biosensors for detection of inhibitors of the peptidoglycan biosynthesis pathway. This project will seek to optimize the sensitivity of these biosensors using directed evolution and synthetic biology circuits, and will generate, validate and optimize biosensors for other target pathways in the bacterial cell (e.g. protein synthesis). Once established, these biosensors will be used for high-sensitivity screening of actinomycetes and other natural product producers to identify novel antibacterial drug candidates.

Amount: £149,873
Funder: The Wellcome Trust
Recipient: University of Leeds

Probing and manipulating viral receptor-sugar interactions using novel DNA-based multivalent carbohydrate ligands. 12 Dec 2011

Our previous work suggests that tetrameric viral-binding receptors, dendritic cell receptor DC-SIGN and closely related endothelia cell receptor DC-SIGNR, employ a new strategy in interacting with viral (e.g. HIV, HCV and Ebolas viruses) surface glycoproteins via adjusting their flexible CRDs to achieve selective, high affinity binding. The key goals here are 1) to verify CRD reorganisation in DC-SIGN/R upon ligand-binding; 2) to unravel the molecular basis of different multi-sugar ligand bindin g and HIV transmission efficiencies in DC-SIGN and DC-SIGNR; and 3) to develop effective inhibitors for blocking DC-SIGN-HIV interaction and hence prevent primary infection. I will develop novel DNA-based multivalent sugar ligands where the sugars are attached to rigid DNA scaffold and therefore having well-defined and adjustable inter-sugar distances via changing the DNA scaffold length. The CRD flexibility will be studied by comparing binding affinities of receptors to different spaced sugar -ligands by calorimetry and SPR. Direct CRD movement will be investigated by measuring FRET-pair labelled CRD distances before and after ligand binding using single-molecule FRET. Molecular basis for structural difference between DC-SIGN and DC-SIGNR will be elucidated from mutagenesis studies. Inhibition efficiency of the DNA-based ligands to DC-SIGN-HIV interaction will be evaluated by competition assays in a cellular context.

Amount: £400,301
Funder: The Wellcome Trust
Recipient: University of Leeds

Coordinated use of the hepatitis C virus genome during the virus lifecycle. 04 Oct 2011

My vision is to achieve a comprehensive understanding of key events in the hepatitis C virus (HCV) lifecycle, with the ultimate goal of developing new antivirals. The research questions that underpin this vision are to define in molecular detail the processes by which the virus genome is replicated and packaged into virus particles, and determine how these events are coordinated.Specifically, I propose to exploit a combination of cell biological, biochemical and biophysical approaches, to address the following major overarching and unanswered questions: 1) What is the structure and compositionof the macromolecular complex that replicates the genome? 2) How is the viral genome packaged into nascent particles? 3) What are the mechanisms that allow the genomic RNA to be selected for either of these two processes? Addressing these questions is fundamentally important in the future development of much needed new therapies for the treatment of HCV, a pathogen which leads to long-term liver disease with a poor prognosis, infecting 3% of the global population with a further 3-4 million new cases each year. Despite the advent of candidate direct-acting antivirals targeted to HCV, treatment options for patients remain limited, in stark contrast to the situation for patients infected with HIV. Driven by remarkable progress in molecular understanding ofHIV biology, 30 different compounds are available for treatment of HIV infection; these have six distinct well-characterised modes of action and effectively control disease. The challenge is to provide HCV patients with similar therapeutic opportunities, the lesson from HIV is that this can only be achieved if underpinned by a comprehensive molecular understanding of virusbiology. Attaining this goal is at the heart of my research vision, by offering new insights into the HCV lifecycle and providing a solid platform for the development of novel chemotherapeutics, it also maps directly on to the Wellcome Trusts major challenge of combating infectious disease.

Amount: £1,610,588
Funder: The Wellcome Trust
Recipient: University of Leeds

Structural and mechanistic insights into ligand binding in P2X7 receptors. 25 Jun 2012

The human P2X7 receptor (hP2X7R) is a ligand-gated cationic channel which plays a key role in mediating a number of diverse physiological functions induced by extracellular ATP. Alteration in receptor expression and/or function is linked to pathologies including chronic pain, rheumatoid arthritis, neurodegenerative diseases and cancers, which has made the P2X7R anattractive therapeutic target to the pharmaceutical industry. A thorough understanding of the P2X7R structure-function relationship is therefore increasingly crucial to develop P2X7R ligands as therapeutics. This project aims to: 1. Produce models of the P2X7R from different species and use these models andligand docking to map ligand-receptor interactions. These models will then be used to identify a subset of residues within the hP2X7R which are key for ligand-receptor interactions. 2. Investigate the role of key residues identified from modelling and docking by combining site-directed mutagenesis and patch-clamp recording to gain insights into interactions of ATP and antagonist with the hP2X7R. 3. Determine the conformational changes in the hP2X7R between the closed and ATP-bound open states and antagonist-receptor interactions using electron microscopy. These studies will enable us to build a structural and mechanistic understanding of the hP2X7R to facilitate development of therapeutic compoundsand understanding of disease mechanisms.

Amount: £150,048
Funder: The Wellcome Trust
Recipient: University of Leeds

Development of a microfluidic device to study single cells in controllable microenvironments 01 Apr 2016

The project is coming together of two exciting areas of sciences, which we think will make a significant contribution to our understanding for the nature of basic unit of life, the cells. The first aspect is the use of microfluidic technology as a quantitative and reproducible method for monitoring individual cells. The second aspect is the research of Embryonic Stem (ES) cells representing an excellent system to study the interaction between intrinsic and extrinsic factors in cell fate decisions. The primary goal of this research is the development of a microfluidic methodology that enables study of the gene expression occurring in a single cell, and controlling the microenvironments enclosing cells. The microfluidic technology will open the possibility of exploring problems in eukaryotic cells as much of our ability to harness the potential of ES cells will depend on our ability to control interactions between the cell and the signals that determine its behaviour.

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

Design and synthesis of Inhibitors of PfDHODH: Towards a new treatment for malaria 01 Apr 2016

An estimated 3.3 billion people are at risk of malaria, with populations living in sub-Saharan Africa having the highest infection rates, resulting in ~219 million documented cases of malaria and in excess of 660,000 deaths in 2010. The treatment and control of malaria is increasingly difficult due to the spread of resistance to antimalarial drugs. This is a concern even for artemisinin-based combination therapies (ACTs)- the first-line of treatment, where there is evidence of altered parasite sensitivity in a number of countries. In order to eradicate malaria it is clear we will need new classes of antimalarial with novel mechanisms of action and defined pharmacological profile. It is reassuring that several potential drugs are entering clinical trials but their success or longevity is unknown, necessitating development of new inhibitors operating on novel targets. Work at Leeds and elsewhere has identified the enzyme DHODH as an attractive target for the development of new antimalarial drugs. This project will apply structure-based drug design and synthesis to produce drug-like DHODH inhibitors as potential new antimalarial drug leads, which will then be evaluated biologically.

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