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Results

Investigating the Structure of FcγRIIa and its Interactions within the Membrane 30 Sep 2018

Human Fcgamma receptors (FcgammaRs) are proteins found on the surface of immune cells. They bind to antibodies, which are produced by the body, in response to infection. Some antibodies produced recognise their own tissues and are found in many diseases, including rheumatoid arthritis and lupus. It has been shown that genetic changes in the FcgammaRs are found more frequently in rheumatoid arthritis sufferers compared to healthy individuals. This project will focus on FcgammaRIIa, which is present on cells which are responsible for the destruction of many antibody-bound objects. Through a combination of cutting edge techniques, spanning physics, biology, immunology and medicine, we will uncover fundamental information within this field. This information would aim to inform the production of effective therapies to treat diseases such as arthritis, which put a huge strain on the NHS every year.

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

A structural investigation into the action of and resistance to ribosome-targeting antibiotics 30 Sep 2018

Antibiotics are crucial to modern medicine, allowing treatment of life-threatening bacterial infections and making many surgeries like transplantations possible. However, pathogenic bacteria are rapidly evolving to resist their effects. Protein synthesis is one of the main antibiotic targets in bacterial cells. I will use structural biology techniques, principally cryoEM and single particle image processing, to understand how both novel natural products and clinical antibiotics bind to the ribosome to bring about their inhibitory effects on protein synthesis. Furthermore, I will investigate the cause of toxicity of certain ribosome-binding antibiotics by examining how they bind to the mammalian mitochondrial ribosome. Finally, I will use a combination of cryoEM and protein X-ray crystallography to elucidate how certain ribosomal-protecting proteins form complexes with the ribosome in order to bring about antibiotic resistance. On an individual level, these studies will allow an assessment of the viability of novel natural products as suitable clinical antibiotics. More generally, they will contribute to our knowledge of how different classes of antibiotics target the ribosomes of pathogenic bacteria, and how these bacteria evolve resistance. This knowledge will help the development of methods to rationally design new ribosome-targeting antibiotics that are able to overcome or circumvent resistance.

Amount: £0
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

Revealing how extracellular matrix glycans define chemokine gradients 31 May 2018

The diffusion of chemokines in the extracellular matrix is a requirement for the formation of chemokine gradients that guide immune cell migration to sites of inflammation, and controlled by matrix glycans of the glycosaminoglycan family. The focus of this research is to use well-defined models of the extracellular matrix to probe the interaction between the chemokine CXCL12 and the glycosaminoglycan heparan sulphate, and how this defines the mobility of CXCL12. The first key goal of the project is to design and produce a fluorescently-tagged CXCL12 mutant with modulated glycosaminoglycan binding which can be compared against the wild-type chemokine and other mutants already available. The second key goal is to use the biophysical method of fluorescence recovery after photobleaching to characterise the differential diffusion of mutant and wild-type CXCL12 in glycosaminoglycan-rich matrices. This project thus combines biochemistry and biophysics to gain a better understanding of the molecular mechanisms underpinning the formation of chemokine gradients in extracellular matrix.

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

Specialised Ribosomes – Does KSHV modulate ribosome composition 30 Sep 2018

Historically, ribosomes have been viewed as unchanged homogeneous units with no intrinsic regulatory capacity for mRNA translation. Recent research is shifting this paradigm of ribosome function to one where ribosomes may exert a regulatory function or specificity in translational control. Emerging evidence has identified heterogeneity of ribosome composition in specific cell populations, leading to the concept of specialised ribosomes. Specialised ribosomes may therefore exhibit control and regulation over the translation of specific mRNAs, resulting in a substantial impact on how the genomic template is translated into functional proteins. Due to the emerging concept that cells can control the composition of ribosomes to regulate protein expression, it would seem highly likely that viruses could also manipulate host cell ribosome compositions to enhance the production of viral proteins. We have quantitative proteomic and ribosomal profiling data suggesting Kaposi's sarcoma-associated herpesvirus (KSHV) manipulates ribosomal biogenesis. Firstly, we will investigate changes in composition and stoichiometry of proteins within the ribosome, driven by KSHV. We will isolate ribosomal complexes by tandem affinity purification, during KSHV infection and analyse changes by LC-MS/MS and cryo-EM. We will elucidate how these changes exert ribosome-mediated specificity to promote KSHV lytic infection using a number of cellular and molecular techniques.

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

Understanding the role of retinoic acid in cyanobacteria 31 May 2018

We will be investigating the viability of using cyanobacteria as a model for our own by exploring the evolutionary links as well as the similarities between human cells and cyanobacteria cells in terms of the communication and cell differentiation. This will allow us to use the cyanobacteria as a model for human stem cells. There are 3 cases which will be investigated: metabolism of retinoic acid, nitrogen-fixing cells and prostaglandin cell signalling. In each case, we will be blocking the signal, modifying the bacteria and studying how this affects the bacteria. The production of proteins and the chemical signalling are amongst the several responses we will be monitoring. Using information gained from this we will be able to see if there is a viable link that can be used to monitor cyanobacteria that have human orthologues spliced into it.

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

Non-genetic oncogenesis in adenocarcinoma of the oesophagus and gastro-oesophageal junction: characterising the stress-inducible FGFR2-GRB2-miRNA axis. 30 Sep 2018

Oesophageal adenocarinoma (OAC) is a type of cancer affecting the lower part of the oesophagus (the gullet). The number of patients diagnosed with OAC has increased substantially over the past three decades. As a result, OAC is now the most common type of cancer affecting the oesophagus. Unfortunately, there are currently few effective treatments for OAC. Many patients with OAC will however first be diagnosed with Barrett's oesophagus. This is a condition in which the normal lining of the lower oesophagus becomes glandular and starts to grow abnormally. It is not clear why this happens but it may be related to reflux of stomach contents (such acid and bile) into the oesophagus (as happens in patients who frequently experience heartburn). Our research suggests that bile and acid may be able to change the concentrations of proteins within the glandular cells. The altered levels of these proteins may then contribute to the cells becoming cancerous. This work will look to see if this is the case and ma help us to find new drug targets to prevent and treat Barrett's and OAC.

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

Modulating protein activity using peroxisomal re-localisation 30 Sep 2018

The majority of small molecule drugs on the market only target a very small range of potential targets. They function by their binding event causing a direct modulation of their target protein’s function, however it is not clear that all proteins involved in disease can be targeted in such a manner. In this project, I aim to develop drug molecules with a different mechanism of action. One half of the molecule will be able to bind to a protein involved in a disease pathway and the second half of the drug would be capable of dragging the molecule to an enclosed cell compartment, known as the peroxisome. Such re-localisation will trap the disease pathway associate protein making it unable to carry out its function providing a new strategy for therapeutic intervention.

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

Developing Electron Microscopy as a Tool in Structure-Based Drug Design 31 Jan 2017

Structure-based drug design has relied heavily upon X-ray crystallography to yield atomic resolution structures of protein targets, subsequently used for inhibitor design. However, the structures obtained are in a static state which may not be a true representation of how the protein exists under physiological conditions. The advances in Electron Microscopy (EM) has led to an increase in the number of near-atomic resolution structures solved and enabled conformational information to be obtained for dynamic systems. Therefore, the project’s ultimate goal is to use EM structures to aid the design of novel therapeutic agents against two different proteins which could be used to treat toxoplasmosis; vacuolar ATPase (V-ATPase) and cytochrome bc1 complex. In silico drug design, including virtual high throughput screening (vHTS) and de novo design, will be conducted to produce putative inhibitors. The compounds will be designed against the most populated functional state of the protein and will be synthesised and screened for their biological activity using in-cell and enzymatic assays. EM can then be used to probe the mode of inhibitor binding to the complex leading to one of the first examples of EM structures being used as a tool in drug discovery.

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

Structural and Functional Characterisation of BK Agnoprotein as a Novel Viroporin 31 Jan 2017

BK polyomavirus is ≥90% seroprevalent in the global population, causing nephropathies and ultimately acute rejection in renal transplant recipients. Previous work has shown that the agnoprotein of BK polyomavirus is a critical egress/release factor during the viral life cycle. The proposed project aims to further our understanding of the putative viroporin function of BK agnoprotein, and determine whether the agnoprotein would be a suitable target for anti-viral therapeutics. These aims will be achieved using a combination of structural and biochemical techniques to provide the first structural information about BK agnoprotein, characterisation of agnoprotein pore formation in in vitro assays, and screening of small molecule compound to identify potential agnoprotein inhibitors. In addition, the project will take advantage of existing primary kidney cell culture systems to study viroporin function during the BK life cycle. Should inhibitors of viroporin be identified, their efficacy will be tested against a number of clinical isolates of BK, obtained from our collaborators in the kidney transplant unit at Leeds. Together, these studies will provide new insight into the structure and function of agnoprotein and may validate a novel target for anti-viral therapeutic intervention.

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

Understanding control of protein concentration and cell fate in the absence of extracellular stimulation 31 Jan 2017

Intricate cellular signaling pathways are essential for maintaining cellular homeostasis and enabling the cell to respond appropriately to extracellular stimuli. Aberrant cell signaling has been implicated in many diseases in particular cancer. The non-stimulated state is particularly important for cancer research as it mimics the early stages of tumourgenesis, when cells at the centre of a growing tumour are unable to receive any stimulus due to surrounding cells. In the absence of extracellular stimulation aberrant signaling can be caused by fluctuations in protein concentrations. Grb2 is a ubiquitously expressed adaptor protein, essential to many signaling pathways. Preliminary data suggests that Grb3-3 a naturally occurring isoform of Grb2 exerts dominant negative control over Grb2. Therefore the balance between the intrinsic levels of these two proteins will influence key signaling pathways. Grb3-3 expression was observed in non-cancerous breast cells but was reduced in breast cancer cells suggesting a potential role of Grb3-3 in rescuing deregulated Grb2 mediated signaling. The aims of this project are to determine structurally and mechanistically how Grb3-3 binds and inhibits Grb2, to investigate their expression in normal and cancer cells and to understand what controls the levels of these two proteins in the cell.

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

Investigating the Structure and Regulation of Fibroblast Growth Factor Receptor 3 (FGFR3) 31 Jan 2017

Receptor tyrosine kinases (RTKs) are cell surface receptors which play a critical role in cell proliferation, homeostasis and survival, mediated by initiation of intracellular signalling cascades in response to extracellular ligand binding. The fundamental importance of RTKs is underlined by the prevalence of pathologies associated with their dysregulation. Despite extensive research in the RTK field, there remain many unanswered questions with regards to the structural and dynamic mechanisms of activation and regulation, both in physiological and pathological settings. Crucially, the key question of how the binding of growth factor to the extracellular domain results in choreographed conformational transitions at the intracellular kinase domain to trigger downstream signalling remains an enigma. To elucidate this question, I will use cryo-electron microscopy to determine structures of full-length fibroblast growth factor receptor 3 (FGFR3), an RTK. Hsp90, a member of the cellular protein-folding machinery, is thought to regulate kinases and protect oncogenic variants from proteasomal degradation. Though glimpses of the mechanisms underlying kinase-(co)chaperone interactions are beginning to appear, the structural determinants of chaperone-dependence of kinases are unclear, especially for RTKs. Thus, in parallel, I will use NMR spectroscopy to investigate the dynamic interactions of the FGFR3 kinase domain with the Cdc37-Hsp90 chaperone system.

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

Discovery of small molecules that modulate transient protein-protein interactions leading to amyloid formation 31 Jan 2017

The development of anti-amyloid drugs has been hampered by the mechanistic complexity of amyloid formation pathways. In order to gain a greater understanding of the conformational changes and dynamic motions associated with fibrillogenesis, this project aims to develop and use small molecules to study an archetypical amyloid protein, beta2-microglobulin (beta2m) – specifically, the amyloidogenic truncation variant, DeltaN6. Small molecule fragments which are compatible with site-directed screening methods will be synthesised, so as to allow amyloid-modulating regions of DeltaN6 to be targeted. Hits which are identified in site-directed screens will be optimised as necessary, in order to produce small molecules which are capable of perturbing amyloid formation pathways upon binding. Understanding the link between small molecule-induced changes in DeltaN6 dynamics (to be studied using nuclear magnetic resonance spectroscopy), and changes in the rate and outcome of fibrillogenesis, will provide both beta2m-specific and generic insights into amyloid formation pathways.

Amount: £0
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

The electrophysiological correlates of action and selection errors in human decision-making 27 Apr 2017

If you lose a point playing tennis, how should you approach your next shot? To respond optimally, we must solve a "credit assignment problem" - was the lack of reward due to wrong shot selection or poor execution? Understanding how the brain responds to these distinct sources of error is important because this information could be used to predict subsequent behavioural responses. To this end, this project will use scalp-recorded EEG and the ERP analysis technique to examine the neural correlates of processing outcomes related to execution and selection error. Specifically, participants will complete a decision-making task involving arm reaches towards targets on a screen with three possible outcomes: (1) Success- when a target is successfully hit and provides a reward; (2) Execution error- when the target is missed; and (3) Selection error- when the movement is accurate but no reward is given. The specific goal is to examine variation in a putative neural marker of reinforcement learning processes in the human brain- the feedback-related negativity (FRN) following selection and execution errors. This will allow us to uncover how the brain discriminates errors of action and selection for reinforcement learning.

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

"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.

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