- 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
Young people in sub-Saharan Africa are central to ending the HIV epidemic. However, uptake of proven protective interventions is low and evidence on who does/does not engage is limited. Theory predicts that behaviours and intervention uptake cluster within social networks. Interventions in other settings have successfully leveraged social ties to improve intervention impact. I aim to: (1) use novel methods to identify how social networks pattern risk for HIV acquisition; and (2) test the feasibility of using such knowledge to improve intervention uptake. I will undertake this work at the Africa Health Research Institute in rural KwaZulu-Natal, South Africa. Following qualitative interviews with young people exploring their social networks and social norms, we will then quantitatively follow 600 15-24 year-olds, together with their close friends and family, for three years. Using these longitudinal data, we will statistically model how social contacts influence behaviour and HSV/HIV acquisition. We will then quantitatively and qualitatively evaluate the feasibility of using network-selected peer-educators to promote uptake of HIV self-tests and subsequent treatment. We will compare how influential peer-educators differ from randomly selected ones in terms of willingness to be involved, training dynamics and health impact.
Lung cancer development is an evolutionary process, involving accumulation of mutations within a given environment. However, although driver alterations and mutational processes in lung cancer evolution have been elucidated, an understanding of the constraints and selection pressures that govern cancer development and their evolution and genomic regulation is unclear. Moreover, while studies have revealed that driver alterations can be present in ‘normal’ tissue, the differences between such somatic genomic evolution and cancer evolution is unclear. I hypothesise that knowledge of the genomic and transcriptomic mechanisms underpinning tumour evolution, coupled with an understanding of constraints and selection pressures that shape tumour development, can inform approaches to tackle cancer. I have previously developed bioinformatics methods to disentangle a cancer’s life history from multi-region sequencing data (e.g. de Bruin and MCGRANAHAN, 2014 SCIENCE; McGRANAHAN et al., 2016 SCIENCE), and developed tools to elucidate immune escape (MCGRANAHAN et al., 2017 CELL). I propose to extend these methods using normal tissue sequencing, public and private data from collaborators, to obtain a pan-cancer database of the evolutionary trajectories of thousands of tumours. Evolutionary maps, including immune micro-environmental and therapeutic selection pressures over space and time, will provide a systems level understanding of cancer evolution.
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.
Background Prescribing for bipolar disorder is a major clinical dilemma as long-term pharmacological treatment is often necessary. Lithium is the most effective mood stabiliser. However, only 30% of individuals have a good therapeutic response. Presently, there is no reliable way to predict response or adverse event risk, or if an alternative treatment would be better for that patient. Aim To personalise prescribing for people with bipolar disorder via prediction models that quantify potential benefits and risks of existing treatments based on clinical phenotypic characteristics of the individual. Objectives Identify individualised clinical predictors of lithium and second-generation antipsychotic response. Determine clinical predictors of chronic kidney disease in individuals taking lithium. Determine clinical predictors of pathological weight gain in individuals taking second-generation antipsychotics. Methodology Data sources Swedish population registers, Hong-Kong health registers, Taiwanese health insurance database, UK primary care data linked to secondary care admission records, and UK mental health care data. Analyses Traditional epidemiological and machine learning methods; drawing on the strengths of each approach. Prediction model generation I will combine predictors from different datasets; resulting in models predicting drug response, chronic kidney disease and weight gain. Application Prediction models will be presented as online and smartphone application clinician decision aids.
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.
Lysosome turnover in health, aging and disease 17 Jul 2018
Lysosome dysfunction is implicated in lysosomal storage diseases, and multiple age-related neurodegenerative diseases, including Parkinson’s, Alzheimer’s and age-related macular disease. Lysosomes are signalling organelles central to maintaining cellular homeostasis. Nutrient sensing on the lysosome can lead to nuclear translocation of the transcription factor, TFEB, and lysosomal gene transcription. However, it remains unclear how newly synthesised lysosomal proteins are packaged into new lysosomes and how old/damaged lysosomes are cleared. We recently established models of lysosomal aging/dysfunction in retinal pigment epithelial cells, taking advantage of their huge degradative burden, and identified conditions that upregulate lysosome biogenesis/activity. We propose to identify the trafficking steps and molecular machinery underlying lysosome biogenesis and test the relative contributions of lysosome exocytosis and lysophagy (lysosome autophagy) to cellular clearance of aged/damaged lysosomes. Our ultimate goal is to exploit these mechanisms to promote damaged lysosome clearance or rejuvenation and/or promote lysosome biogenesis for the treatment of diseases where lysosome activity is compromised. Treatment efficacy in upregulating lysosome activity, whilst readily measurable in culture, is difficult to assess in vivo. We will establish a molecular signature of aged/damaged lysosomes in cultured RPE that can be used to identify damaged lysosomes in aged/diseased retinae.
Efficient and transparent methods for linking and analysing longitudinal population studies and administrative data 05 Jul 2018
The Wellcome Trust LPS Strategy states that research is needed to i) underpin efficient linkage of multiple datasets, ii) quantify potential biases resulting from linkage, and iii) to handle linkage error in data analyses. We propose a programme of methodological research to develop efficient and transparent methods for linkage and analysis, to help maximise the joint potential of existing longitudinal population studies and multiple administrative datasets. Our proposed work packages will focus on linkage of LPS and multiple administrative datasets: WP1: Facilitate development of innovative linkage methods for multiple datasets, by developing shareable software to generate synthetic datasets that are generalisable to a range of research settings. WP2: Develop methods for efficient linkage of multiple datasets by expanding existing probabilistic linkage methods to the setting in which multiple administrative or LPS datasets are to be linked dynamically, and where there are multiple sets of identifiers (e.g. collected at different time-points). WP3: Provide appropriate tools for analysis of linked data by extending existing imputation methods for handling linkage uncertainty and avoiding bias within analysis. WP4: Maximise the value of approaches developed in WP2-3 through evaluation using exemplar linkages and dissemination of methods to the LPS community and other key stakeholders.
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.
Cellular mechanisms underlying the morphogenetic biomechanics of mammalian neural tube closure 30 Sep 2018
Primary neurulation is a biomechanical process whereby the flat neural plate folds into a closed neural tube (NT). Closure initiates at the hindbrain/cervical boundary and "zippers" bi-directionally to form the cephalic and spinal NT. Failure of NT closure results in defects including spina bifida, which continue to affect 1:1,000 pregnancies. Despite advances in delineating its genetic control, we lack an integrated understanding of neurulation as a biomechanical morphogenetic process. To this end I have combined mouse posterior neuropore (PNP) live-imaging, laser ablation, and novel strain-mapping workflows to describe the tissue-level biomechanics of spinal closure. These revealed that the PNP is biomechanically coupled by a far-reaching actomyosin network, identified teratogenic/genetic models in which altered PNP biomechanics predict spina bifida, and identified a novel closure-initiation point ("Closure 5") which forms at the embryo’s caudal extreme. We now propose to determine: Are mechanical forces which promote and oppose NT closure balanced through actomyosin-dependent contractility overcoming tissue rigidity, up to a failure threshold? Do biomechanical differences between spinal and cephalic closure account for the latter’s apparent predisposition to failure? Does Closure 5 formation critically facilitate completion of spinal neural tube closure in humans and mice, and how is its morphogenesis regulated?
Although two broad cell types, neurons and glia, compose the brain, neurobiologists have tended to focus on neurons, the electrically excitable cells that process information. Glia were thought of primarily as neuronal support cells. Recent work challenges this view and shows that glia play essential roles not just in supporting neuronal function but also in instructing their development. I propose three aims to address how glia regulate two key aspects of brain development, neuronal birth and neuronal identity: (i) A major challenge in neurobiology is defining the origin of neuronal identity (and thus diversity). I will investigate how signals sent by glia to naïve precursors determine the unique neuronal fates that these cells adopt. (ii) Although the brain has little regenerative potential, under restricted circumstances differentiated glia can act as stem cells to generate neurons. I have identified one such example and will probe the signals that reprogramme glia to generate neurons. (iii) I will explore how different glial types differ in their regulation of neural development. I will begin with a systematic survey of the signals released by different glial-subtypes and then manipulate these while evaluating their effect on neighbouring neural precursors and neurons.
Understanding how nNOS signaling in the gut influences the development, maintenance and function of interstitial cells of Cajal. 21 May 2018
Loss of neuronal nitric oxide synthase (NOS1, a.k.a nNOS) neurons has been implicated in a range of gastrointestinal motility disorders including Achalasia, Gastroparesis and Diabetes. Recent studies have demonstrated that global knockout of Nos1 results in reduced populations of interstitial cells of Cajal (ICC). This key population is crucial for pacemaker function and neurotransmission within the gut wall. Interestingly, rescue of NOS1+ neurons in the Nos1-/- colon after transplantation of enteric neural stem cells leads to restoration of ICC numbers, suggesting NO signaling may be critical for the development of ICC. However, it is unclear whether such changes in ICC are a direct result of NO (nitric oxide) signaling or are a secondary consequence of other phenomena. The goal of this project is to: assess the effects of temporal perturbation of NO signaling on the functional development of ICC. The key aims of this project are to: i) develop an inducible Nos1 conditional knockout mouse model to allow temporal control of NO signaling. ii) assess neuronal composition and iii) the development/function of ICC after inducible knockout of Nos1. This study will provide key evidence as to NO-regulated ICC development, which might play a key role in normal motility and disease.
Our past experiences are captured in autobiographical memories that serve to sustain our sense of self, enable independent living and prolong survival. Despite their clear importance and the devastation wreaked when this capacity is compromised, the neural implementation of autobiographical memories has eluded detailed scrutiny. My goal is to understand precisely how autobiographical memories are built, how they are re-constructed during recollection and how these memory representations change over time. My aim is to identify the mechanisms involved in these processes and thereby establish a theoretically enriched account of their breakdown in pathology. This endeavour will be enabled by cutting-edge, multi-modal technology that includes a new wearable MEG system and ultra-high-resolution MRI. The ventromedial prefrontal cortex and hippocampus are heavily implicated in autobiographical memory. I will test a novel hierarchical model that specifies their distinct roles and how they interact to produce the seamless encoding and recollection of our lived experiences. Overall, this new extension of my work will expose autobiographical memories as never before, revealing the millisecond temporal dynamics, and the laminar-specific and hippocampal subfield processing that supports their evolution from the point of inception, through initial sleep cycles and then over longer timescales.
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.
Lung cancer remains the leading cancer-related cause of death in the UK. Early detection and treatment are critical to improving outcomes. Our lab has collected a unique set of lung tissue samples from patients with pre-cancerous disease, some of whom have gone on to develop cancer. By studying the genetic and molecular profiles of these samples we aim to elucidate the mechanisms of progression from pre-cancerous disease to invasive cancer. By doing so we can identify future methods of treatment and prevention. My work focuses on analysis of vast quantities of data produced by this program. We have recently studied the genetics of these samples, including which genes are expressed, which are mutated, and how they are regulated. From these complex networks we identify key signals of instability in the genome, which we believe are driving progression to cancer. These data provide a snapshot of early cancer. The first aim of this project is to investigate the dynamics of this process using longitudinally collected samples, and new techniques which can probe these samples on a single-cell level. The second aim is to study the immunological mechanisms by which some pre-invasive lesions regress and do not become invasive cancer.
Genomic instability triggers catastrophic events that restructure parts of the genome and provide a proliferative advantage to the cancer cell (e.g. through oncogene amplification) in up to 30% of cancers. There is recent evidence that suggests these types of events may also impact immune responses, by affecting genes that are involved in the interaction between cancer cells and their microenvironment. This project aims to study the impact of two well defined catastrophic events, chromothripsis (massive chromosome-wide rearrangements) and kataegis (hypermutated regions), on genes involved in immune-related pathways in oesophageal adenocarcinoma. The student will work with whole-genome sequencing data from 120 samples of oesophageal tumours available from the International Cancer Genome Consortium and will employ bioinformatics approaches to address the following key goals: (1) identify chromothripsis and kataegis events using computational protocols previously established in the group; (2) identify the genes affected by these events via genomic overlap methods; (3) summarise the proportion of the genes affected that are involved in immune signalling pathways (as recorded in relevant pathway databases). This will enable us to assess the likely impact of such catastrophic events on immune system processes and further clarify their implication in immune evasion during cancer development.
Neural circuits in the brain underlie sensory perception and motor control, functions that are often impaired during neurological disorders. However, many aspects of circuit function remain unclear. These include how sensory and motor information is represented and transformed as it flows through neural circuits. In this project, I will study the properties of Golgi cells, a particular type of inhibitory neuron in the cerebellar cortex, a brain area that helps coordinate movements and predict thier sensory consequences. To do this I will use a new high speed 3-dimensional microscope technology that can measure signals as they rapidly flow through complex neural circuits deep within the brain of mice expressing fluorescence reporters of neural activity. By examining how the activity of populations of inhibitory neurons change during different behavioral tasks and during learning, I will determine how these neurons contribute to information processing in the cerebellum. By combining this imaging method with methods for manipulating neuronal activity and network models of circuit function I will identify the underlying mechanisms. This research will lead to fundamental new insights into cerebellar function and will provide a framework for understanding what goes wrong during neurological disorders.
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.