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Recipients:
University College London

Results

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

Dissecting the neural components of the hippocampal cognitive map 05 Jul 2016

The existence of place, directional, boundary and grid cells in the rat hippocampal formation provides strong evidence that this part of the brain functions as a cognitive map. This theory suggests that the hippocampal formation contains map -like representations of familiar environments which enable the animal to identify its current location together with desirable and undesirable locations and to generate the vectors to move towards or away from these. I propose to use novel behavioural tasks, high-density extracellular recording probes, 2-photon imaging, and pharmacological and optogenetic manipulation of cell activity to explore in-depth the properties of these spatial cells and the role of different components of the hippocampal formation in spatial memory and navigation. Specifically I will address the following questions: How well does the activity of place, head direction and grid cells correlate with the animal’s perception of the different aspects of space and which cells are important in supporting navigation to an unmarked goal? What are the relative roles of external landmarks versus internal path integration signals in determining the firing of place cells? Do the l grid cells signal distance travelled in a particular direction or something else such as the shape of the environment?

Amount: £2,837,189
Funder: The Wellcome Trust
Recipient: University College London

The role of Innate Lymphoid Cells in the Gut to understand HIV pathology 01 Jun 2016

HIV pathology precipitates irreversible loss of mucosal barrier integrity. Innate Lymphoid Cells (ILCs) are crucial for rapid tissue repair and homeostasis and stimulate epithelial cell proliferation at gut mucosal barrier sites. I have shown that HIV-1 infection depletes ILCs in the circulation, and that this depletion correlates with disease stage and is not restored by antiretroviral treatment (ART) in chronic infection. Critically, ART initiated during early acute infection prior to peak viremia preserved ILC depletion1. This is a strong rationale for a role of ILCs in HIV pathology that involves gut barrier breakdown. However, the impact on ILC function at mucosal gut barrier sites remains unclear and is the specific focus of this proposal through studies of unique gut samples not available in Europe and US. Goals: 1: To define the role of ILCs in gut barrier integrity during different stages of HIV infection and study the impact of ART treatment. 2: To study the impact on gut epithelial cells after HIV infection and investigate those mechanisms using the "mini-gut model". 3: To use ILC and epithelial cell interaction as a first step to develop a novel treatment strategy focused on restoring gut dysbiosis to prevent immune activation and AIDS.

Amount: £1,241,654
Funder: The Wellcome Trust
Recipient: University College London

Transforming visual images to cognitive maps 24 Feb 2016

The visual system and hippocampal formation are two of the most studied areas of the brain. However, we do not understand how these areas work together. My goal is to understand the neural circuits and computations through which signals from sensory visual images are progressively transformed to create a cognitive map. Specifically, I will test the hypothesis that visual signals are processed along two parallel streams for navigation: one which processes landmark related signals, and a second stream that processes signals related to self-movement. I will then test two specific hypotheses regarding how the hippocampus integrates signals from multiple sources. Finally, I will test the causal influence of specific pathways on the hippocampal representation of space and animals’ spatial decisions, by inactivations using opto-genetics. I will address these questions in mice, using techniques such as rodent virtual reality, large-scale electrophysiology recording, computational modeling, and optogenetic interventions. My key goals are: 1) Identify the circuits involved in creating a cognitive representation from visual images. 2) Determine the computations by which visual signals are transformed into cognitive signals. 3) Understand how the hippocampus combines signals from multiple streams, and is affected by manipulations to pathways of the vision-to-navigation circuit.

Amount: £906,060
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

Better understanding of affective behaviour through functional dissection of ventral subicular circuitry. 21 Oct 2015

The overall aim of the proposed work is to understand the control of affective behaviour, from the level of individual synaptic and cellular mechanisms through to the complex circuitry in which they are utilised. To achieve this I will investigate the ventral subiculum (vS). vS is considered crucial for affective behaviour, but due in part to its complex circuitry, how it carries out this important role is unknown. I will use a powerful combination of in vivo and in vitro circuit analysis to gai n a mechanistic understanding of how affective behaviour is controlled by vS circuitry, and altered by disease. I will first address the long-standing, but poorly tested hypothesis that distinct populations of projection neurons in vS have disparate and unique roles in the generation of affective behaviour using in vivo imaging and optogenetics. I will then investigate the afferent circuitry in vS that determines the activity of the different vS projection types, to provide a mechanistic m odel for how vS circuitry, and thus affective behaviour, is controlled. Finally, I will investigate cocaine-induced synaptic alterations in vS, and aim to provide a direct and mechanistic link between classically observed synaptic changes, circuit function and pathological behaviour.

Amount: £1,209,072
Funder: The Wellcome Trust
Recipient: University College London

Heterogeneities in stem cell mechanics during division and exit from pluripotency 19 Apr 2016

Embryonic stem cells are pluripotent cells that can give rise to the three germ layers. Evidence indicates they can maintain pluripotency whilst giving rise to progenitor cells for all the embryo cells, suggesting that they are capable of asymmetric division. However, the cell biology of embryonic stem cell division is poorly understood. Interestingly, embryonic stem cells have mechanical properties very different from their differentiated counterparts, and their fate is strongly influenced by the mechanical properties of the substrate, suggesting that stem cell division might be asymmetric with respect to daughter cell mechanics. We propose to explore the geometry, mechanics and physical control by the environment of stem cell division using mouse embryonic stem cells as a model. We will follow cell division and the fate of the daughter cells at the single cell level and in colonies. Altogether, this project will broaden our understanding of the molecular and biophysical control of embryonic stem cell division, a process key to stem cell homeostasis and embryonic development, and will clarify how cell shape and mechanics influence embryonic stem cell fate.

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

Improving the long-term impact of child soldiering 31 Jan 2016

Little is known about the longitudinal effects of child soldiering onto the lives of these participants in wars, particularly in the children’s transition to adulthood. A culturally-grounded understanding of the multiple levels in which this experience shapes their subsequent lives in highly politicised communities is needed. My aim is to conduct a pilot assessing the feasibility of a future study on the long-term effects of early age involvement in political violence in the context of Nepal. This pilot will lay the foundation for a future application of funding for a larger research project. Knowledge of these effects will inform policy-makers and the rehabilitation services’ ability to support this population into adulthood. The funding will enable the facilitating of: i) A pilot in Nepal where I will reengage with my former PhD cohort of informants; ii) Workshops in Nepal and the UK to discuss the results of the pilots with scholars, informants, and stakeholders; iii) Time to prepare an academic paper. The key outputs will be: i) an assessment of the feasibility of the study; ii) the development of a network of collaborators; iii) an academic paper drafted for an academic journal. Key words: child soldiers, ethnopsychology, longitudinal research, war.

Amount: £10,000
Funder: The Wellcome Trust
Recipient: University College London

Development of a novel bioartificial liver device for the treatment of patients with liver failure 30 Sep 2016

In the UK, over 16,000 patients a year die of liver failure. Their livers have the capacity to repair and regenerate, but do not have time to do so. A device temporarily replacing liver function would save lives and reduce the necessity for liver transplantation worldwide. Dr Clare Selden and her team at UCL have developed a prototype 'bio-artificial liver' (BAL) to address this unmet need. Its key element comprises functioning liver cells in an external bioreactor. Plasma from a patient with liver failure will be passed through the bioreactor, contacting the alginate encapsulated liver cells, so that the cells replace those functions that the sick liver cannot perform. The machine will buy time for a patient's liver to improve or, if damage to the liver is irreversible, may buy time until liver transplantation can be arranged. The technology combines alginate encapsulation of a human liver cell line and subsequent culture of the encapsulated cells in a fluidised bed bioreactor - providing a convenient, manipulatable biomass in a form which maximises mass transfer between cells and perfusing plasma. The team have Translation Award funding to complete the design, specification, performance characterisation and manufacture of this fully biocompatible BAL.

Amount: £66,434
Funder: The Wellcome Trust
Recipient: University College London

Investigating the neural odometer function of entorhinal grid cells in rats navigating a multi-planar environment. 01 Apr 2016

It has been proposed that the grid cell system in the medial entorhinal cortex acts as a ‘neural odometer’, encoding both distance travelled and an animal's position in space. These features may be necessary for spatial computations such as path integration, but the relationship of grid cell firing patterns to behaviour remains speculative. In not-yet-published work, it has been shown that for a rat climbing a wall with its body plane aligned vertically the grid fields are expanded, as if the cells underestimate distance travelled. If grid cells support spatial computations then rats should also underestimate distances in this plane. To test this hypothesis rats will learn a distance match-to-sample task leading to triangle completion while both sample and choice phases are in the same plane (both horizontal or both vertical). In probe trials, the sample will be horizontal but the choice vertical. Distance underestimation in the probe trials (walking too far on the vertical wall to achieve a match to the horizontal sample) will link grid cells to behaviour, while the basic distance-matching task will serve as a springboard for neurobiological studies investigating the role of grid cells in odometry generally.

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

Epilepsy inducing mutation of the GABA-A receptor alpha 1 subunit 01 Apr 2016

We will investigate how a newly discovered mutation to the GABA-A receptor alpha 1 subunit gene (GABRA1) is causing epilepsy in a young child. A single mutation has been identified, which resides in the receptor's first transmembrane domain. This is near the previously identifed neurosteroid binding site from which endogenous neurosteroids can positively modulate GABA-A receptor activity. To investigate the implications of this mutation we have formulated the following aims that will be addressed using heterologous expression of GABA-A receptors in a cell line: 1. To establish the effect of the mutation on GABA concentration response curves and current voltage relationships for typical synaptic and extrasynaptic-type GABA receptors. 2. To determine if known allosteric modulators of GABA-A receptors are affected by the alpha1 subunit mutation. 3. To deduce if the expression levels and receptor mobility at the cell surface are affected by the alpha 1 subunit mutation. To achieve these goals, we will use a combination of patch clamp electrophysiology and single particle imaging techniques. This should establish whether the mutation is causing a gain- or loss-of function, or affects receptor trafficking.

Amount: £2,000
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

Cloning of a galactosyl transferase gene promoter to understand the mechanism linking genetic variation to the altered enzyme activity found in IgA nephropathy 01 Apr 2016

IgA nephropathy (IgAN) is the most common glomerulonephritis and is a major cause of kidney failure worldwide. IgAN is characterised by abnormal deposition of galactose-deficient IgA (Gd-IgA) in the kidney, and levels of Gd-IgA are raised in the serum of patients, with levels correlating with clinical outcomes [1, 2]. Why some people have elevated Gd-IgA is unknown, but we have shown that Gd-IgA levels are highly heritable [3, 4] and recently performed a genome wide association study (GWAS) that showed that the presence of a haplotype across a particular galactosyl transferase gene is strongly correlated with Gd-IgA level (p-10), implying that common genetic variation across the locus modulates enzyme activity in the population. Fine mapping of the locus using imputed genotypes, and consultation of available expression quantitative trait loci (eQTL) maps disclosed the set of common variants across the region that might explain the effect, and we now wish to understand the mechanism linking the known genetic variation with altered enzyme activity. The aim of this project is to clone the promoter region of the gene from individuals with and without the associated haplotype for studies using a reporter gene to assess promoter activity of different allotypes.

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

AMARI: African Mental Health Research Initiative 05 May 2015

Mental, neurological and substance use (MNS) disorders are a leading, but neglected, cause of morbidity and mortality in sub-Saharan Africa [1]. MNS disorders account for >25% of all years lived with disability globally, more than cardiac disease or cancer [2]. The treatment gap is vast, only 10% of people with MNS disorders in low-income countries access evidence-based treatments, compared to 33% in high-income countries [3]. Reasons for this include low awareness ofthe burden of MNS disorders and limited evidence to support development, adaptation and implementation of effective and feasible treatments. While pockets of mental health research excellence exist in Africa, MNS research capacity is generally limited, particularly in mental health intervention, service and system research. Mental health research excellence is currently undermined by restricted opportunities for training and mentorship, unclear career pathways, lack of integration in general medical settings, limited multi-disciplinary collaboration and the lack of a critical mass of MNS researchers and leaders. The overall goals of the African Mental Health Research Initiative (AMARI) areto build an African-led network of MNS researchers in Ethiopia, Malawi, South Africa and Zimbabwe, equipped to lead high quality mental health research programmes that meet the needs of their countries, and to establish a sustainable career pipeline for these researchers with the emphasis on integrating MNS research into existing programmes such as HIV/AIDS, maternal and child health. The objectives are to: 1. Select and train MNS research fellows from a range of disciplines at masters (n=25), PhD (n=20) and post-doctoral (n=6) levels in research excellence; 2. Build leadership skills of 26 fellows through adaptation of KCL Career Development Series on Leadership, Management and Mentoring; 3. Design and test an advocacy and systems change strategy for each country, aimed at building sustainable career pathways in MNS academia; 4. Develop a web-based support platform for training, supervision and networking. In year 1 we will undertake preparatory work to inform course development, thedesign of the advocacy and systems change strategy and gather baseline data for each country, for evaluation purposes, conducting qualitative and quantitative interviews with local policymakers and service users to identify needs and priorities through a theory of change map. We willtrain local supervisors, run pre-application workshops for potential applicants and assess existing training materials. . In years 2-5, fellows will begin higher degrees and courses as relevant. Trainingwill be mostly in Africa and using a) joint supervision by local and external supervisors with multidisciplinary expertise, b) taught modules in advanced MNS research methods, writing, and engagement with policy makers, and c) undertaking high priority MNS research. The underlying ethos of AMARI will be to ensure LMIC partner capacity is strengthened progressively towards self-sufficiency to ensure sustainability longer term. AMARI will be led by University of Zimbabwe College of Health Sciences (UZ-CHS). All consortium institutions will provide course facilitators and supervisors, with the Centrefor Global Mental Health (CGMH), University of Cape Town (UCT) and University College London (UCL) providing external supervision, research experts and materials for adaptation.

Amount: £49,068
Funder: The Wellcome Trust
Recipient: University College London

Sexy glia: developmental plasticity during glia-derived neurogenesis 11 Jul 2017

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.

Amount: £1,453,931
Funder: The Wellcome Trust
Recipient: University College London

Sir Henry Dale Extension: Inferring the selection history of world-wide populations in relation to phenotypes 31 May 2017

I will construct efficient statistical algorithms to identify selection effects that have several advantages over current approaches, in particular: 1) increased power from exploiting correlations (i.e. linkage disequilibrium) among nearby genetic variants 2) no requirement for classification of individuals into discrete populations that may not have clear ancestral meaning 3) robustness to variant ascertainment bias 4) increased power to detect selection from standing variation 5) ability to test selection in single individuals (e.g. single samples from ancient human remains, or aDNA) These new approaches will automatically identify genetic regions subjected to selection and the individuals affected when jointly analysing data from world-wide groups. Through application to novel genome-wide data obtained through the PI's Sir-Henry-Dale-Fellowship, including >3700 African individuals from >100 ethnicities spanning 15 countries, I will identify selection events both unique to and shared amongst geographic regions, pointing to shared past environmental pressures. Using collaborators' world-leading aDNA collections, I will furthermore unearth the timing of selection events. I will test for enrichment of selection signals in gene pathways and/or variants previously associated with phenotypes, elucidating how chronic and infectious disease have driven selection. Overall this fellowship will produce a comprehensive picture of selection effects in humans.

Amount: £519,660
Funder: The Wellcome Trust
Recipient: University College London

Towards an individualised, mechanistic understanding of resilience to mental illness during development: the role of affective processing in adolescence 19 Apr 2017

This project examines how individual differences in affective processing contribute to the development of psychiatric traits in adolescence. My two-pronged approach tackles this question from complimentary angles: 1) applying sophisticated statistical methods to currently-available large-scale data to understand individual differences in affective processing and 2) developing more sensitive measures of these individual differences. I will build upon statistical techniques for large-scale data analysis utilising two existing cohorts of adolescents/young adults (Objective 1). Using Structural Equation Modelling, I will investigate how individual differences in multi-level longitudinal measures of affective processing map onto risk for the development of mental illness. Second, I will use computational and psychophysics approaches to build upon established computational models of face perception. I will develop a facial emotion-processing task to quantify individual differences in emotion perception and assess the degree of variability in an individuals’ emotion perception (Objective 2a). I will then relate this variability to individual differences in behavioural traits associated with common mental health difficulties including anxiety and conduct problems (Objective 2b). Together, these approaches link large-scale investigation of mechanisms (Objective 1) with a more refined way of measuring individual differences in these mechanisms (Objective 2) to understand vulnerability to mental illness in adolescence.

Amount: £250,000
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

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

Developing gene therapy for the inherited childhood epilepsy, Dravet Syndrome 27 Apr 2017

Dravet syndrome is a rare, incurable epilepsy which affects young children. Before two years of age they have seizures, incoordination and cognitive impairment. They carry mutations in the SCN1A gene, which codes for voltage-gated sodium channel NaV1.1. This protein is expressed in hippocampal inhibitory interneurons. Gene therapy offers several advantages over conventional drugs. It is a treatment which targets the cause of the disease by delivering the corrected copies of the SCN1A directly to brain cells. Our hypothesis is that we can incorporate a promoter to achieve persistent expression specifically in inhibitory interneurons of the hippocampus. We aim to compare two novel promoters against a pan-neuronal promoter, synapsin. The first is a truncated endogenous promoter, Gad67. The second is a synthetic promoter identified by in silico analysis. Before the project commences, we will clone these two promoters into lentiviral vectors. These, and a synapsin vector, will be injected intracranially into neonatal mice. At the start of the project the brains from four mice will be co-stained with antibodies directed against GFP and inhibitory interneurons to assess colocalisation. To measure persistence of expression from these promoters, the four remaining mice will be subject to whole-body bioluminescence imaging twice-weekly.

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