- 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
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.
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.
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.
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.
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.
We will develop data-sharing platforms to assimilate and collaboratively interrogate global data on i) schistosomiasis ii) soil transmitted helminths, iii) visceral leishmaniasis, iv) melioidosis and v) scrub typhus. This proposal will support the development of the technical platform and curation of data from tens of thousands of patients enrolled to treatment trials and programmatic data of these diseases for use in collaborative meta-analysis to answer key public health questions. The platform’s technical infrastructure will include secure data upload, auditable mapping of multi-disciplinary datasets to a standardised data structure, searchable data inventory and systems to request and receive data. The governance framework will ensure terms of data access that follow principles of equitable and ethical data sharing under the guidance of Science Advisory Committees nominated by the relevant disease communities. Support for the coordination and production of scientific output from the platform will be provided to ensure impact. Platform construction will leverage the expertise and investment in our existing malaria data platform, the WorldWide Antimalarial Resistance Network (WWARN). Prior funding has supported the development of successful pilot platforms for visceral leishmaniasis and schistosomiasis/soil-transmitted helminths, and we will assess the feasibility and impact of establishing platforms for melioidosis and scrub typhus.
This five-year collaborative programme will develop approaches for understanding laboratory animal research as a nexus, asking how reconceptualising connections and generating communication across different perspectives can contribute to improving the future of animal research. New research will draw attention to historical independencies between science, health and welfare; identify challenges emerging at the interfaces of animal research and create opportunities for informing policy and public engagement. We suggest collaborative approaches are essential for understanding how rapid transformations across science and society are changing the patterns of responsibility, trust and care which hold together, or constitute, this nexus. We will deliver new: integrated research across the social sciences and humanities, using historical research to inform understanding of present challenges and create new engagement opportunities for the future; interactive research projects, co-produced with researchers, animal suppliers, veterinarians, publics and patients, to investigate the contemporary dynamics of animal research; interfaces for generating cultures of communication with publics, policy-makers and practitioners across the animal research nexus. This programme brings together five leading researchers on the social and historical dimensions of animal research, uniting the strengths of five institutions, engaging creative practitioners, and advancing the work of five early career researchers and three PhD students.
Bridging funds for transition to ISARICC's 2018-2022 Strategic Plan
Modelling the impact of poor quality antimicrobials on patient outcome and drug resistance – a pilot study to inform policy in the absence of empirical data 30 Sep 2017
Antimicrobial resistance (AMR) is an increasingly serious and pressing global public health problem. Poor antimicrobial quality is increasingly realised as an important rectifiable impediment to global public health. There has been little discussion or evidence as to its comparative importance, in relation to other drivers such as poor prescribing and adherence, for both poor patient outcomes and AMR. In the absence of field data on the relationship between AMR and antimicrobial quality, mathematical modelling based on pharmacokinetic-pharmacodynamic relationships and rates of genetic change provides estimates which can be used to predict outcomes and inform policy. We propose a two phase modelling approach examining how poor quality essential medicines may affect patient outcomes and resistance selection and spread, modelling in Phase 1 antimalarials and in Phase 2 anti-tuberculosis and anti-hepatitis C medicines. This pilot project will build on the existing Wellcome investment in the Mahidol Oxford Research Unit (MORU) Network (though core funding) and the Infectious Diseases Data Observatory (through the MAPQAMP Biomedical Resources grant and core funding) for modelling, PK/PD and medicine quality resources and skills. The growing interest in medicine quality by nations and international organisations and the invitation by the WHO Member State Mechanism (on medicine quality) to the IDDO/MORU Medicine Quality Group to be a stakeholder, facilitates synergistic discussions with multiple partners and nations. We are also discussing expanding our collaboration with the United States Pharmacopeia PQM program on medicine quality & AMR. We are organising the first Conference on Medicine Quality & Public Health for September 2018 and we intend that the initial results from this work would be presented at this meeting. This project will therefore give the first objective evidence, rather than opinion, on the importance, or otherwise, of medicine quality on patient outcome and AMR, in comparison to poor adherence and poor prescribing. It will link in extremely well with the diverse activities of the MORU Network, IDDO, WHO, USP and diverse other stakeholders and be opportune for influencing policy for both medicine quality and AMR. This project will be linked to the parallel project proposed to Wellcome by Dr Elizabeth Pisani on ‘Understanding the political barriers to tackling sub-standard and falsified medicines’.
Structural and functional dissection of the RH5:CyRPA:RIPR complex required for erythrocyte invasion by Plasmodium falciparum 05 Dec 2016
Invasion of human erythrocytes by Plasmodium falciparum is essential for parasite replication and occurs before the symptoms of malaria. It is a complex process involving many parasite surface proteins. Recently, one of these, RH5, emerged as the leading vaccine candidate to target the ‘blood stage’ of the parasite life cycle. RH5 interacts with erythrocyte basigin while monoclonal antibodies that prevent binding also prevent erythrocyte invasion. Immunization with RH5 protects animal models from parasite infection and RH5 enters human clinical trials in 2016. We already determined the structure of RH5 bound to basigin and inhibitory antibodies: a major goal of my investigator award. On the merozoite surface, RH5 forms part of a larger complex, interacting with CyRPA, RIPR and a fourth, GPI-anchored component. RH5, CyRPA and RIPR are each essential for erythrocyte invasion and are targets of antibodies that block invasion. Despite this, their functions are unknown, leaving a major gap in our understanding of erythrocyte invasion by Plasmodium falciparum. We will now undertake structure-function studies of the RH5:CyRPA:RIPR complex. Working with Simon Draper, we have developed eukaryotic expression systems to produce RH5, RIPR and CyRPA. We assembled them into a complex and showed that this is elongated, homogeneous and rigid by negative stain electron microscopy. Monoclonal antibodies targeting each component havebeen generated. We will now determine the structure of this recombinant RH5:CyRPA:RIPR complex using electron cryo-microscopy, and investigate where inhibitory monoclonal antibodies bind.
The translational potential of mass spectrometry and next-generation sequencing in patients with central nervous system infections in Vietnam 22 Nov 2016
Central nervous system (CNS) infections are devastating conditions worldwide, especially in low- and middle-income counties (LMIC). Clinical outcomes are dependent upon the rapid identification of the causative agent and instituting effective antimicrobial therapy, although the causative agent is only identified in This Fellowship will focus on the translational potential of mass spectrometry and next-generation sequencing (NGS) in clinical diagnostics of CNS infections in Vietnam, and has three key goals: To determine whether Mass spectrometry of cerebrospinal fluid (CSF) will identify protein/peptide signatures associated with different infectious aetiologies. To determine whether NGS-based metagenomic analysis will identify a broad range of known/unknown pathogens in the CSF and improve upon current standard laboratory assays. To determine whether NGS can provide rapid, whole genome sequence-based prediction of antimicrobial susceptibility for Mycobacterium tuberculosis and Streptococcus pneumoniae. I aim to provide proof-of-principle that CSF proteomics- and NGS-based methods can improve upon the diagnostic assays currently available in hospital settings, especially in LMIC, and thereby potentially improve patient outcomes.
The ATP-sensitive potassium (KATP) channel is a plasma membrane protein present in beta cells of the pacreas which plays a key role in insulin secretion. KATP acts as a metabolic sensor, alerting the beta cells when blood glucose raises too high and stimulating them to release insulin. In diabetes, normal KATP function is disrupted and beta cells no longer secrete insulin properly in response to blood glucose levels. The molecular structure of the channel is closely linked to its function; there have been several genetic studies linking various mutations (which often only affect one molecule in the channel!) to neonatal diabetes or increased propensity to type II diabetes. Our research aims to identify precisely how these small mutations can have such drastic changes in the activity of the channel by using a combination of fluorescent labels and channel current measurements to watch the KATP channel move in real time. We can then try to construct a model of how the channel converts different stimuli into movements, and how this is affected in mutations linked to diabetes.
My research is focused on uncovering the molecular mechanisms of DNA interstrand crosslink (ICL) repair in humans. Disruption of the underlying DNA-repair pathway causes Fanconi Anemia (FA), with serious cancer susceptibility. Also, ICL-forming drugs are used therapeutically in non-FA cancer patients, however resistance is a major problem. Targeting the FA-pathway could allow clinicians to treat these patients. A key and fundamental event in the FA-pathway is the recruitment of repair proteins to ICLs. Specific and timely recruitment is essential for accurate repair. We have recently discovered proteins specifically detecting ICLs and we have obtained the cryo-EM structure of other ICL-repair proteins. My aim over the next five years is to advance the field further by uncovering mechanistically how repair factors are activated and recruited to ICLs at the single-molecule level. We will: 1) Dissect the mechanism of initial recruitment of repair factors to ICLs. 2) Uncover functions of identified proteins in FANCD2-complexes in ICL-repair. 3) Determine roles of novel phosphorylation sites on FANCD2/FANCI. 4) Elucidate mechanism of FANCD2/FANCI activation. Addressing these central questions will not only greatly advance our understanding of ICL-repair, but will also likely enhance our understanding of other DNA repair pathways utilizing analogous mechanisms.
Wnt secretion, trafficking and pathway activation: towards a structure-based understanding 30 Sep 2018
In recent years of cancer research, significant focus has been dedicated to the definition of the so-called "hallmarks of cancer", i.e. common alterations underlying and unifying the apparent diversity of this extremely multifaceted, complex and heterogeneous disease. A recurrent theme identified both in early setting of tumour initiation - particularly in relation with maintenance of cancer stem cells - as well as in advanced and metastatic settings, relates to alterations in the Wnt pathway. This is a pivotal signalling way controlling growth and body organization in the embryo; in the adult life, it governs tissue regeneration and homeostasis in a tightly regulated manner. My aim is to investigate the events involved in the activation phase of the signalling cascade, with a special attention to the mechanisms of secretion and extracellular trafficking of the activating ligand (the Wnt protein itself). I will do that using the tools of structural biology, in particular x-ray crystallography and, where applicable, cryo-EM. Coupled with a detailed functional analysis based on the structural findings, the work will help shedding light on a so-far unclear molecular picture, in turn enhancing the options for a targeted modulation of the pathway for therapeutic purposes.
The neural network mechanisms of inferential reasoning The ability to make inferences, as defined by conclusions drawn from given evidence (Peirce, 1868), is a hallmark of higher cognitive function (Vasconcelos, 2008) that relies on internal models of past knowledge, including that of experienced environments (Markovits and Vachon, 1990; Piaget, 1987). The neural representation of such mnemonic models is thought to be shaped by life experience (Barlett, 1929, Lee, 2009) but the neural circuit-level mechanisms supporting the neural representation-to-behaviour translation of inferences remain to be identified. The goals of my project are: To investigate the neural circuit mechanisms underlying the ability to make an inference based on prior knowledge with large-scale neural recording techniques in the mouse brain. To test whether dopamine promotes neural mechanisms underlying inferential reasoning using state-of-the art neural manipulation methods.
I am interested in understanding the mechanism of how eukaryotic cells inherit their genetic material at each round of cell division. I have been studying the kinetochore, the macromolecular protein complex that drives chromosome segregation. Although it was widely believed that the structural core of kinetochores would be composed of proteins that are conserved in all eukaryotes, I discovered an unconventional class of kinetochore proteins (KKT1–20) in Trypanosoma brucei, an evolutionarily-divergent kinetoplastid parasite. My current goal is to understand how they carry out conserved kinetochore functions such as binding to DNA and microtubules. Based on preliminary data, I propose that two homologous protein kinases KKT2 and KKT3 lie at the base of the kinetoplastid kinetochore. I will aim to understand how these proteins localize specifically at the centromeric DNA using a variety of approaches. I will also characterize the KKT4 protein to reveal the mechanism of microtubule interaction. To understand the design principle of kinetoplastid kinetochores, I will reconstitute and characterize kinetochore subcomplexes. Finally, I will examine how the evolutionarily-conserved Aurora B kinase regulates the function of unconventional kinetoplastid kinetochores.