- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
The role of the Wallerian axon-death pathway in neuronal and axonal vulnerability in Parkinson's disease 24 Apr 2018
Parkinson’s disease (PD) involves preferential loss of substantia nigra pars compacta (SNc) dopaminergic neurons and their projecting axons to the striatum. SNc neurons have huge, highly branched and vulnerable axons, whose distal ends are lost first in PD, so preventing this will be essential for any disease modifying therapy. Our preliminary data suggest the involvement of an axon-death pathway in PD shared with the loss of injured axons (Wallerian degeneration). The Wallerian pathway is initiated by loss of the activity of the essential NAD-biosynthetic enzyme NMNAT2 in axons. Crucially, axons expressing lower levels of NMNAT2 are more vulnerable, raising the possibility that SNc neuron and axon susceptibility in PD reflects a particular sensitivity to Wallerian pathway activation. To test this hypothesis, I will use cutting-edge research strategies from three leading laboratories in axon degeneration and Parkinson’s disease, combining expertise in mouse primary neuronal cultures, human iPSC-derived dopaminergic neurons and mouse and zebrafish in vivo models of PD. The proposed research will greatly advance our understanding of mechanisms of SNc neuron and axon death in PD. In the longer term, this work has significant clinical implications since axons are lost early in PD and the Wallerian pathway can be potently blocked.
STRatifying Antihypertensive Treatments In multi-morbid hypertensives For personalised management of Blood Pressure (STRATIFY-BP) 06 Jun 2018
Polypharmacy (five or more prescribed medications) is common in older people and is associated with an increased risk of adverse drug reactions. Preventative medications, such as those used to manage blood pressure and cholesterol, are common in polypharmacy and often require large numbers of people to be treated to prevent a small number of cardiovascular disease events. This leaves many individuals on drugs of little benefit, some of whom may be susceptible to side effects such as falls, kidney problems and muscle pain. As patients get older, the risks and benefits of their treatments may change, but doctors and patients have little information to inform their understanding of when this might happen. This proposal will use electronic health records with prediction modelling, causal inference and systematic review methods to establish the strength of association between antihypertensive therapy and side effects and build calculators which predict the likelihood of adverse events. These will be used to develop decision tools which predict an individual’s likelihood of benefit and harm from taking therapy. This approach will be applied to other preventative treatment areas and the resulting tools will help patients and doctors to make better informed decisions about starting or continuing these drugs.
CD4+CD25+Foxp3+ regulatory T cells (Tregs) are central to immune regulation and are a promising therapy for the treatment of autoimmunity and transplant rejection, where I am currently leading a clinical trial. Adaptive immune responses are regulated by environmental factors including hypoxia which reduces the activity of prolyl hydroxylase domain (PHD) enzymes thereby activating Hypoxia Inducible Factor (HIF) transcription factors. Effects on cytotoxic T cell activity have been reported, but the interplay between hypoxic signalling and Treg function is less clear. We have recently investigated this PHD/HIF axis using novel tetracycline-inducible PHD knockdown mice. Preliminary data suggest a previously unreported role for PHD2 and HIF-2a in the modulation of Treg activity. I now propose to characterise further the relationship between the PHD/HIF pathway and Treg activity, and to identify therapeutic targets that may be harnessed to modulate Treg function. Effects of further genetic (and pharmacological) manipulations will be tested in sensitive Treg functional assays and transplantation models. The cellular and metabolic mechanisms will be investigated in detail through phenotypic, transcriptomic and metabolic profiling. Overall, these data will broaden our understanding of the relationship between oxygen-sensing mechanisms and immune regulation which I am ultimately well placed to translate to the clinical setting.
Understanding immune metabolism on the single-cell and structural levels in the normal and autoimmune germinal centre reaction 23 May 2018
There is a growing understanding that metabolic state can profoundly influence the outcome of the immune response, through mechanisms still under exploration. However, how immune metabolism varies at the single-cell level, in time and space, in vivo, and in disease, is almost unknown. The germinal centre (GC) reaction is tightly spatially organised and, critical for the production of high-affinity antibodies. The GC reaction is dysfunctional in lupus, because self-reactive antibody specificities escape deletion. The metabolic demands on B cells undergoing the GC reaction are expected to be considerable. There is evidence that proteins with links to metabolism have important effects on GC B cells. However, there has been no measurement of the metabolome of the GC. I hypothesise that metabolism is organised in space and time in the GC. To understand metabolism on the structural level, I will use imaging mass spectrometry to study normal and autoimmune GCs from patients. To determine dynamic changes, I will use biosensors to image metabolite levels in vivo. I will genetically disrupt key metabolism pathways in the GC in mice, and I will also examine how the glycogen synthase kinase-3 signalling pathway affects B cell responses, and its potential as a therapeutic target.
The maternal antibody paradox: Characterising mechanisms and devising solutions for rotavirus vaccination 23 May 2018
Maternal antibodies (MA) are transferred to fetus and infant via the placenta and through breast milk, providing protection against pathogens when the immune response is immature. However, MA also suppress the development of B cell responses to pathogens via mechanisms that are not well defined. MA can therefore result in poor vaccine performance in the infant, placing them at risk against potentially life-threatening pathogens such as rotavirus. Rotavirus infection poses a substantial threat to human health globally. The virus is a major cause of acute gastroenteritis in young children, resulting in ~215,000 deaths each year. Rotavirus vaccines have recently been applied with great success in developed countries, however it is unknown why rotavirus vaccines are much less effective in low-income countries. Whilst malnutrition and the gut microbiome may contribute to poor vaccine efficacy, interference by MA is also considered to be a major prohibitive factor. This study aims to unravel the mechanisms by which MA limit development of effective antibody responses to rotavirus vaccination in infants. This project also aims to translate mechanistic results into rational design of improved vaccines. This work has the potential to generate vaccines that induce protection against rotavirus in younger children across all economic areas.
Staphylococcus aureus is major cause of infection worldwide. This bacterium persistently colonises the nose (its natural niche) in around 20% of the population, which increases their risk of S. aureus infection. Why some people carry S. aureus while others never do is not understood, but is likely to reflect a complex trait influenced by multiple factors. This may include the human genome, host immunity, the nasal microbiota, bacterial-nasal epithelial cell interactions and lifestyle choices. We propose that key determinants for S. aureus carriage can be defined in a powered cohort study in which these parameters are established. Our study will capitalise on existing cohorts (INTERVAL & COMPARE) of healthy volunteers who have been extensively characterised through human genome sequencing and phenotypic profiling. We will screen 25,000 INTERVAL participants for S. aureus carriage, and using sequencing methods define their nasal microbiota composition. We will use existing as well as generate additional data on lifestyle. These datasets will be mined during a series of genome-wide and phenotypic association studies to identify factors that influence the nasal microbiota and S. aureus carrier status. Selected phenotypic and genetic variants of interest will then be tested in relevant experimental systems.
On January 1, 2018, California enacted Senate Bill 27 (SB27), first-of-its-kind and potentially precedent-setting legislation, which will require a veterinarian’s prescription for use of antimicrobial drugs and ban non-therapeutic antimicrobial uses for routine disease prevention and growth promotion in livestock. To assess the effectiveness of this important legislation at reducing antimicrobial resistant bacterial infections in humans, we propose the following specific aims: Aim 1. Quantify the effect of SB27 on E. coli, Campylobacter and Salmonella resistance rates from retail meat. Aim 2. Estimate the proportion of human Campylobacter, Salmonella, and extraintestinal pathogenic E. coli infections caused by strains of food-animal origin in California. Aim 3. Characterize the effect of SB27 on the antimicrobial susceptibility of Campylobacter, Salmonella, and extraintestinal E. coli infections caused by strains of food-animal origin in California. Implementation of SB27 provides a unique natural experiment to assess the effectiveness of restrictive agricultural antimicrobial-use policies at reducing antimicrobial-resistant human infections. The proposed research will have a positive impact by prospectively measuring the effect of this policy on the antimicrobial susceptibility of E. coli (an important colonizing opportunistic pathogen) and Campylobacter and Salmonella (two frank foodborne pathogens) and thereby maximizing the information gained from this singular opportunity
Defining the innate-like mucosal T cell response to bacterial infection in airways disease 30 Sep 2018
Exacerbations cause most morbidity, mortality and economic costs of asthma. Most are driven by infections and constitute a significant unmet clinical need, particularly in non-eosinophilic disease. The 2017 AMAZES trial showed azithromycin reduced exacerbations in severe asthma, but raises several critical questions, especially, the relevant mechanisms of action, whether anti-microbial, anti-inflammatory or immunomodulatory, remain unknown. AIMS 1.To discover the mechanisms of macrolide activity in neutrophilic asthma. 2.To define how non-typeable Haemophilus influenzae (NTHi) establishes a niche in neutrophilic airways. 3.To explore the role of mucosal associated invariant T (MAIT) cells and their ligands in infection and asthma. OBJECTIVES 1.In vitro modelling of bacteria/epithelial/immune cell interactions in NTHi-infected human airway epithelium at air-liquid interface. 2.Murine modelling of mucosal immune responses to NTHi and effects of azithromycin on pulmonary inflammation in vivo. 3.Characterisation of human airway cellular immunology and microbiology using bronchoscopy before and after azithromycin therapy to confirm the human relevance of these pathways in asthmatics with/without bacterial airway infection. This work will i) elucidate the basic immunology of host-pathogen interactions and MAIT-cell biology; ii) identify mechanisms and biomarkers key to informing and refining future human clinical trials of macrolides in airways diseases; and iii) explore the therapeutic potential of MAIT-cells.
Proteomic characterisation of secreted antiviral factors in cell-mediated immunity to human cytomegalovirus 30 Sep 2018
Human cytomegalovirus (HCMV) is a widespread human pathogen, infecting 60-80% of the population. Infection is asymptomatic in immunocompetent individuals but causes disease in immunocompromised patients, such as transplant recipients. Current therapeutic tools are limited, with no available vaccine and a limited array of antivirals. HCMV triggers a broad and robust immune response involving both the innate and adaptive immune systems. Antiviral immunity is mediated in part by proteins secreted by immune cells and infected cells. In order to counteract this immunity, HCMV encodes numerous evasion factors that modulate the function of immune cells and the array of proteins they secrete (‘secretomes’). In this project, I will apply mass-spectrometry to generate comprehensive profiles of the secretomes produced by different immune cells when exposed to HCMV-infected cells. Using this technique, it will be possible to identify important and potentially novel secreted antiviral factors that can subsequently be validated and investigated to determine their mechanism of action. This will contribute to a better understanding of HCMV immunity and may facilitate the design of novel effective vaccine candidates and therapies.
Complete humanisation of adaptive cellular immunity in the mouse: Vaccine and therapeutic TCR discovery 30 Sep 2018
Adaptive cell mediated immunity is one of the central components of immunological homeostasis. While the basic mechanisms are conserved the components that encounter antigen are subject to rapid evolutionary change driven by species specific pathogens co-evolving with the host and divergence of the host genome against which antigen receptors are negatively selected. Thus, epitopes that direct protective immunological responses differ between species. Consequently, translation of results obtained from immunisations conducted in model organisms to humans remains a pernicious issue. The long term goals of this proposal are to identify and validate vaccine candidates and discover therapeutic T cell receptors To achieve these goals we will build mice in which all components of adaptive cellular immunity have been humanised, building on the technical success, biological insights and health-care benefits accrued from the construction of a mouse with a complete human immunoglobulin repertoire. We will use this humanised mouse as platform to isolate therapeutic T cell receptors for acute myeloid leukaemia in which the nucleophosmin gene has been mutated. In an independent and parallel work stream we will systematically explore the Plasmodium falciparum genome to identify vaccine candidates protective against the liver stage of the pathogen.
The world has agreed to take action on Antimicrobial Resistance (AMR). The UN General Assembly Resolution on AMR commits UN Member States to addressing AMR therefore they called for the establishment of an ad hoc Inter- Agency Coordination Group (IACG). Equally importantly, both health and agriculture sectors are being brought together to address this problem. with the UN Secretary General in consultation with the WHO, the UN FAO and the OIE establishing this multidisciplinary group composed of 13 UN organisations and 13 independent experts. The IACG is mandated to report on progress and recommendations for the next steps to ensure sustained effective global action. The global governance mechanisms to deliver on an AMR strategy are crucial. Without some global coordination, none of the public or private stakeholders in this issue will move very far. To this end, as part of IACG's work an analysis of existing governance mechanisms is required by March/ April 2018 to inform the discussion on possible future governance mechanisms for AMR. The paper we are proposing will undertake these analyses and lay out how international cooperation could best be organized to manage the urgent problems emerging from AMR.
Epigenetic transgenerational inheritance of metabolic, reproductive, and endocrine phenotypes through the male germline: effects of developmental bisphenol A and dexamethasone exposure 30 Sep 2018
The majority of heredity is accounted for by transmission of genetic material from one generation to another. However, in recent years evidence has accrued that some environmental factors can cause variations in phenotype that are inherited through the germline without changes in DNA sequence – so-called environmental epigenetic transgenerational inheritance. We are interested in how metabolic/reproductive/endocrine effects of developmental exposure to two exogenous endocrine insults – bisphenol A, an endocrine disrupting chemical that leaches from plastics and thermal paper, and dexamethasone, a synthetic glucocorticoid administered to pregnant women at risk of preterm delivery – may be transmitted inter/transgenerationally through the male germline. We will expose mice to human-equivalent doses of these chemicals and breed for three generations to obtain both phenotypic data and spermatozoa for epigenetic analyses (using RNA-seq, RRBS, and ATAC-seq). We will investigate the functional significance of any spermatozoal epigenetic changes detected; for example, using zygote pronuclear microinjection to determine the role of spermatozoal non-coding RNAs. The ubiquity of human exposure to these chemicals means that even small inter/transgenerational epigenetic effects would have significant implications at the level of public health; we therefore expect this work to be of interest to the wider scientific and medical community.
Streptococcus pneumoniae (the pneumococcus) is a major disease causing pathogen and can cause sepsis, meningitis and pneumonia especially in at risk populations such as young children and the elderly. Understanding genetic factors in disease virulence, transmissibility, and drug resistance informs the management and treatment of infectious disease. By using deep sequenced patient samples of S. pneumoniae it is possible to build a clearer picture of its within host diversity. I aim to develop statistical and computational methods for the analysis of deep sequenced pathogen data that are also able to deal with large datasets, of the order of thousands of samples. I aim to apply these methods to the analysis of deep sequencing data derived from nearly 4000 S. pneumoniae samples taken from patients in the Maela refugee camp, Thailand. The methods I develop will help to identify significant genetic factors for disease dynamics and antimicrobial resistance. The project will contribute to the understanding of S. pneumoniae and will also provide tools of more general applicability to the investigation of deep sequenced pathogen data.
Cells are surrounded by a lipid membrane, which isolates the cell content from the extracellular solution. The hydrophobic core of the membrane is impermeable to many hydrophilic substances including amino acids. To circumvent this problem, cells use transporters that can translocate amino acids across the membrane. This translocation process can sometimes be proton-coupled, but in some cases, certain transporters appear to function without the need for proton coupling. The reasons why some transporters are proton-coupled while others are not and how the proton coupling works, remain elusive. Humans contain two closely related types of amino acid transporter, the cationic amino acid transporters (CATs), which are proton independent and the proton-coupled amino acid transporters (PATs), which use protons for transport. Recent work in the Newstead laboratory has characterized a bacterial homolog of CATs that is proton-dependent, which was surprising. My DPhil project is trying to understand the mechanism of proton coupling in these transporters using a comparative approach between these two example proteins. Comparison of residues at key locations provides a working hypothesis of which residues may give rise to proton dependence. We will investigate this via the use of biochemical and cell-based transport assays, X-ray crystallography and molecular dynamics simulations.
Large-scale data integration to advance mechanistic inference and precision medicine in type 2 diabetes 17 Jul 2018
Advances in understanding the genetic and genomic basis of complex diseases have had limited impact on the delivery of translational goals, including those concerning personalised management. Recently, we have shown that, by integrating information on quantitative trait associations and tissue-specific regulatory annotation, genetic variants influencing type 2 diabetes (T2D) predisposition can be characterised in terms of the pathophysiological processes through which they operate. The central hypothesis of this proposal is that this allows a deconstruction of T2D pathophysiology that addresses phenotypic and clinical heterogeneity, promotes mechanistic insights, and reveals novel translational opportunities. The approach begins with generation of "process-based" genetic risk scores that better capture patterns of individual T2D-predisposition and phenotype. I will refine these risk scores, more precisely characterise the cellular, molecular and physiological events they reflect, and describe their relationships to clinical outcomes. For multifactorial diseases, there are limits to the clinical prediction achievable through genetics alone: I will combine genetic risk scores with measures of individual external and internal environment, and with clinical and biomarker data, to generate "integrated risk profiles".This approach aims to advance understanding of the pathophysiological basis of T2D and deliver precise, personalised information for key clinical outcomes including complication risk and therapeutic response.
Having experienced the Ebola epidemic first-hand, we realised that the majority of the population did not know what a pathogen was, creating fear and misbeliefs that hampered outbreak control. There is a clear need for science engagement and an opportunity to provide it now. We have found school children to be highly tuned into discussions about Ebola and other pathogens. Now is the right time to broaden their awareness of infectious diseases beyond Ebola, and to engage their curiosity through science creating a positive legacy. We aim to: - Engage young people in Sierra Leone in the science of infectious diseases that are all around them, sparking their scientific curiosity and making conversations about pathogens commonplace. - Empower young people with the understanding that if they know how infectious diseases spread, they can prevent infections, improving their health and that of those around them. - Excite young people about science and encourage scientific studies and careers.
Antibiotic resistance in Vietnam is amongst the highest in the world, driven by high levels of antibiotic use for human and animal health. However, community knowledge and understanding about the role and proper use of antibiotics is poor. There are few examples of public engagement around appropriate antibiotic use in low and middle income countries, and there is a huge need to improve public understanding. We hope to encourage community-wide change in the way people use antibiotics for treating common human and animal health problems, and how health-workers prescribe and use antibiotics in hospitals. We will train activators in participatory action research methods, and they will form groups in communities and hospitals. They will guide groups through a four-phase action cycle covering: 1. Understanding the problem of antibiotic resistance; 2. Planning and implementing strategies to tackle inappropriate antibiotic use; 3. Monitoring strategies and generating evidence; 4. Evaluating strategies and planning what to do next. We will evaluate the impact of these action groups on knowledge and behaviour through a mixture of qualitative and quantitative methods – household and hospital surveys, patient record reviews, and in-depth interviews. We will engage local researchers and policymakers through formative discussions and dissemination meetings.
The association of menstrual synchrony with the moon relates back to ancient mythologies. Historians largely dismiss the relevance of a lunar theory of menstruation by the Middle Ages, but the moon’s ability to disturb a woman’s womb through her menstrual blood was continuously discussed by early modern medical and natural philosophical writers. This project asks how the sympathetic connection between menstruation and the moon was manifest in learned discourses, vernacular knowledge, and everyday practices. Answering this requires studying women’s knowledge, the relationship between natural and occult philosophy, and the link between theory and practice in medicine. This research draws together rich, diverse manuscript and printed sources to demonstrate how the influence of the moon over the female body was ubiquitous in early modern medicine and natural philosophy. In vernacular medical handbooks, the moon was a popular socio-cultural symbol of femininity and sexual difference. Its power over the female body was demonstrated through practice in recipe books, casebooks, female-authored almanacs and medical treatises on phlebotomy. The cause and consequences of its influence were debated through learned discourse, highlighting the temporal dynamics of menstruation, and the continuous significance of fluids to changing intellectual frameworks of the body.
Virtual Fly Brain 06 Jul 2017
Neuroscience is accelerating: the capability to generate circuit level hypotheses is now matched with the ability to visualise, manipulate and record from individual neurons, in vivo. Drosophila, with its complex adaptive behaviors, powerful genetic toolkit and small nervous system, for which we will soon have complete connectomes, is uniquely placed to contribute to this work. Virtual Fly Brain (VFB) is a unique resource for Drosophila neuroscience, integrating disparate, large-scale datasets and linking them to curated literature and other resources. VFB works with international data providers and bioinformatics resources to ensure efforts are complementary, non-redundant, and make best use of resources. VFB users browse and query curated information from many sources to understand structure, function and relationships in the brain. Critically, VFB provides the data to generate circuit hypotheses and identify research tools to test them. This proposal continues this vital service and extends it to incorporate rich new data types. We will incorporate synaptic resolution connectomic data, develop bridging registrations to make it bidirectionally queryable from light level data. We will add phenotypic and transcriptomic datasets and enhance tools that enable researchers to find reagents. We will enable users to upload, view and query their own 3D datasets.