- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 30 Sep 2017
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Water resistance: a study of environmental justice, resilience and citizen science activism in Mexico City 02 May 2017
This research will explore resilience in the context of environmental justice, with a focus on water insecurity in Mexico City. The concept of resilience is central to public health and climate change discourse, but is rarely critiqued. Addressing this omission is crucial: resilience frameworks can conceal social inequalities, uphold political status quo, and overlook local experience. Equally, few anthropological studies have examined resilience and urban water insecurity. In Mexico City these gaps are especially prescient. The third most water-stressed city in the world, low-income neighbourhoods have limited access to water. Communities often protest in response. Drawing together an ethnographic study with the digital participatory methods of citizen science, the goals of this research are to: Understand the meaning and practices of resilience amongst people who experience water insecurity. Investigate the role of digital technology and citizen science in this space. Inform future uses of resilience in environmental justice research, design and policy. Through these objectives, the research acts at the intersection of social inequality, public health and the environment. The outcomes will contribute to anthropological theory and knowledge, open the potential for trans-disciplinary collaborations, and bring a more sensitive and ethical perspective to the overlap of climate change and health.
Central nervous system compartmentalisation and drug resistance in HIV-1 sub-type C infection 30 Sep 2017
My research proposes to study HIV compartment shifts from the CNS to the peripheral blood, the evolution of drug resistance in the CNS and the relationship between CNS co-infection with other neurotropic organisms and CNS compartmentalisation in HIV-1 subtype C. Within a longitudinal cohort I will conduct a proof-of-principle study with the aim of testing the hypothesis that the CNS is a reservoir for HIV, where independent replication with the possibility of developing drug resistant mutations that may seed into plasma on treatment interruption. I will track the dynamics of compartment shifts and the evolution of drug resistance in paired plasma and CSF before and during the course of ART over 2 years. I will follow-up patients in this cohort initiating first-line therapy, and go on to repeat paired sampling of plasma and CSF in those with low level viraemia (LLV), where I expect 20% to have CNS compartmentalised HIV. Finally, I will capitalize on collaboration with an ongoing therapeutic clinical trial of cryptococcal meningitis (CM) (the ACTA trial) to examine HIV CNS compartmentalisation and the emergence of ART resistance in the brain in patients with CM. I will benefit from having access to stored samples of paired CSF and plasma from 680 patients in this multi-centre trial in Africa. Phenotypic drug susceptibility using pseudotyped viruses with patients’ derived gag-pol in a single cycle infection assay system and genotypic assessments of compartmentalised viruses will be performed, using next generation sequencing and single genome amplification. The project builds upon the continuing close collaboration between Dr Ravi Gupta’s group at UCL and Professor Deenan Pillay at the Africa Health Health Research Institute in KZN, South Africa. The proposal complements and extends the research programs in both centres. I will have access to superb experimental science facilities in Durban where there is a major focus on HIV drug resistance and with clinical and population based research excellence at the epicentre of the HIV epidemic. The Gupta laboratory at UCL specializes in HIV drug resistance, HIV reservoirs, particularly within macrophages, with complementary skills and interests in Durban.
Exploring the epidemiology of respiratory syncytial virus in young children in the community using sparse serological survey data 12 May 2017
Bronchiolitis caused by respiratory syncytial virus (RSV) leads to over 30,000 hospital admissions annually in infants in England. RSV infection only confers transient immunity, and early RSV infection is associated with asthma in later childhood. Several vaccine candidates are currently in clinical trials. We currently know very little about how age at first infection is affected by, for example, the number and age of siblings, or what factors influence protection from maternal antibody. We will carry out the first community serosurvey of RSV in the UK using a unique collection of serial baby blood samples linked to maternal, family and symptom data from the Born in Bradford study. We will develop novel statistical methods to estimate the age at first and subsequent RSV infection in the first two years of life, and validate our findings against parent questionnaires and routinely collected primary care data. This study will provide important information about who to vaccinate, and when, to ensure babies are protected from early RSV infection, novel methods to estimate age at infection from sparse serological data, and validated methods for a larger, pan-European study of the role of RSV infection in early life and respiratory health in later childhood.
The overall goal of this proposal is to elucidate the cellular and molecular mechanisms that regulate natural glia-to-neuron cell-fate switches. Stably differentiated cells can sometimes display a remarkable degree of plasticity and switch fates to another differentiated cell type, in a process termed transdifferentiation. In the vertebrate nervous system, radial glia act as neural progenitors during embryogenesis. Suprisingly, stably differentiated glia can also act as neural progenitors during adult neurogenesis. We have recently discovered two cases in which stably differentiated glial cells undergo a glia-to-neuron cell-fate switch during sexual maturation in the nervous system of C. elegans, allowing us to study these events at the single-cell level in a genetically tractable system. We will combine classic genetic approaches with state-of-the-art molecular and next-generation sequencing approaches to characterise the molecular and epigenetic changes that occur during natural glia-to-neuron transdifferentiation. We will elucidate the role of cell division in this process, identify novel molecular regulators and determine the reprogramming abilities of the factors we identify. Unleashing the neurogenic potential of glia offers tremendous therapeutic possibilities.
Imaging and activation of glymphatic clearance: a novel strategy for Alzheimer’s Disease 26 Oct 2016
There is a critical need for early and accurate biomarkers of the pre-symptomatic phase of Alzheimer's disease (AD), to maximise the efficacy of emerging therapies. Recent evidence implicates cerebral glymphatic exchange as a key mechanism in early AD pathogenesis [Figure 1] [1-4]. I will develop the first non-invasive method for the quantitative assessment of glymphatic clearance, using MRI. These novel methods will be carefully validated by comparison with the invasive measures , that I have previously established, in normal, aged and AQP4 null mice. I will apply these novel techniques longitudinally to mouse models of ageing and AD (amyloid and tau) to investigate impairment of glymphatic clearance relative to more established markers of AD pathogenesis such as structural imaging, perfusion and histological assessment of plaque/tangle burden. As such, these data will be the first to elucidate the chronology of abnormal glymphatic clearance in AD pathogenesis. Finally, I will combine these methods with targeted optogenetics to assess the interaction of vessel tone and vasomotion to rates of glymphatic clearance in order to characterise the underlying mechanisms that drive CSF-ISF exchange.
Generalised anxiety disorder (GAD) is a common and debilitating condition. Its core symptoms are strongly related to subjective feelings evoked by uncertainty. This fellowship will build on advances in computational modelling to characterise the role of estimations of uncertainty about aversive events in GAD. The project has three key goals: 1) To develop behavioural tasks, and computational models of these tasks, that allow estimations of uncertainty during aversive reinforcement learning. I aim to achieve this by building on existing reinforcement learning tasks that manipulate uncertainty through changing stimulus-outcome contingencies, combined with models that allow explicit estimation of participants’ perceived uncertainty. 2) To determine whether individuals with GAD overestimate uncertainty, or overestimate the likelihood of negative outcomes in uncertain situations. To do this I will exploit tasks and models developed in phase 1 of the proposal to compare subjects with GAD and healthy individuals on their estimation of uncertainty in aversive environments. 3) In this phase I aim to identify the neural basis of these abnormalities using functional neuroimaging (fMRI), by combining these tasks and models with fMRI to identify neural systems underlying uncertainty estimation in aversive contexts, and examining the differential function of these systems in patients with GAD.
Studying murine behaviour and extending the hippocampal place cell model to 3 dimensions 27 Apr 2017
In previous decades, studies focussing on hippocampal place cell activity have resorted to using 2-dimensional simulation models. I argue that such a paradigm proves to be insufficient when extending it to real-world, heavily 3D-biased, applications. As such, in this project, I propose an alternative approach to the study of place cells in which a rat’s neuronal activity is wirelessly monitored while it is allowed to freely explore a lattice maze in all directions of Cartesian space. Most importantly, I aim to show that receptive fields are of similar sizes in the horizontal and vertical directions; I also hypothesise that concatenating receptive fields (RFs) from several place cells will yield a layered organisation with inter-RF distances being larger in the x-z/y-z planes than the x-y plane. Incidentally, this study will also provide data which I hypothesise will confirm the horizontal bias model in murine behaviour proposed by Jovalekic et al. (2011).
CoAlation is a novel post-translational modification to proteins whereby Coenzyme A is covalently attached to proteins. It occurs as part of the oxidative stress response as an alternative mechanism to protein glutathionylation. It is specifically a modification of enzymes involved in cellular metabolism and protects catalytic thiol groups on active site cysteine residues from irreversible damage by reactive oxygen species and reactive nitrogen species. Applying oxidizing agents to cells results in induction of apoptosis. Such agents also induce protein CoAlation. The aims of this project are to monitor induction of apoptosis in HEK293 cells in response to treatment with oxidizing agents using anti-PARP3 and anti-Caspase 3 Western blot and Fluorescence-activated Cell Sorting and to analyse the pattern of CoAlation at different stages of apoptosis using anti-Coenzyme A Western blot.
Integrative and conjugative elements (ICEs) are mobile genetic elements present in both gram-positive and gram-negative bacteria. They mostly reside in the host chromosome and under certain conditions, will excise and transfer to a new host via the conjugation machinery. ICEs have been found to provide the host with a wide range of phenotypes, including antibiotic and heavy metal resistance and the ability to colonise a eukaryotic host, promote virulence and biofilm formation. The ability of ICE to spread to different species of bacteria through horizontal gene transfer is a major factor in bacterial evolution. Bioinformatics approaches have been increasingly used to identify possible ICEs through sequence similarity. In this project, we aim to find out the effectiveness of using an algorithm, DLIGHT (Distance Likelihood based Inference of Genes Horizontally Transferred) that was originally used to detect lateral gene transfer, to identify integrative and conjugative elements. We will achieve this by assessing DLIGHT's ability to recover already documented ICEs. We will also use DLIGHT to test certain sequences which we suspect to contain ICEs. The predictions of new ICEs will then be vetted through manual analysis and collaboration with experimentalists.
The lymph node is a meeting point for lymphocytes with antigen-presenting cells, and rapidly expands during immune responses. Lymph node structure is highly compartmentalised, and the complex internal architecture is maintained during lymph node expansion. Therefore, mechanisms must exist to balance lymph node integrity with the need to remodel very rapidly. Fibroblastic reticular cells (FRCs) are the most abundant lymphoid stromal cell population, and span the full volume of the tissue. They provide structural support and are highly contractile. FRCs ensheathes bundles of extracellular matrix, termed the conduit, which filters draining lymph. The Acton lab works to understand how lymph nodes are remodeled during expansion and has shown that interaction between FRCs and dendritic cells change FRC behaviour. This project asks how the microtubule networks within FRCs are reorganised as the FRC network expands. Phosphoproteomic screening has revealed that LL5-beta, a protein targetting microtubules to adhesion sites is regulated by interactions between FRCs and dendritic cells. This may provide a mechanism by which FRCs uncouple from underlying matrix, and target secretion of proteases or new matrix to the expanding network. This project will investigate whether LL5-beta coordinates organization of microtubules in FRCs and whether dendritic cell contact changes LL5-beta activity.
Noroviruses cause annual epidemics of gastrointestinal infection resulting in significant ill-health and disruption to health services. Frequent genetic mutation causing drift of epidemic strains and recombination leads to worldwide spread of pandemic strains. Approximately 3 million cases/annum occur in the UK with health-care costs exceeding £100M1. The advent of new vaccines against two genotypes is encouraging. However, ignorance about the drivers of norovirus strain evolution and spread is a barrier to effective vaccine design and deployment. This multidisciplinary consortium will investigate, through integrated studies, host and pathogen factors that lead to epidemic and pandemic norovirus spread and affect disease severity. Our international team has expertise in norovirus genome sequencing, phylogenetic analysis, norovirus antigen mapping, public health epidemiology and mathematical modelling. We will make use of existing clinical and public health datasets and samples, and an ongoing community study of norovirus burden to answer questions about transmission and carriage. Norovirus genome sequencing and phylogeography, in the context of international sequence-databases and antigenic mapping of sera will elucidate the origins and evolution of pandemic strains and outbreaks. Mathematical models, developed and fitted to the available data will provide novel insights into norovirus pathogenesis and transmission, informing vaccine design and immunisation strategies.
Neuroscience is entering an exciting period when it will be possible to decipher the neural codes underlying perception and cognition. Novel genetic, molecular, physiological, optical and behavioural approaches will allow the monitoring of activity across ensembles of neurons in behaving rodents, and the manipulation of this activity in a temporally and spatially precise manner. For the first time we will establish causal links between patterns of neural activity and behaviour, and carry out decisive tests of both new and long-standing hypotheses about the computational properties of neural circuits. Members of the consortia seek to understand the patterns of neural activity underlying sensory, motor and cognitive representations, and the rules by which they are assembled. The core of the present proposal is the development and testing of a major stepchange in silicon-based electrode technology to rapidly accelerate the pace of this work by greatly increasing the simultaneous sampling of extracellular electrical signals within and across multiple brain regions.
PhD studentship costs 17 Jan 2014
Chronic pain is prevalent and its clinical treatment remains limited. The London Pain Consortium (LPC) will advance knowledge of chronic pain mechanisms through internationally competitive research and provide multidisciplinary training of clinical and biomedical scientists to promote careers in neurobiology in general and pain studies in particular. In man and animals, we will: 1) identify molecular and genetic influences on pain processes; 2) study the integrative functions of these influenc es and their translation as therapeutic targets; 3) provide research and training resources for the wider scientific community.
Dynamic brain networks throughout development and their relationship to network abnormalities in paediatric patients with developmental epilepsies 15 Sep 2014
Neuronal networks change throughout development, from neuron physiology to large-scale connectivity. Abnormalities in the dynamic behaviour of networks have been implicated in the pathophysiology of childhood epilepsies. Electroencephalography (EEG) is suited to measuring neuronal dynamics, as it has a good temporal resolution, and is easily tolerated. In this study we are aiming to comprehensively characterise the development of cortical dynamics in childhood. Using both resting state EEGs, and well characterised event related potentials (ERPs), we will evaluate classical EEG and ERP measures (e.g. frequency/power distribution), as well as deriving network wide mathematical models of dynamic cortical function (e.g. dynamic causal models of effective connectivity). We can then empirically test predictions from cellular level physiological changes in normally developing children in terms of their network-wide effects. The same measurements will be performed in children with specific epilepsy syndromes. This will allow us to progress from the phenomenological comparison of EEG features between healthy controls and children with epilepsy, and instead we will be aiming to derive from the EEG neurobiologically relevant parameters that allow inference on the network abnormalities that contribute to the inherent seizure-susceptibility of the neuronal networks in children with epilepsy.
Cortical and subcortical mechanisms underlying movement generation and inhibition: a view through the mirror neuron system. 03 Dec 2013
The observation of the actions of others is central to our social lives. Action observation rarely triggers movements in ourselves, despite the presence of significant activity within the cortical motor network, including its corticospinal outputs. I propose that studying the mirror neuron system, which is active both during action-observation and action-execution, could offer novel insights into both the command signals that do characterise motor execution, and the mechanisms for suppression of unwanted movements, a key feature of human behaviour. Suppression may be exaggerated in Parkinson patients leading to the pathological slowing of movement. I will record single mirror neuron and local field potential (LFPs) activity in the cortical and subcortical motor network, during execution of skilled hand movements, during motionless observation of the same movement, and when movement is prepared but subsequently withheld. This will identify the motor system si gnals specifically associated with movement generation. I will search for the cortical and subcortical sources of movement inhibition that occurs during action-observation. In particular, I will investigate the role of cortical neurons projecting to the subthalamic nucleus (STN) through the hyperdirect pathway, since this projection may play a role in movement suppression, and may contribute to Parkinson disease (PD) pathophysiology. I will test the effects of Deep Brain Stimulation of STN on these neurons. My research will advance understanding of cortical activity evoked by action-observation as useful signals for brain-machine interfaces, and the mechanisms underlying the therapeutic effects of DBS for motor symptoms in PD.
Exploring the Gut Microbial Action of Metformin: Targeting the Gut Microbiota to Treat Metabolic Disease. 06 Nov 2013
Gut microbiota is a determinant of host health, influencing nutrition-related syndromes such as type-2 diabetes, obesity and ageing, and can be modulated by xenobiotic drugs. Metformin is the most widely prescribed drug to treat type-2 diabetes. However, its therapeutic potential goes far beyond its anti-hyperglycaemic action, also reducing the risk of ageing. Despite significant research into the functions and molecular mechanisms of metformin, little is known about its specific cellular target (s), in particular those underlying the long-term wide-range effects on mammalian health. Our prediction is that metformin alters the function/structure of the microbial communities, which confers long-term health benefits in the host. Objectives to be tested empirically: 1) Does the anti-diabetic drug metformin require gut microbiota to exert beneficial effects on the host? 2) Are the long-term positive effects of metformin mediated by gut microbial changes upon treatment? 3) Can we target gut microbiota with metformin or genetically engineered microbial strains to treat metabolic disease and ageing in the host? To this end, we will utilise germ-free rodent and C. elegans applying high-end metabolomic and transcriptomic techniques. Therefore, this proposal aims to clarify the causality between host-microbe interactions and metabolic disease, and its modulation by the anti-diabetic drug metformin.
In experimental studies it is non-trivial to investigate mechanical roles of proteins, such as in generating tension, independent from their biochemical functions. The mechanical regulation of tissue growth can be effectively investigated with approaches that allow for independent probing of mechanical properties. To address this requirement, I will carry out computational studies at tissue and cellular levels in 3D, to investigate the mechanical and physical aspects of tissue growth and shape f ormation. I will develop a tissue scale model of the Drosophila wing disc to investigate forces and mechanical properties driving the self-folding of the tissue, and a cellular model to investigate the mechanical regulation of morphology changes required for mitosis. Unequal or directional cell division profiles can change the shape of the tissue, and also generate tension/compression gradients. The collective forces, actively generated by the cells, contribute to the tension/compression gra dients, and drive changes in the architecture of the tissue. In a two-way interplay, while proliferation contributes to the generation of forces, these forces in turn influence cell division. By approaching the problem at both tissue and cellular levels, I will be able to probe this interplay between internal dynamics of proliferating cells, and tissue scale morphodynamics.
In the context of the UCL initiative for the creation of an ethnically Chinese Medical Humanities www.ucl.ac.uk/chinahealth, we propose a collaborative workshop (UCL China Centre for Health and Humanity [UCL CCHH], Peking University [PKU] Institute of Medical Humanities and King's College London [KCL]) to develop new topics for teaching. Building on the experience of an existing UCL CCHH course on Film and the Body taught together with experts across the three institutions, we will explore the p otential of film for speaking to the challenges of the discipline. The workshop anticipates a larger conference to be held across the institutions involved, looking at the future of the teaching of Medical Humanities in and about China and what it can contribute to the wider field. It is envisaged that the proceedings of both workshop and conference will generate publications and online open access teaching materials. Support is sought for the travel and accommodation of key contributors and fun ds are matched by both Peking University and UCL.
Supplementary funding 16 Sep 2013
Over the last decade, the comprehensive longitudinal data generated from the Africa Centre surveillance has been extensively used to provide empiricalevidence on the socio-demographic and health impact of the HIV epidemic ina severely affected, rural population. The mutually beneficial partnership between the Centre and Department of Health in the delivery of the HIV Treatment and Care Programme has allowed the evaluation of the impact of the programme at population level and informed understanding of clinical outcomes at an individual level. Building on this extensive body of work and supportinghealth care improvements, our aim in the next quinquennium, 2012-2017, is to demonstrate substantial reductions in the spread of HIV for current and futuregenerations of adults, virtual elimination of mother-to-child transmission andchanging HIV from a major source of mortality and morbidity to a chronic, manageable condition. We will achieve this overarching aim by focusing our research on identifying the impacts of combined approaches to HIV prevention and treatment on the individual, the household, the community and the health care and social systems. Our long-term goal is to be instrumental in the elimination of HIV transmission and acquisition and the mitigation of its impact in this rural population.