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Recipients:
University College London

Results

Homeostatic gene networks in Drosophila models of epilepsy and dyskinesia 31 Jan 2017

Transcriptional and translation control in neurons is highly plastic, allowing firing frequency and synaptic output to be regulated with high temporal precision. Recent research has demonstrated that the complement of ion channels within a neuron can undergo homeostatic remodelling in response to altered neuronal excitability. However, the extent to which this occurs in neurological diseases is unknown, as are the alterations in ion channel expression that may buffer disease-linked mutations to the greatest degree. We aim to investigate these questions using the fruit fly, Drosophila melanogaster. Using homologous recombination, we will generate a novel knock-in fly model of Generalized Epilepsy and Paroxysmal Dyskinesia (GEPD). This disorder is caused by a gain-of-function mutation in the KCNMA1 BK potassium channel – the mammalian homologue of Drosophila slowpoke (slo). We will characterise changes in ion channel expression in GEPD slo knock-in flies through RNAseq, and using this data, perform a modifier screen to determine which alterations are compensatory or pathogenic. Genetic suppressors identified via this strategy will represent promising targets for future therapeutic interventions.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

How do cells integrate signals? Roles of timing in neural induction 31 Jan 2017

During embryonic development cells have to integrate up to eight molecular pathways in order to choose between alternative fates or behaviours. However, even in combination, these eight pathways cannot provide enough information to specify the many (perhaps as many as 104) cell types that comprise the adult body. Timing seems to be important. One of the earliest fate decisions in embryonic development occurs soon after gastrulation during neural induction when one part of the epiblast is set apart, acquiring neural identity in response to signals from the organiser, Hensen’s node. A recent view is that neural induction is highly regulated in time and that it involves several steps. Competent cells, capable of responding to signals from the organiser, go through different states of specification before committing to the neural fate. Here we aim to understand how timing orchestrates neural induction. Specifically, we will uncover whether competence to respond to inducing signals is regulated by a cell-autonomous clock or by external instructions, how competent cells can sense exposure to signals of different duration and how this signal changes over time to generate an appropriately regionalised neural plate.

Amount: £12,700
Funder: The Wellcome Trust
Recipient: University College London

Utilising electronic health records and Mendelian randomisation to investigate the relationship between liver function biomarkers and gastrointestinal disease; an example of bilirubin 30 Sep 2017

Liver function tests (LFTs) are commonly performed in clinical practice and are often associated with malignant and inflammatory diseases. Bilirubin has an anti-oxidant, cytoprotective function, and reported inverse associations with conditions including cardiovascular disease, inflammatory bowel disease, colorectal cancer and overall mortality. We will use linked primary care, hospitalisation, disease registry and mortality data in England (the CALIBER programme), [1] and include people aged 18 or older with no underlying gastrointestinal disease at baseline. We will use Cox models to estimate cause-specific hazard ratios (HRs) for the association of baseline bilirubin with onset of gastrointestinal disease. We will further compare outcomes in gastrointestinal disease and malignancy cohorts including hospitalisation rates, relapse-free survival, net survival and mortality. Finally, we will determine whether the associations detected (with serum bilirubin) are likely to be causal by utilising a Mendelian randomisation approach.

Amount: £253,846
Funder: The Wellcome Trust
Recipient: University College London

Cellular and network mechanisms of hippocampal -prefrontal coordination during memory consolidation 09 Nov 2016

Consolidation of newly acquired memories takes place during sleep and involves the interaction of hippocampus and prefrontal cortex. The cellular mechanisms and synaptic pathways underlying this process are not fully understood but it has been hypothesized that synchronous hippocampal ripples and prefrontal cortex spindles mediate it. The present project proposes a multimodal approach to investigate these mechanisms in rodents. The first goal will be to dissect the fine-scale dynamics of memory reactivation in hippocampus and cortex during sleep after learning of a spatial memory task. This aim will be achieved with simultaneous large-scale recordings in both structures and advanced analysis of population activity. The second goal will be to unveil which anatomical regions and synaptic pathways are mediating this inter-regional synchronization. Simultaneous electrophysiological and functional magnetic resonance recordings will be performed in sleeping rats before and after the task and wide-brain activity will be assessed at times of high hippocampal-prefrontal synchrony. The last goal will be to causally verify the participation in inter-areal coordination and memory consolidation of the key synaptic pathway(s) pointed out in the previous stage. To achieve this, closed-loop optogenetic silencing of specific cellular populations would be performed at times of hippocampal-prefrontal synchrony during sleep memory consolidation.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

Vacation Scholarships 2017 - University College London 16 Jun 2017

Vacation Scholarships 2017 - University College London

Amount: £25,500
Funder: The Wellcome Trust
Recipient: University College London

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).

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

Investigating the sleep modulating effect of oxytocin in zebrafish models of autism. 27 Apr 2017

In this project I will test the hypothesis that oxytocin expression and development of oxytocin-expressing neurons are altered in zebrafish with mutations in the ASD risk genes cntnap2 and chd8. I hope to find evidence for the sleep modulating effects of oxytocin, and posit whether deficiencies in oxytocin signalling pathways may contribute to sleep disorders in autism mutants. I will examine oxytocin mRNA levels across the day/night cycle for both wild-type and mutant fish established in the Rihel lab. I will then analyse the pattern of oxytocin expression in the brains of mutant embryos and their wild-type siblings. From the findings in related studies with cntnap2 mutant mice and the Rihel lab zebrafish models of autism (see references [3] and [6]), I expect to see an alteration in the amount of oxytocin mRNA for day/night between the wild-type and mutant embryos, and a change in the number of neurons expressing oxytocin. If such changes are found, they could explain the sleep phenotype observed in cntnap2 autism mutants, and elucidate a link between neuronal circuit dysfunction and behavioural perturbation in this animal model.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

The Countdown to 2030: Global Health and Climate Action 30 Sep 2016

Climate change threatens to undermine the foundations of human wellbeing, and to reverse the last five decades of gains in global health. The 2015 Lancet Commission on Health and Climate Change concludes that the barriers to tackling climate change and improving public health are no longer economic or technological, but largely political. The report also concludes that "tackling climate change could be the greatest global health opportunity of the 21st century", with reduced greenhouse gas emissions yielding substantial health (and economic) gains. The Commission is an institutional collaboration between European and Chinese academic centres, led by University College London, Tsinghua University (Beijing), the University of Exeter, and Sweden’s Stockholm Resilience Centre and Umea University. It published its work on the 23rd of June, 2015 in The Lancet, with 11 launch events around the world. The authors of the Commission report recognise the need to carry their work forward- and to help deliver the required change. They propose a "Countdown to 2030: Global Health and Climate Action" as a mechanism for tracking progress on the implementation of policies designed to respond to climate change and protect public health. This idea draws upon the success of the Countdown to Child Survival, which galvanised evidence, interest and action to improve progress on child mortality over the past decade. The Countdown will exist as an independent, international, and multi-disciplinary coalition of organizations. The combined networks of The Lancet and the partner institutions will be utilized to ensure global reach to academics, policymakers, and the health community. It will produce an annual synthesis report on (i) the health impacts of climate change; (ii) progress in mitigation policies and the extent to which they protect and promote public health; (iii) progress with broader adaptation action to reduce population vulnerability, to build climate resilience, and to implement low carbon, sustainable health systems. The Countdown will continue its collaboration with The Lancet, who commit to publishing these Countdown Reports, as well as a number of related country- or issue-specific articles throughout each year.

Amount: £499,186
Funder: The Wellcome Trust
Recipient: University College London

Role of grid cell replay in consolidation and navigation 11 Feb 2016

I aim to build a neural level understanding of how information about the environment is stored, updated, and retrieved from memory. To this end I will study spatial memory and its representation in the rodent hippocampal formation. The results from experimental work including multi-site single unit recordings, pharmacological and optogenetic interventions, along with behavioural manipulations, will be combined with state of the art computational modelling. In turn computational work will suggest and refine further experimental manipulations. This joined-up approach is necessary to close the existing gap between our current neural-level understanding of the brain and cognitive functions. My key goals are to understand: 1) How entorhinal and hippocampal spatial representations are modulated by the level of certainty an animal has about the spatial configuration of its environment. 2) The role of cholinergic modulation in signalling environmental novelty, and more generally spatial u ncertainty. In particular, the effect of cholinergic modulation on theta-frequency rhythmicity and the scale of spatial representations. 3) How changes in the scale of the entorhinal spatial representation may contribute to, and even trigger, memory formation.

Amount: £143,293
Funder: The Wellcome Trust
Recipient: University College London

The Genomics of Multidrug-Resistant Tuberculosis Transmission 18 May 2016

An estimated 37 million lives were saved by tuberculosis treatment between 2000 and 2013. However, multidrug-resistant tuberculosis threatens this treatment success, costs 10 times more to treat and requires toxic antibiotics. The Mycobacterium tuberculosis genome is more variable than previously thought. This variability may explain differences in drug-resistance acquisition, bacterial fitness and transmission between lineages. Identifying which bacteria are most likely to survive, spread and acquire drug-resistance could allow expanded antibiotic therapy and contact tracing to be tailored to the bacterial genome. Preliminary analysis of 470 multidrug-resistant tuberculosis genomes in collaboration with world leading tuberculosis geneticists has demonstrated that multidrug-resistant tuberculosis strains independently evolve mutations in cell surface immunogenic proteins. Our hypothesis based on these findings is that these mutations improve bacterial fitness and facilitate multidrug-resistant tuberculosis spread. Genome sequencing two unique high-coverage cross-sectional Mycobacterium tuberculosis DNA collections, with metadata and epidemiological links, assembled during the candidate’s Wellcome Trust Fellowship in 2009 and 2013 will address these key questions: 1) What is the Mycobacterium tuberculosis sub-lineage association with drug resistance acquisition? 2) How is multidrug-resistant tuberculosis adaptively evolving to overcome the fitness cost of drug resistance? 3) Which adaptive mutations are expanding most rapidly in the population over time?

Amount: £354,546
Funder: The Wellcome Trust
Recipient: University College London

Avoiding on-target off-tumour toxicity in cancer immunotherapy. 19 Nov 2015

Chimeric antigen receptors link MHC-unrestricted antigen specificity with T-cell signalling, facilitating potent and regulatable antigen-specific cancer recognition and killing. Clinical trials of CAR gene modified T-cells show unprecedented clinical responses, with the major limitation of on-target off-tumour toxicity due to expression of most cancer antigens on some normal tissues. In my Wellcome clinical training fellowship I identified a novel method of avoiding such toxicity by designing CA Rs for use in gdT-cells. These gdT-CAR cells combine innate killing limited to sites of cancer or injury with CARs providing co-stimulation to overcome the immunoinhibitory tumour microenvironment. I demonstrated proof of concept using two model antigens, GD2 and CD33, applicable to solid cancers (e.g. neuroblastoma) and myeloid leukaemias (e.g. AML) respectively. In my fellowship I will develop this by: 1) Identifying mechanism and relative efficacy of different co-stimulatory CAR endodomains in gdT cells 2) Investigate selectivity of co-stimulatory CARs in gdT against acute myeloid leukaemia compared with healthy blood cells bearing the same tissue antigen. 3) Investigate the use of mass cytometry for high-dimensional signalling analysis to inform CAR design. Efficacy, toxicity and mechanism will be assessed in a staged manner using cell lines and primary tissue.

Amount: £275,672
Funder: The Wellcome Trust
Recipient: University College London

Understanding within-patient Mycobacterium tuberculosis genetic diversity to prevent drug-resistance 29 Jun 2016

Tuberculosis, caused by Mycobacterium tuberculosis (M.tb), is a major public health problem. Drug-resistant tuberculosis (DR-TB) cases are increasing, creating a significant barrier to disease control. DR-TB is difficult to diagnose and treatment often takes years. M.tb was traditionally thought to be genetically homogenous within the human host, but deep whole genome sequencing (WGS) data have revealed evidence of within-host genetic heterogeneity (GH), particularly in drug-resistance genes. Changing GH patterns over time can cause acquired drug-resistance (ADR). However, how and where in the host GH arises, or how important it is for ADR is not known. I hypothesise that GH represents isolated M.tb subpopulations in separate lung lesions within a patient, and that development of GH is related to local pathology or drug penetration. I will investigate this by WGS of M.tb extracted from resected human lung tissue, and comparing GH to pathology type and local drug concentrations. To evaluate whether GH causes ADR, I will follow patients with newly diagnosed MDR-TB and perform WGS of sequential sputum samples over 6 months for WGS. I will evaluate if ADR is related to baseline GH. Understanding the role of GH in ADR could help develop prevention strategies.

Amount: £380,125
Funder: The Wellcome Trust
Recipient: University College London

Homeostatic monitoring and control of regional brain blood flow 05 Apr 2016

This research programme is designed to explore cellular and molecular mechanisms underlying homeostatic metabolic control of regional brain blood flow by addressing the following fundamental questions: (Q1) How are the changes in brain parenchymal PCO2/[H+] detected and what are the mechanisms underlying the effect of CO2/H+ on cerebral vasculature? (Q2) What are the mechanisms responsible for hypoxia-induced dilation of cerebral vasculature and what is their role in the redistribution of regional brain blood flow in accord with parenchymal O2 content? (Q3) What is the role of CO2/H+-sensitive mechanisms of astroglial/vascular interface in neuronal activity-dependent control of cerebral vasculature and in generation of the blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signals? (Q4) What are the cellular identity, sensory transduction mechanism and physiological role of an intracranial baroreceptor capable of sensing decreases in brain perfusion pressure? These questions are addressed by genetic targeting and blockade of hypothesized signalling pathways, in vivo two-photon excitation imaging of neurovascular interface ([Ca2+]i in astrocytes/neurones and parenchymal vasculature) and assessment of regional cerebral blood flow and cerebrovascular reactivity using BOLD and arterial spin labelling fMRI in experimental animals (rats and mice).

Amount: £1,295,793
Funder: The Wellcome Trust
Recipient: University College London

The neural circuits of social preference 01 Jun 2016

Social preference requires the ability to recognize and approach individuals of the same species (conspecifics). In humans, these behaviours are present from birth and are thought to be impaired in developmental disorders, such as autism, that are characterized by aberrant sociality. The innate brain circuitry that underlies human social preference is conserved in other social vertebrates, including the genetically accessible zebrafish. I have recently shown that larval zebrafish exhibit social preference from just two weeks post fertilization. At this developmental stage, larvae are transparent and thus amenable to the full range of modern optical techniques for single cell resolution circuit analysis. I will first use reporters that integrate neural activity to highlight the anatomical correlates of the social preference circuit. Two-photon calcium imaging during the presentation of virtual social stimuli will then be used to characterize the functional properties of the identified circuit elements. Finally, given that fish development occurs ex utero, I will monitor the development of this essential circuit and precisely document the impact of environmental and genetic manipulations that have been implicated in models of human disease.

Amount: £1,181,701
Funder: The Wellcome Trust
Recipient: University College London

Functional dissection of neural circuitry underlying pain signalling. 21 Oct 2015

It is estimated that up to one in five Europeans suffers from chronic pain. This has a large impact on the quality of life of individuals and on our society as a whole. The lack of effective treatments is largely because the fundamental mechanisms that signal pain remain obscure. The proposed research aims to understand how sensory information is encoded at nociceptors and then processed in the spinal cord. Advanced optical and genetic tools will be used to precisely control the activity of two nociceptive primary afferent neuron subpopulations that project into the dorsal horn of the spinal cord with little overlap. The specific aims are to determine: 1) How nociceptors encode sensory information, by defining their tuning and how their spiking activity relates to behaviour; and 2) how spinal cord circuits process nociceptive input, by examining how information is integrated in the spinal cord, and how it is transformed in models of chronic pain. The proposed research aims to dissect o ut these mechanisms with the goal of leading to better treatments for chronic pain.

Amount: £1,111,487
Funder: The Wellcome Trust
Recipient: University College London

Multisensory Integration in Time and Space. 11 Nov 2015

Although the majority of neuroscience research focuses on isolated sensory cues, in natural environments, the brain is invariably faced with a vast array of sensory stimuli. Animals must continually evaluate which of these multimodal cues should be associated with a single physical object, and which are separate. To this end, animals, including humans, take advantage of two types of correlation: spatial and temporal. Psychophysical studies of this phenomena are abundant, but neural recordings re main minimal and have been limited to specific brain areas like the superior colliculus and parietal cortex. In addition, past work has been focused on spatial correlations between multisensory cues, largely ignoring the effects of temporal correlations. I propose to characterize both the spatial and the temporal aspects of multisensory integration by exploiting advanced behavioral and recording techniques in the mouse cortex. I will 1) train mice to perform novel behavioral tasks which neces sitate multisensory integration, 2) identify cortical regions responding to audiovisual correlations in space and time using widefield imaging and two-photon microscopy during passive viewing, and 3) identify the neural correlates of multisensory integration using optogenetic perturbations and two-photon imaging during behavioral tasks.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

A cross-cohort comparison of unhealthily low BMI in early adolescence – a feasibility study and development of research protocol 31 Jan 2016

Childhood thinness (unhealthily low body mass index) has been linked to poorer health and development but has received relatively little research attention in high income countries. Contemporary routine data reported by the National Child Measurement Programme (NCMP) point towards a possible U-shaped socio-economic gradient in thinness in 10-11 year olds (whereby those living in the most and least deprived areas have elevated rates of thinness). However, since the main focus of the NCMP is overweight and obesity, this social patterning in thinness has not been emphasised or further investigated. The U-shaped socio-economic distribution in thinness may be explained by food poverty in more disadvantaged areas, and issues of body image and eating disorders in more advantaged groups. UK cohort studies provide an untapped resource for examining this issue, because they contain rich, individual-level data, spanning different time periods (exposed to different social and economic contexts). However cross-cohort comparisons can be challenging and require a lot of input at the planning stage. This proposal therefore comprises of a feasibility study for a cross-cohort investigation of individual-level socio-economic inequalities in thinness in young people (and possible reasons behind them).

Amount: £2,100
Funder: The Wellcome Trust
Recipient: University College London

Intracellular sodium and its effect on neuronal Gene Expression 01 Apr 2016

This project will involve investigating the effects of intracellular sodium on the gene expression in Dorsal root ganglion neurons. The key aims of the project will be to determine the role of sodium mediated signalling in neuronal gene expression. To determine this, high affinity sodium binding protein will be investigated; a cloned DNA construct of the protein will be transfected in to HEK (Human Embryonic Kidney) cells and then DRG neurons with a Nav1.7 knock out. The effect of low intracellular sodium concentration on expression of Penk will be assesed by analysis of the DRG neurons.

Amount: £1,750
Funder: The Wellcome Trust
Recipient: University College London

Pathophysiological consequences of mutations affecting the mitochondrial calcium uptake pathway 01 Apr 2016

Mitochondrial calcium uptake plays critical roles in cellular energy homeostasis. Alterations both in mitochondrial function and in cellular calcium signals play major roles in the pathophysiology of many major diseases, including ischaemic injury, neurodegenerative and neuromuscular diseases. The very recent discovery of the proteins mediating mitochondrial calcium uptake provides a new opportunity to understand the physiological roles of the pathway and pathological consequences of its dysfunction, as seen in patients with mutations of MICU1 described by the host lab. The patients have learning difficulties, muscle weakness and a progressive extrapyramidal motor disorder. The mechanism whereby mutations of MICU1 cause this particular constellation of symptoms are not understood. We will use iPS cells which we have generated from patient derived fibroblasts, differentiated into neurons and myotubes – the tissues most affected in the patient – and explore the consequences of MICU1 mutations for mitochondrial calcium signalling and for mitochondrial bioenergetic function. The project will illuminate the underlying mechanisms causing symptoms in the patients and point the way to therapeutic strategies.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University College London
Amount: £163,124
Funder: The Wellcome Trust
Recipient: University College London