- Total grants
- Total funders
- Total recipients
- Earliest award date
- 20 Nov 1998
- Latest award date
- 05 May 2020
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
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.
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.
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.
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.
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.
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.
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.
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.
Peripheral gate in somatosensory system 17 Jul 2018
Peripheral nerves are responsible for haptic, somatic and visceral sensations including that of pain. Healthy nerves conduct action potentials from their peripheral endings to the dorsal spinal cord, where synaptic transmission first takes place. It is assumed that the peripheral somatosensory signals are first integrated in the spinal cord and subsequently analysed in the brain. Our recent findings has challenged this view and suggested that peripheral somatosensory ganglia (such as dorsal root ganglia, DRG) are capable to regulate pain transmission utilising GABAergic somatic cross-talk mechanisms. I hypothesize that somatosensory ganglia represent a new type of a ‘gate’ within the somatosensory system. My overarching goal is to develop a comprehensive mechanistic understanding of the peripheral somatosensory gating. I will use in vivo electrophysiology, mouse transgenics, chemo- and optogenetics, behavioural models and other cutting-edge approaches to address the following specific aims. (1) Secure direct in vivo evidence for peripheral somatosensory integration at the DRG. (2) Moving beyond GABA: identify other major ganglionic communication mechanisms. (3) Elucidate physiological context of signal integration in the DRG. (4) Identify subcellular structures involved in somatic integration. These studies will change current understanding of somatosensory processing and will provide new ideas for pain treatment at the periphery.
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.
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.
Lead identification of a novel anticoagulant agent targeted against activated factor XII for the prevention of thrombosis without the risk of bleeding associated with current antithrombotics 01 Oct 2017
At the University of Leeds, Dr Helen Philippou (PI) and Prof Robert Ariens (Faculty of Medicine and Health), with colleagues (Faculty of Mathematics and Physical Sciences) Dr Richard Foster and Prof Colin Fishwick with Prof Gregory Lip (University of Birmingham) have secured a £3,021,002 Wellcome Trust Seeding Drug Discovery award to develop new safer anticoagulants with minimal risk of bleeding. The medicines available to treat patients who suffer from an increased risk of blood clotting are effective but carry a significant risk of causing bleeding. Current treatments therefore involve a balance between reducing blood clots with inducing bleeding. The objective of this proposal is to discover highly specific compounds which block a protein, Factor XIIa, which is involved in clot formation, and for which there is good evidence to suggest inhibition will not cause bleeding. This will allow patients to be treated more safely with minimal risk of bleeding without needing therapeutic monitoring. The aim is to produce an agent which will be given by mouth daily.
This proposal aims to identify new genes and proteins involved in eye development by studying a cohort of consanguineous families with recessively inherited microcornea, cataract and iris coloboma. This combination of signs and inheritance pattern has not been reported before, though similar conditions have been described. Preliminary analysis showed that two of these families map to new genetic loci on chromosomes 10 and 20 while a third has a mutation in a gene only previously implicated in ca taract alone. I now propose to complete the genetic analysis of the remaining families, screen known genes where they are implicated by the genetics and look for mutations in new eye development genes at the new loci. Initially I will prioritise positional candidate genes then sequence them directly, but if necessary I will use Next Generation sequencing to generate a complete list of all sequence variants within one of the loci to ensure I find the gene involved. Once I have found such a gene I will use the techniques of molecular and cellular biology to characterise it further in order to better understand how the eye develops and how mutations in this gene cause an inherited developmental defect.
The goal of this proposal is to gain a mechanistic understanding of how cytoplasmic dynein, the large microtubule-based motor protein, is regulated to produce essential movement of cargo towards the cell interior (towards the microtubule minus-end). An initial step in many dynein transport events is its targeting to the plus-ends of microtubules, which grow and shrink near the cell periphery. Here, dynein is thought to search-and-capture cargos before transporting them towards the minus-end. T he recent advance of a dynein expression system in yeast makes in vitro reconstitution and detailed dissection of these critical regulatory processes possible. I will establish the minimal proteins required to target dynein to the microtubule plus-end, and analyse their behaviour using single-molecule fluorescence microscopy. The structural basis for control of dynein s motility will be elucidated by single-particle electron microscopy and chemical crosslinking, using non-natural amino acids to precisely insert reactive probes within dynein s large structure. I will also isolate a dynein cargo protein and use optical tweezers to test if it forms a load-bearing interaction with dynein. This combination of biochemical, biophysical and structural approaches will shed new light on the regulation of motor proteins inside living cells, which I will develop into a molecular movie.
"Transforming bodies: New directions in medical humanities and cultural disability" to be held at Liverpool, Birmingham and Leeds from November 2010-May 2011 14 Jun 2010
Under the emerging banner of Cultural Disability Studies and with the specific focus of the 'transforming body', the proposed seminars seek to establish a dialogue between scholars working in the Arts and Humanities (especially on issues of representation, cultural history and ethics) and Health Sciences, medical praCtitioners, and those involved in disability advocacy and community work. Narrative- and representation-based methodologies are central to humanities-based Disability Studies as well as being at the forefront of recent innovative scholarship in the Medical Humanities. These seminars will seek to develop productive conversations between these perspectives, engaging with a range of academic disciplines as well as medical and health practice. The series focuses on three pivotal disability issues: prosthesis, prenatal screening, and ageing. Around each of these, priorities in medical advancement, healthcare and technological innovation combine with concerns about personhood, lived experience, ethics and activism. The objective is to move towards a genuinely multiand trans-disciplinary approach to theorising disability and culture, and to locate cultural disability scholarship within methods and arguments stemming from practice-based approaches. Equally, the seminars will suggest the value of engaging with issues of representation, narrative and reception to offer new perspectives on clinical, medical and community encounters with disability.
"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.
Philosophy in Research Ethics. 15 Feb 2010
Philosophy in Research Ethics will initiate a structured discussion of distinctively philosophical issues around research ethics and ethics review. There is currently no group regularly working on these issues. The conference is intended to be the first of a regular series of events and so the essential first step in consolidating the theoretical basis in which research ethics is considered and ethics committees work. It will establish an initial network of academics with philosophical interest in research ethics and research ethics committees, focus attention on the issues of principle that risk getting lost amongst the practical considerations which are the stock in trade of many ethics committees, and provide a forum for the investigation of those issues. The conference will focus on specifically philosophical work in relation to ethics, ethics review and ethics committees. As the first in a series, it will start to develop a map of the theoretical terrain: the questions that need to be asked, the strategies available for answering them, and the constraints which apply to those answers. Just as importantly, it will enable the dissemination of work that is already underway in this area.
'Angels and Adventuresses: Images and Experiences of First World War Nurses' to be held at the Wellcome Trust Conference Centre 9-10th September 2010 20 Oct 2009
The workshop aims to bring together 13 world-class academics in the fields of history and literary studies. Each has already published scholarly work in the area of First World War nursing, and has a recognized reputation for work in this field. Working within different disciplines, however, these researchers have rarely (if at all) had opportunities to interact, debate and discuss their approaches collectively. The workshop will be an invaluable opportunity for participants to develop a new piece of work for publication, while productively engaging with approaches to the sources gleaned from different disciplines (history, history of medicine, gender studies, literary studies). It will extend across two days, and will give each participant the opportunity to present his or her sources and initial findings and then engage in discussion and debate with colleagues. The intended output from the event is an edited book with the working title: 'Angels and Adventuresses: Images and Experiences of First World War Nurses'. The objectives of the project are therefore: to hold a two-day workshop of world-class scholars in the field of First World War nursing; to develop a series of interlinked papers, which will collectively form a comparative, interdisciplinary and scholarly publication; to use the workshop as a forum for exchange and debate, thereby shaping these individual pieces in order to give them coherence as parts of a larger work; to produce an edited text for publication by a major academic publisher.