- Total grants
- Total funders
- Total recipients
- Earliest award date
- 22 Nov 2005
- Latest award date
- 01 Nov 2019
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Regulation of CD25 expression and IBD risk 31 May 2018
The inflammatory bowel diseases (IBD) Crohn’s disease (CD) and ulcerative colitis (UC) are chronic disorders of the gastrointestinal tract affecting 1 in 400 people in the UK. Both have a complex aetiology involving genetic predisposition and environmental triggers which is not yet fully understood, but may result in persistent bacterial infection, defective mucosal barrier, or a dysregulated immune response. Genome-wide association scans (GWAS) have identified over 200 IBD-associated loci (Lui et al 2015). One locus encompasses the gene encoding the IL-2 receptor alpha chain (CD25). CD25 is expressed by activated T cells and important in signalling pathways that regulate the immune response. Our fine-mapping data (Huang et al 2017) show that the GWAS signal at IL2RA/CD25 is due to a single SNP associated with CD, in intron 1 of the gene and co-localising with a super enhancer that regulates expression (Fahr et al 2015). This SNP is also associated with Type 1 diabetes and multiple other autoimmune disorders. In this study we will identify additional recently recruited IBD patients who are homozygous for the CD risk allele at this SNP by genotyping and investigate alteration in the expression of IL2RA by qPCR in flow-sorted regulatory and effector T cells.
Sustained-release drug products are useful in prolonging the action of a drug in the body by maintaining therapeutic concentrations of the drug over extended time periods. Here, we are particularly interested in polymeric vaginal rings for long-acting vaginal administration of drugs (1). Various steroid-releasing vaginal ring products are currently marketed for hormonal contraception and estrogen replacement therapy, and a new ring device – developed in part by the Queen's University Belfast (QUB) and offering sustained release of the antiretroviral drug dapivirine for HIV prevention – is due to reach market soon. However, a major limitation of current vaginal ring technologies is that they are generally not useful for administration of either large molecule drugs or drug-loaded nanoparticles, due to limited solubility and/or diffusion in the polymeric materials used to manufacture rings. Here, we propose for the first time to test a novel vaginal ring developed at QUB for sustained release of drug-loaded nanoparticles, with potential applications in prevention/treatment of sexually transmitted infections, mucosal immunisation, and treatment of cervicovaginal cancers. The ring device comprises orifices in the ring surface which expose the underlying drug-loaded core. The ring is easy to manufacture using highly-scalable and conventional injection molding technologies.
Design and Synthesis of a Bifunctional Linker for generating Haptenated Flagellin Bioconjugates for Improving Vaccine Reach and Lifespan 31 May 2018
The protein, flagellin, has been shown to enhance vaccine responses in systemic and mucosal sites, and bolster long-lived Ab responses. The ability of flagellin to migrate to mucosa opens up a strategy for delivering other antigens to the gut mucosa to elicit a more robust immune response, which is desirable for a vaccine to maximise its potential to protect. Activated iNKT-cells elicit potent systemic IgG responses but their ability to modulate mucosal antibody responses, including IgA, is less clear. If we could administer iNKT-cell agonists systemically in a way that ensures they reach mucosal sites, we would be able to examine this in depth. We now propose to use flagellin–iNKT-cell agonist conjugates to do just this, by employing flagellin as a carrier to deliver iNKT-cell antigens to the mucosa and in so doing, hopefully induce a robust mucosal antibody response. This Summer research project will focus on the synthesis of a bifunctional molecule which we will use to attach a potent iNKT-cell glycolipid agonist, which we have previously assembled, and then use the second functionality to conjugate the iNKT-cell agonist to the flagellin molecule selectively through surface-exposed Tyr residues that are concentrated in the hypervariable region of the flagellin molecule.
Lipoxygenase (LOX) enzymes are expressed by infiltrating immune cells and are involved in innate immune and inflammatory response, all of which are fundamental processes in wound healing. The overarching aims of this larger body of work is to evaluate the role of 12/15-LOX in the cellular orchestration of wound healing using a murine model. We have induced full thickness (4mm) wounds in wildtype and 12/15-LOX knockout mice, then measured wound closure rates and harvested skin tissue at various time points post wounding and conducted histological evaluation of skin sections. Our initial data has found that in 12/15-LOX knockout skin there is enhanced fibroblast expansion, and a reduced infiltration of macrophages, both of which might be beneficial in chronic wound states where failure in fibroblast proliferation and an overt inflammatory state occur. However chronic wounds also displays deficits in wound re-epithelialisation and given that 12/15-LOX products can inhibit epidermal hyperplasia (by modulating cyclin/CDK signalling), we believe that KO mice might also display an enhanced re-epithelialisation phenotype. Therefore, to test this hypothesis we will explore the rate of re-epithelialisation and the cytokeratin profile of epithelial keratinocytes in KO and wildtype mice at various time points post wounding.
Regulation of microglial phagocytosis 30 Sep 2018
Microglia are the brain's immune cells. They constantly survey the brain to search for invading micro-organisms, unwanted molecules (such as amyloid plaques in Alzheimer's disease) or dying cells, but also play a key role in sculpting the circuitry of the brain by removing unnecessary cells and synapses during development. The mechanisms by which microglia constantly move their processes to survey the brain, and then remove invading micro-organisms, plaques, cells or synapses, are poorly understood. I will use 2-photon and confocal imaging techniques to investigate these events, taking advantage of recent discoveries from the Attwell lab which have revealed the importance of microglial potassium channels and purinergic receptors in controlling these events.
During the course of development, cells divide, migrate, and specialize to form major organ systems. Furthemore, among most mammals and birds, mouse cells differentiation follows a unique morphology. Understanding the molecular mechanisms underlying such process is a core issue in Biology and a curiosity in mouse, which despite differences still share fundamental properties during the process. The challenge has been addressed by leveraging current high-throughput technologies such as single cell transcriptomics. The amount and complexity of this data requires innovative mathematical frameworks that take advantage of current computational capacities. I am intersted on resolving mesodermal diversification during mouse gastrulation. Based on the premise that single cell profiles represent snapshot measurements of expression as cells traverse a differentiation process, I will use probabilistic modeling among other statistical and mathematical methodologies to reconstruct a measure of a cell’s progression through some biological process, and to model how cells undergo some fate decision and branch into two or more distinct cell types. In particular, Bayesian Inference has shown to be a useful approach to take advantage of computational resources, and to include prior knowledge into models, by providing a formal probabilistic framework that allows learning from the data in order to make predictions.
Neglected Tropical Diseases (NTDs) affect more than one billion people per year and have a severe impact on the economy of developing countries. This threat is heightened for communities affected by poverty, poor sanitary infrastructure and contact with transmission vectors or infected livestock. Chagas disease, part of the NTDs is a potentially life-threatening disease caused by Trypanosoma cruzi parasites, and is commonly spread by infected triatomine bugs. Up to 10 million people are estimated to be infected worldwide, predominantly in endemic countries such as Latin America but the disease is spreading to non-disease endemic locations such as Europe, the United States of America and Canada. Benznidazole and Nifurtimox are the only approved medicines for use by the World Health Organisation but these drugs are ineffective in treating the chronic phase of the disease and have potentially fatal side-effects. Dr Bhambra’s research group has identified a novel drug scaffold displaying antichagastic activities whist remaining non-toxic to mammalian cells. Therefore, this scholarship will include the design, syntheses and safety screening of further novel compounds with drug-like properties, and aim to deliver molecules with greater on-target potency and reduced off-target effects leading to promising compounds suitable for further preclinical investigation.
Reaching TB elimination: the use of emerging technologies for TB control in high burden settings 30 Sep 2018
Tuberculosis (TB) is a leading cause of death as an infectious disease. Recent surveillance data from India has revealed the TB epidemic to be larger than expected. Although TB incidence is decreasing, the End TB Strategy of reducing TB incidence by 90% by 2035 is unlikely to be met with current control measures that predominantly target patients with active TB disease. In order to help reach the End TB Strategy goals, new tools to reduce TB incidence and mortality are needed. These tools can target different stages along the TB health care cascade. For example, tools can be developed to prevent non-infectious latent infections turning into infectious active disease, or tools can be developed to reduce the amount of time infectious individuals spend in the community. I will use transmission-dynamic models to explore the potential impact of emerging technologies on TB in Southeast Asia, a high TB burden region. These studies will help determine the optimum use of new and emerging technologies for TB control, as well as what the investment priorities are for high burden settings, such as India.
Gene Editing using CRISPR/Cas9 for Gene Correction in Recessive Dystrophic Epidermolysis Bullosa (RDEB) 31 May 2018
Conventional gene therapy approaches rely on the addition of a corrected gene copy via viral vector transduction. Such strategies are currently being applied to recessive dystrophic epidermolysis bullosa (RDEB) where there is defective collagen type VII protein. However, use of constitutive exogenous promoters in viral vectors results in sustained gene expression that is not subject to the normal regulatory mechanisms of C7 expression. Integrating properties of vectors also pose risk for insertional mutagenic-derived events and efficiency of gene transfer has been challenging given the large size of COL7A1 cDNA. Whereas, gene-editing tools can be designed and engineered to target and repair specific defined regions of DNA, thereby alleviating genomic toxicity and maintaining endogenous gene expression control. Existence of well-known mutation hotspots within COL7A1 allows CRISPR reagents to be designed that would target the mutations found in the UK population with RDEB. Investigations outlined in this proposal aim to identify the most effective CRISPR reagent for a chosen mutation hotspot within COL7A1 gene. In skin, keratinocytes predominantly produce collagen type VII. Therefore, this project will evaluate feasibility of gene editing approaches using CRISPR/Cas9 system in HACAT keratinocytes cell line, and help address critical aspects of CRISPR/Cas9 efficiency at a chosen loci.
Role of Protease Activated Receptor 4 Signalling in Regulating Differentiation and Proliferation of CD4+ T cells 31 May 2018
CD4+ T-cells are components of the adaptive immune system and are divided in Th1, Th2, Th17 and Tregs each with a defined function. However, their function is regulated by different innate receptors. While the way that T-cells are controlled by toll-like receptors and complement receptors has been demonstrated, very little is known about how another family of innate receptor, protease activated receptors (PARs) are regulating T-cells. PAR receptors are members of the innate G-protein-coupled receptors and while PAR1 has been already shown to modulate T-cell function, nothing is known about the role of PAR4. The host laboratory has already data showing that Treg function is increased in the absence of PAR4 expression. The hypothesis that will be tested is that PAR4 regulates T-cell differentiation. To address this, T-cells will be obtained from PAR4+ and PAR4- mice. T-cells from the spleen of these mice will be cultured in cocktail of cytokines known to differentiate CD4+ T cells in Th1, Th2, and Th17 and the phenotype, proliferation and cytokine production will be compared between PAR4+ and PAR4- T-cells. The results of this study will contribute to our understanding of the function of PAR expression on T-cells.
Peptides, as a class of antimicrobials, raise particular challenges and opportunities around antimicrobial resistance. The opportunity of antimicrobial peptides (AMPs) is the breadth of the class, with different modes of action among many, readily synthesised, sequences. Spontaneous resistance rates vary among antimicrobials. Thus, while ‘evolution-proof antimicrobials’ is over-blown, there is real opportunity to identify AMPs with lowered resistance rates. But the vastness of sequence space is also a challenge – possible peptides just 10 residues long are as numerous as cells in the human body. Another challenge is the innate immune system’s use of AMPs – AMPs might, clinically, make human-associated microbes dangerously cross-resistant to human AMPs. This project will address both challenges and opportunities. Focusing on Staphylococcus aureus, the first goal will be to measure resistance rates across a systematic library of AMPs. Such assays will reveal sequence effects on resistance rates, without testing an impossibly large universe of AMPs. The second and third goals will use the set of resistant strains generated by the first goal to understand the processes of AMP resistance and cross-resistance, both at the phenotypic and genetic levels. Together, these offer a new route into rational design of novel antimicrobials with minimised resistance rates.
Improving the Usefulness of Return on Investment Analysis to Decision-Makers: A Case Study on Specialist Treatment Access for Alcohol Dependence in English Local Authority 30 Sep 2018
In deciding what health-producing interventions to adopt, decision-makers are interested in all relevant benefits in addition to health gains to make the most value for money[1,2,3,4,5,6]. Additionally, decision-makers put their values such as those of the agency for which they work, a stakeholder group, or society alongside evidence of costs and benefits. While certain types of economic evaluation such as cost-benefit analysis, cost-consequence analysis or return on investment (ROI) analysis can capture a wide range of outcomes, the usefulness of economic evidence to support resource allocation decisions has not been significant. Hence, the proposed research will identify challenges/constraints associated with (non-)use of economic evidence by decision-makers in English local authority such as Chief Executives, Directors of Public Health and Councillors using Specialist Treatment for Alcohol Dependence as case study. Some challenges have been identified in a systematic review such as budget constraints and affordability, political influences and insufficient evidence on impact on various areas of local authority responsibility. This research shall then evaluate whether addressing such challenges in the ROI analysis will improve uptake of economic evidence. This work shall support local authority decision-makers who need sufficient and unambiguous information on how they can effectively and efficiently provide specialist treatment.
Influence of experience and circadian rhythms on Infra slow oscillations (ISOs) in the rodent brain 31 May 2018
Infra-slow oscillations (ISOs) of
Searching for rare variants in autism 31 May 2018
The research is centred on discovering rare genetic variants that are involved in autism. The key objectives for this research project are to identify, list and annotate the rare genetic variants found in an Irish family with autism. Genomic information from the family (parents and two affected sisters) will be interrogated for rare variants associated with autism and their predicted effect on brain development.
Ischaemic tolerance induced by pre and postconditioning is a promising endogenous mechanism of brain ischaemia protection, illustrating an ability to prevent or reverse neuronal injuries in ischaemic stroke. The neuroprotection is associated with hypoxia-inducible factors (HIFs), which are master regulators of the hypoxia/ischaemia response in cells. The presence of HIF in cells is tightly controlled by HIF prolyl hydroxylases (PHD). It has been proposed that modulation of HIF-PHD activity is of potential therapeutic use in ischaemic stroke, owing to the direct connection between oxygenase-dependent catalysis and the physiological response to hypoxia. The inhibition of HIF-PHD not only exerts pleiotropic neuroprotective effects as a consequence of HIF induction but also has anti-oxidant and anti-inflammation effects. HIF-PHD inhibition engages multiple downstream effector pathways indicating it can challenge the heterogeneity in stroke pathophysiology present in humans. The proposed study will investigate the potential role of Daprodustat, a selective PHD inhibitor, on ischaemic neuroprotection, and elucidate the molecules involved in the protective effect of HIF-PHD inhibition. The project outcomes will aid the development of small molecule HIF PHD inhibitors, which can activate brain endogenous adaptive programs and address the complexity inherent in cerebral ischaemia pathophysiology. Keywords: neuroprotection, ischaemia, stroke, HIF, PHD, daprodustat
Evidence suggests that electrical muscle stimulation (EMS) can evoke sensory feedback to the central neural system and create adequate functional muscle activation and force perception by notational motor commands generated within the CNS. Despite being widely explored, the mechanisms of force perception and generation remain subject of controversy, which hinders EMS application for recovery of everyday life functions in post-stroke survivors. This study aims to identify the feasibility of using EMS to evoke adequate judgments of force and heaviness during weight holding. Ten healthy adults will perform a 2-stage trial. First, the activation patterns of 8 major upper-limb muscles and the elbow and wrist joint angles during holding for 30s randomly presented 5 objects of similar size and shape but different weight will be recorded using surface electromyography and 2D electrogoniometry, respectively. Time-amplitude and cross-correlation analyses will establish weight- and joint-angle dependencies of muscle activation and inform the EMS program design. Then, the task will be completed without visual feedback by holding the object or replacing it with the respective EMS. Perceived comfort and similarity between the tasks will be tested following an adapted protocol for determining the running speed preference. Data reliability will be evaluated by repeating the trial.
Epithelial closure is a process that is frequently used to close holes or gaps in epithelial sheets. The process can be observed during wound healing and multiple morphogenetic events. The fusion of the epithelial sheets is co-ordinated by the cells at the leading edge of the sheets. These cells create dynamic actin protrusions that recognise and pair with the protrusions from the opposing sheet, and join the sheets together in a 'zippering' process. Correct alignment of the sheets is crucial to ensure that the fusion is accurate. The actions and signalling of the leading edge cells is influenced by the Jun N-terminal kinase (JNK) pathway. This pathway is known to regulates multiple genes, but its exact impact on the events occurring in leading edge is still unknown. In this project we alter the levels of selected JNK target genes and observe how this affects epithelial closure. This is done by fluorescence imaging of live and fixed Drosophila embryos during dorsal closure. The aim is to identify the key regulatory proteins and determine how they control actin protrusions on the leading edge. This research will further our understanding of the events during epithelial closure, and has applications in treating developmental defects.
Effects of unilateral lower limb eccentric training on neuromuscular and musculoskeletal characteristics associated with fall risk in older people 31 May 2018
Age-related musculoskeletal functional decline is multifaceted with comorbidities including sarcopenia, osteoporosis, compromised strength and balance, limiting the capacity to perform daily activities and increasing fall risk. Therapeutic activities to alleviate this decline often have poor adherence, and therefore efficacy, in elderly populations as a low aerobic capacity and fear of falling limits exercise tolerance. A previous project confirmed the efficacy of chair-based eccentric exercise targeting the hip and knee muscle groups to improve muscle strength and mass in older people, however balance remained unchanged. The current project has been designed with these findings and the requirements of older people in mind. The project will examine the impact of unilateral eccentric contractions that simulate loaded downhill walking using newly developed equipment (BTE Eccentron). However, the exercise will be modified to ensure the ankle muscle group is targeted specifically to improve the likelihood of influencing balance in addition to muscle mass and strength. Cognitive attentional demands (visual feedback) will require subjects to match the predetermined intensity during every ‘step’, also improving engagement throughout the entire activity. Key goals include: 1. Identify adaptations and size of effect 2. Disseminate findings rapidly in high-impact international journals 3. Provide evidence-base for larger funding applications
Chronic suppurative lung disease (CSLD) in children - Characterisation of a tertiary hospital cohort 31 May 2018
Chronic suppurative lung disease (CSLD) in children is a broad term including a range of lung diseases of different aetiologies characterised by intense neutrophilic inflammation, chronic productive cough, poor airway clearance and progressive lung injury with increased risk of recurrent infections. Robust epidemiological data on children with CSLD is sparse globally. There are also no long-term prospective studies in children to guide clinical care and management into adolescence and adulthood. Indeed, guidelines for management of paediatric CSLD are usually based on expert opinion alone. This project aims at identifying and characterising a cohort of children aged
Mapping the targets of RNase MRP 30 Sep 2018
Cartilage hair hypoplasia, or CHH, is an uncommon disease. Patients with this disease have short limbs and thin hair. They also have problems with their immune system, making them vulnerable to infections. These patients have a mutation in their DNA, in a gene called RMRP. In healthy people, we think RMRP helps build ribosomes. Ribosomes are the cell’s factories which turn the instructions in DNA into the proteins which make up the body. But this happens in all cells, and so it is hard to understand why people with CHH only have problems with their bones and immune system, while most other organs work well. Understanding this is a first step to thinking about new treatments. We will use recently developed techniques to map all the molecules in the cell which interact with RMRP. We will initially apply these in yeast cells, which are similar to human cells, and in human cells grown in the laboratory. We will then determine what happens when we introduce the DNA changes seen in patients into these cells, and into a laboratory mouse strain. This will give us a better understanding of how RMRP normally works, and what goes wrong in the patients.