- Total grants
- Total funders
- Total recipients
- Earliest award date
- 20 Nov 1998
- Latest award date
- 31 Mar 2020
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Communication between immune and stromal cells is key to immunological memory within pathogen infected tissues 10 Apr 2018
Pathogens trigger an accumulation of immune cells in the infected tissue. Incoming immune cells adapt to their new environment, communicating with infected stromal cells to ensure pathogen control. Tissues do not immediately return to homeostasis following pathogen clearance. Some pathogen-specific T cells remain, differentiating into Tissue Resident Memory cells (Trm). The tissues’ stromal cells also retain an imprint of the infection with prolonged expression of immune-related genes. Currently, we have only limited understanding of the cells and molecules involved in establishing and maintaining these infection-induced changes and how immune and stromal cell communication impacts on protective immunity. These are key question for vaccines that aim to induce immune protection within tissues to provide rapid protective immunity. This proposal is based on our findings that antigen-presentation and inflammatory cytokine production drives prolonged changes in lung CD4 Trm cells and epithelial cells and fibroblasts. Our key goals are to define the mechanistic basis for these changes by identifying the cells and molecules that influence the generation, maintenance and protective responses of infection-altered immune and lung stromal cells. This research will provide a conceptual breakthrough in our understanding of how cell commination influences protective memory and novel insights relevant to improved vaccine design.
Neurodegenerative disorders, including Parkinson's Disease and dementia with Lewy bodies, are devastating diseases, with no known cure. They share a common histopathological feature, in that the deposits of insoluble aggregates found in the brains of patients are heavily modified by ubiquitin. Several genes that are associated with neurodegenerative disorders encode E3 ubiquitin ligases. One such ligase, Parkin, is mutated in > 50% of autosomal recessive juvenile parksinsonism (ARJP) cases. Furthermore, Parkin is found in the inclusions deposited in the brains of sporadic Parkinsonism patients. Parkin signalling is complex and heavily regulated, and our understanding of how it targets substrates is not well understood. This proposal aims to define the complete catalytic cycle of Parkin function, how proteins are targeted, how ubiquitin is relayed through the catalytic intermediates to target conjugation. This will require a combination of structural biology and chemical biology to capture individual states, and biochemistry to identify molecular determinants of Parkin activity. Understanding these catalytic processes at the molecular level, will not only impact on our understanding of the regulatory events taking place in vulnerable neurons, but will also provide the atomic detail needed to develop pharmacological compounds capable of restoring or disrupting enzyme function.
Pathogenic Neisseria species continue to cause harmful infections in humans. Neisseria meningitidis causes life threatening meningitis and septicaemia infections, particularly in infants, and Neisseria gonorrhoeae causes the sexually trasmitted infection gonorrhoea. There is an urgent need to further study these pathogens particularly N. gonorrhoeae as gonorrhoea cases are on the rise and it is increasingly in the news due to the sharp increase in cases with resistance to antibiotics, leading to the fear that gonorrhoea could soon become untreatable. We will investigate the role that toxin/antitoxin modules play in Neisseria biology. In other pathogens, these systems have been observed to include a toxin able to stall bacterial replication and an antitoxin that neutralises the toxin's activity. When under stress, the antitoxins are degraded leaving a free toxin to arrest bacterial growth. In this non-growing state bacteria are tolerant to antibiotic challenge. There is very little known about how the toxins of Neisseria function and what their role is in infections. This proposal will address this lack of knowledge by discovering the biological systems targeted by the toxins and assessing their effect on Neisseria metabolism.
Characterisation of new and emerging arboviruses causing acute febrile illness in Uganda 30 Sep 2018
Dietary restriction (DR), typically reduced food intake relative to ad libitum fed controls, is the most widely used intervention to slow ageing, increase lifespan and healthspan. Precisely how DR acts to induce its effects is unknown, although recent findings suggest that the gasotransmitter hydrogen sulphide (H2S) may underlie the beneficial effects of DR. H2S can also attenuate accelerated ageing phenotypes in progeroid models. In this project I will utilise different strains of ILSXISS mice that show differential responses to DR- from lifespan extension to lifespan shortening. DR-induced longevity in ILSXISS mice is correlated with increased liver H2S production but this is not observed in strains that show lifespan shortening under DR. The key goal of this project is to investigate components of the transulfuration pathway (TSP); the primary pathway in which H2S is synthesised/metabolised within cells. To this end I will measure protein and transcript levels using western blotting and qPCR of key TSP components (e.g. Cystathione- beta-synthase, cystathione-gamma-lyase, rhodanese, sulphide- quinone reductase-like). I will then examine whether commonality exists in these parameters within the liver following DR in ILSXISS mice with comparison with other tissues such as the brain.
Recognition, activation and targeted degradation of protein kinases clients by the HSP90-molecular chaperone 10 Apr 2018
Many oncogenic protein kinases depend on interaction with the HSP90 molecular chaperone, mediated by the co-chaperone CDC37, for their cellular stability and oncogenic activity. Inhibition of HSP90's conformationally-coupled ATPase mechanism leads to the ubiqtuitylation and degradation of these protein kinase 'clients'. Consequently HSP90 is an important target for therapeutic intervention in cancer. Although there has been substantial progress in this field, important issues remain unresolved. In particular we wish to understand : How protein kinase clients are specifically and selectively recognised by the CDC37 co-chaperone, and recruited to HSP90 ? What structural and biochemical changes are elicited in the client protein by recruitment to HSP90 and by its conformationally-coupled ATPase cycle ? How dephosphorylation of CDC37 by the HSP90-targeted protein phosphatase PP5 regulates client protein release ? How protein kinase clients are targeted for proteasomal degradation when HSP90's ATPase is inhibited ? To address these questions we will use cryoelectron microscopy, X-ray crystallography, NMR spectroscopy, and a range of biochemical and biophysical approaches, to determine structures of key complexes along the pathway from initial client recognition to release or ubiquitylation, and define the structural and biochemical transitions that connect them.
Certain bacterial species can colonise to form biofilms- large structures which protect bacteria from physical and chemical removal e.g. antibiotics. If adhered to biomedical implants, bacteria can cause repeated infections which couldn't be treated by antibiotics and therefore would lead to the removal of the implant. In some patients, this would result in repeated invasive surgery. Our interest is in crystalline biofilms which can block urinary catheters and cause catheter-associated urinary-tract-infections (CAUTI). The main bacterium causing CAUTI is E. Coli in which E. Niba et al. (2008) isolated 110 genes involved in the formation of biofilms. Mutations in key genes will be created using Lambda red recombination which is a highly efficient and well established method for creating precise gene deletions. Deletions will be confirmed using PCR and sequencing. The deletion mutants will be analysed for biofilm formation using a bioflux system which generates shear force by continuous flow of liquid. This is an open system ensuring nutrients are available and thereby favouring biofilm formation. Both pathotypes and their respective mutants will be tested for the capacity to form biofilms at a range of temperatures. Data from the above experiments will be quantified using ImageJ software.
Alpha-GABa receptor modulators for the treatment of cognitive impairment associated with Huntington’s disease 01 Oct 2017
Huntington's disease is a fatal genetic disease characterised by a movement disorder that is accompanied by a decline in cognitive function and changes in mood and behaviour. The decline in cognitive function may precede the movement disorder by a decade or more and is a very important component of the functional disability associated with the disease. There is, however, no effective treatment for enhancing cognitive performance in Huntington's. Professor John Atack at the University of Sussex aims to identify novel drugs that can enhance cognitive performance in subjects with Huntington's disease to address a large unmet medical need.
Stroke affects 152,000 people in the UK each year, and up to 80% experience visual impairment as a result. Post-stroke disorders such as hemispatial neglect (a loss of visual attention to one side of space) are notoriously difficult to treat, and are associated with limited functional recovery and reduced quality of life. In healthy adults, visual processing is modulated by neural oscillations which help to promote or suppress incoming visual information. Specific oscillatory frequencies are known to be disrupted in stroke, yet at present it is unknown how these oscillations are related to hemispatial neglect. I aim to develop a new intervention for neglect via 3 interlinked and interdisciplinary clinical projects: 1) to identify, using electroencephalography (EEG), the oscillatory markers of a temporary, induced improvement in neglect during a phasic alerting protocol, 2) to identify longer-term oscillatory markers of improvement from neglect using magnetoencephalography (MEG) at 1-3 months vs 6-12 months post-stroke, and 3) to compare two targeted interventions to modulate pathological oscillatory activity, using a biofeedback protocol vs non-invasive brain stimulation. This translational programme will bring together knowledge and expertise from cognitive neuroscience and clinical stroke rehabilitation to develop a novel intervention to treat visual impairment after stroke.
What makes phleboviruses tick? Examining the molecular interactions of tick-borne phleboviruses with their arthropod vector. 21 Feb 2018
There is a fundamental lack of understanding regarding how tick-borne viruses replicate in ticks and how the tick innate immune system controls infection. My proposal will focus on tick-borne SFTS phlebovirus, its overarching goals are to understand how tick-borne viruses interact with ticks and tick cells and how this facilitates transmission to mammalian hosts. To achieve my goals, I will carry out in vitro and in vivo studies that can be divided into three specific aims: (i) to elucidate the basic molecular biology of tick-borne virus replication, (ii) to define the innate immune factors that control virus replication in the tick cell environment and (iii) to examine whether virions derived from tick or mammalian cells have similar biological properties and virulence? I will conduct in vitro experiments in tick cell lines to examine virus-vector interactions. Importantly, I will also establish unique tick colonies and infection capabilities for the UK. Through combined cell culture approaches and in vivo animal experiments I will investigate the replication of phleboviruses in the live tick for the first time. I will also explore the infectivity of virions derived from different sources and assess if tick-derived viruses are more virulent to mammals in animal inoculation studies.
The skin as a reservoir for trypanosomes: the key to understanding transmission and disease pathology 28 Nov 2017
Human African trypanosomiasis is a fatal disease caused by trypanosome parasites, transmitted between mammalian hosts by the bite of a tsetse fly. We recently discovered that trypanosomes sequester to mammalian skin during infection, forming an undiagnosed, untreated, reservoir of disease. I hypothesise that this reservoir presents a substantial barrier to current control programmes and that the detection and elimination of skin-dwelling parasites will be crucial for the elimination of trypanosomiasis. I also hypothesise that the molecular pathways involved in extravasation to the skin are shared with those allowing extravasation into other organs, leading to the main pathological consequences of infection (an evolutionary by product of the drive for transmission). I aim to test these hypotheses using a combination of field and laboratory work. The fieldwork is aimed at determining the extent and role of skin-dwelling trypanosomes in humans and livestock (reservoir hosts) and developing a Raman spectroscopy-based non-invasive diagnostic. The laboratory-based work will use transcriptomics and genetic analysis to identify the key genes involved in extravasation. Together these approaches will allow a greater understanding of extravasation that will be key for the development of new diagnostics, transmission and pathology blocking agents as well as identifying novel areas of host/parasite interaction.
Tuft Cell Activation and Intestinal Immunity 17 Jul 2018
Immunity to nematode parasites requires sequential activation of innate and adaptive immunity in a concerted Type 2 response dependent on the cytokines IL-4, IL-13 and IL-25. Our work, and that of others, has identified a novel epithelial cell type that is critical to initiation of this response, known as tuft (or brush) cells. Most significantly, tuft cells are a major source of IL-25 during gastro-intestinal nematode infection, which induces IL-13 production from innate lymphoid cell type 2 (ILC2s), to activate further innate and adaptive cell populations. They also express high levels of the enzymes that produce acetylcholine and lipid mediators implicated in immunity. Tuft cells are found in other mucosal locations, including the lungs, and are highly conserved across the Mammalia, including in ruminants where intestinal nematodes are a major problem. A fascinating aspect is their expression of taste receptors suggesting that they may chemically ‘sense’ the presence of nematodes. In this proposal we seek to (i) determine the immune effector functions of tuft cell mediators; (ii) identify molecules from parasites that may activate tuft cells; and (iii) establish whether tuft cell functions are conserved in ruminants and may lead to new strategies for control of nematode infection in sheep.
Beyond Pairwise Connectivity: developing an information theoretic hypergraph methodology for multi-modal resting state neuroimaging analysis 06 Sep 2018
Resting state network analysis is a fast growing and influential area of neuroscientific research that has exciting potential for both clinical and basic neuroscience. Resting state data is normally analysed by considering pairwise relationships (correlations) between regions that are represented as a mathematical graph structure. However, there may be more complex interactions happening, for example the relationship between two regions might change depending on activity in a third region, or on EEG power in a certain frequency band. I will apply new information theoretic measures of multi-variate statistical interactions to open resting state data from the Human Connectome Project (over 1000 participants). I will represent this higher order structure in hypergraphs (graphs extended beyond pairwise relationships), which will provide finer resolution descriptions of resting state networks. I will also record and openly release long-session simultaneous EEG and fMRI resting state data, and apply my interaction measures to determine relationships between fMRI resting state networks and concurrent EEG activity. This approach will open new avenues for measuring and interpreting resting state brain networks, as well as investigating how they change with ageing, disease or more specific individual traits.
Metastasis is the major driver of mortality in cancer patients. A common feature that potentiates the dissemination of cancer cells is the enhanced secretion of tumorigenic effector proteins. Malignant secretion can be mediated by the phosphoinositides (PIs) family of lipids in conjunction with PI regulator proteins that bind to or act upon each PI. One such PI regulator is phosphatidylinositol transfer protein cytoplasmic 1 (PITPNC1). PITPNC1 is highly upregulated in many human cancers and involved in the promotion of metastasis. The PITPNC1-dependent recruitment of RAB1B, a GTPase, to the Golgi-compartment is known to enhance secretory capacity and drives the release of pro-metastatic proteins. The goal of the project is to validate the reported interaction between PITPNC1 and RAB1B in vitro. To this end, recombinant PITPNC1 and RAB1B will be expressed in Vmax™ Express cells and purified by affinity and size exclusion chromatographies. This will allow validation of the reported interaction by pull-down. Additional insights will be gained from assessing the PITPNC1-RAB1B interaction in solution by performing a NMR chemical shift perturbation experiment using 15N-labelled RAB1B. The effects of lipid/nucleotide exchange on the interaction will also be explored. These studies may contribute to the development of therapies specific to metastatic disease.
Actin and actin-binding proteins are highly conserved across eukaryotes, however, Apicomplexa lack genes for a number of actin regulators including the Arp2/3 complex, a nucleator of actin filaments. In Plasmodium falciparum, Formin 1 is a likely candidate for actin-filament nucleation during invasion, however a clear demonstration of Formin 1 function has yet to be fully achieved. The aim of this project is to use CRISPR/Cas9 in conjunction with the dimerisable Cre-recombinase (DiCre) system to generate conditional knockouts of formin 1 in P. falciparum. CRISPR/Cas9 will be utilised to simultaneously epitope tag Formin1 and introduce loxP sites within and downstream of the gene in a DiCre expressing strain. Cas9 will be directed by designed guide-RNAs to generate specific double strand breaks in the formin 1 gene which will be repaired by a rescue plasmid containing a synthetic gene with internal loxP sites and flanking DNA segments homologous to target DNA. Epitope tagged Formin 1 will be fully characterised for localisation by immunofluorescence assay and western blotting. Resulting phenotypes from Formin1 knockdown will be analysed via growth curves, video microscopy and super resolution microscopy. This will provide insights into the function of Formin 1 and its potential as a novel drug target.
Targeting Mitochondrial Metabolism for the Treatment of Chronic and Acute Myeloid Leukaemias 31 May 2018
Tyrosine Kinase Inhibitors (TKIs) as a standard treatment of Chronic and Acute Myeloid Leukemia mainly target differentiated cells, leaving a population of leukemic stem cells (LSCs) behind, which support relapse of disease. Based on knowledge that cancer cells acquire energy to satisfy their high energy requirements by rewiring metabolic pathways, a previous study at Dr. Helgason's laboratory identified upregulation of oxidative phosphorylation metabolism as vital for LSC survival in Chronic Myeloid Leukemia (CML), providing potential selective targets for elimination of LSC by drugs interfering with mitochondrial function. In order to reduce time needed for treatment to enter clinical trial, Helgason's laboratory carried out drug-repurposing screening for suitable FDA-approved drugs targeting oxidative phosphorylation and identified a strong candidates for validation. The aim is to functionally validate these inhibitors as means to sensitise CML and Acute Myeloid Leukemia cells to TKI treatment in vitro in order to facilitate elimination of the LSC moiety while leaving healthy haematopoietic stem cells unaffected. Mechanism of action of promising candidates will then be studied using CRISPR-mediated genetic inhibition. Successful candidates will then be offered for translation into the clinic.
People with intellectual disabilities (ID) experience health inequalities, are frequently excluded from research and their views are rarely captured in the research process. There is a need to develop robust public engagement methods with this marginalised group to improve quality and diversity in ID health research and to challenge attitudinal barriers that result in the exclusion of people with ID either as subjects or participants in studies. The project will develop an adapted citizens’ jury method, empowering people with ID to deliberate on conceptual and practical issues in ID health research. The specific question for deliberation in the jury (people with ID) will be decided by jury members throughout the capacity building stage of the project. The jury will call expert witnesses to give (accessible) evidence and will undertake supported/informed deliberation on the jury question. At the end of the process they will produce a consensus report with recommendations for the ID research community. Jury members and the project team will lead a knowledge exchange session at the IASSIDD global congress which brings the global ID research community to Glasgow in 2019. The project team have combined expertise in developing innovative, effective communication methods and conducting ID research.