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Recipients:
University College London

Results

Developing a behavioural task for measuring the ability of listeners to perform auditory scene analysis. 27 Apr 2017

The auditory brain separates simultaneous sounds arriving at the ear into identifiable and localisable sources by a process known as Auditory Scene Analysis (ASA). The two steps that are involved in ASA are i) segregation of the simultaneous auditory information and ii) the integration of the sounds from the same source into one stream. To understand how these two steps are connected and how different auditory cues interact to shape the scene, this project will develop a behavioural task and analyse the performance of human listeners. A target vowel will be presented alongside with a distractor vowel, and human listeners will identify what the target is. Listeners will only be able to identify the target if they can separate the two sounds: changing the location and pitch of target and distractor will help this. In order find out whether the separation of competing sounds is facilitated by the formation of perceptual streams, the vowels will also be presented as part of a sound sequence. Our hypothesis is that the ability to identify a target vowel will be improved by the formation of two perceptual streams. The long-term goal is to develop a behavioural paradigm suitable for humans and animals.

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

Up and down regulation of MafB gene in the developing chick hindbrain. 27 Apr 2017

The project's aim is to up and down regulate MafB gene, that is expressed in the Nucleus Laminaris (NL) and Nucleus Angularis (NA), in the developing chick hindbrain and ask questions about: 1) formation of nucleus Laminaris and nucleus Angularis in the dorsal hindbrain; 2) other effects on hindbrain development e.g interfering with fgf8 molecule expression, which in turn would affect the development of the cranial motor nerves VI, VII and nVIa. Such experimental techniques as in ovo electroporation, immunofluorescence and in situ hybridization will be used to look at the genes expressed in the auditory brainstem. The in ovo electroporation constructs used will overexpress MafB and also express a dominant negative version of MafB and immunofluoresce analysis will be carried out to test whether the electroporation was successful. The in situ hybridization analysis will be performed to establish the effect of MafB on the expression of such genes like FGF8, Pou6F2, N-cadherin, gamma catenin, cadherin-13 and cadherin-22 in the hindbrain. These techniques would also allow the analysis of the formation of the nucleus Laminaris in the developing hindbrain.

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

Pathways of nanopore assembly by bacterial toxins and immune effectors 27 Apr 2017

To attack cells in our body, bacteria make use of toxins that drill holes in the cell membranes. Following a similar strategy, our immune system makes use of such pore forming proteins to target cancerous, virus-infected and bacterial cells. In the course of their action, pore forming proteins are first secreted as monomers, bind to the membrane, and next self-assemble into oligomeric pores. Some of the various open questions are how these pore assembly processes take place on more complicated, composite membranes such as bacterial envelopes. This project will aim to contribute to answering these questions, while providing the student research expertise in nanoscale microscopy methods applied to process that is essential for bacterial attack and immune defence. More precisely, the student will image live bacteria (E. coli) as they are attacked by the membrane attack complex. This is part of on-going atomic force microscopy experiments in the supervisors lab, which offer the possibility to visualise bacterial cell wall degradation in real time. Time permitting, the student will also be exposed to computational approaches to analyse such new data as well as past data on assembly and membrane insertion of immune effector perforin.

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

Africa Health Research Institute (GBP record) 30 Jun 2016

Our aim is to reduce the huge burden of HIV and TB in KwaZulu-Natal as a precursor to the eradication of these diseases. This will be facilitated by merging the population based research excellence of the Wellcome Trust (WT)-funded Africa Centre (AC), with the cutting edge laboratory science and experimental medicine approaches of the Howard Hughes Medical Institute (HHMI)- funded KwaZulu-Natal Institute for Research in TB and HIV (K-RITH) to create an exciting, interdisciplinary South African based research initiative. Our 5-year vision is to use basic science, systems biology, health systems and social science research to undertake fundamental discoveries into the susceptibility, transmission and cure of HIV and TB. Our specific questions are: 1. How can new HIV infections best be eliminated? 2. How can TB transmission be interrupted and how can drug-resistance be contained? 3. How can the health of pregnant women with HIV and their offspring be improved? 4. How can we improve the health-system delivery and population-level impact of HIV treatment and other chronic disease care? 5. How is health and wellbeing affected by migration, economic and other inequalities

Amount: £1,912,066
Funder: The Wellcome Trust
Recipient: University College London

A reappraisal of peripheral pain pathways 08 Dec 2015

Action potential propagation velocity provided a useful system for categorising peripheral nerves for 75 years. Now, genetic definition of sensory neuron subsets is providing a more precise functional distinction; individual sensory neurons and their target dorsal horn neurons can be activated, silenced or killed genetically and defined in terms of their transcriptomes, and linked to behavioural changes. In addition, physiological stimuli can be used to drive activity dependent reporters allowing further definition of neuronal subtypes. In this proposal, we show how the exploitation of these methods will inform our knowledge of peripheral pain pathways, the key element in almost all chronic pain syndromes, and identify cell types and molecular targets that are critical for distinct types of pain sensation. Our work will encompass human and animal genetics and should provide clinically significant information.

Amount: £3,631,275
Funder: The Wellcome Trust
Recipient: University College London

TREAT-HD: targeting neurodegeneration in Huntington's disease 08 Dec 2015

Despite their immense public health burden, and after considerable investment in therapeutics research, the pathobiology of neurodegenerative diseases remains poorly understood and we lack treatments to prevent or slow their progression. Our vision is to provide a step-change in the understanding of mechanisms underlying neurodegeneration – and recovery – using Huntington’s Disease (HD) as a model. Our three key goals are to: further understanding of HD neuropathology and its response to gene-silencing treatment. We will exploit a unique opportunity to link with the first human trial of an antisense oligonucleotide (ASO) to reduce levels of huntingtin protein. develop a new generation of ASO treatments by targeting levels of the highly pathogenic exon 1 mutant huntingtin protein. determine the earliest potential time window for therapeutic intervention. We will study a novel cohort of young adult HD gene-carriers decades before expected symptom onset to characterise the earliest signs of disease-related brain changes and identify early functional impairment. By examining this model disease in patients, we will gain understanding of general pathological processes shared across protein-misfolding neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Consequently, this work has fundamental implications for the development of treatment strategies beyond HD to more prevalent neurodegenerative diseases.

Amount: £1,693,006
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

Novel multichannel "SMART" neuroprobe - Enhancement 08 Apr 2016

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.

Amount: £273,651
Funder: The Wellcome Trust
Recipient: University College London

Next generation engineered T-cell therapy for brain lymphoma 23 Nov 2015

Most patients with aggressive brain lymphoma die of their disease. T-cells are white-blood cells that are part of our immune system. T-cells can be imagined as "robots" moving through the body on a "seek-and-destroy" mission against virus infected cells. T-cells do not normally attack lymphoma cells, only infected cells. However, it is possible to genetically engineer T-cells taken from a patient's blood so they now recognize lymphoma cells. These engineered T-cells are called "CAR T-cells" and once they are injected back into the patient, they find and kill lymphoma cells. Dr Martin Pule at University College London will test a CAR T-cell treatment for aggressive brain lymphoma in a clinical study. While CAR T- cells may be good treatments for lymphoma outside the brain, treating brain lymphoma is harder: the brain is more difficult to reach than other parts of the body. Additionally, when CAR T-cells work quickly, they cause inflammation which the brain may not tolerate compared with other organs. The project plans to engineer CAR T-cells in an advanced way so the team can track them using a special MRI scanner and control how quickly they work with a drug. This will allow to safely and effectively develop this new treatment.

Amount: £2,733,673
Funder: The Wellcome Trust
Recipient: University College London

Cartoonist-in-Residence, UCL and UCLH 13 Apr 2016

A portrayal of the experiences of UCL/H staff and their patients, as revealing and humorous stories told in the snapshot form of the cartoon. Ros Asquith will spend one day a week for a minimum of one year at UCL/H - observing meetings, presentations, the Grand Round and the wards, listening to doctors, nurses, research scientists, students, managers and administrative staff. She will then aim to capture each visit’s key experiences as cartoons. Two days already spent exploring this process produced about 30 ideas. I appreciate that the spare time of health professionals is short - fortunately, cartoons can be understood, liked, disliked or improved very quickly. Each week I would circulate by email rough sketches of ideas drawn from that week’s visit, to a representative group nominated by UCL/H. From their recommendations and thoughts, I would then develop the most successful ideas as finished artwork. I intend to run workshops, and discussions and encourage staff and patients to draw, based on my wide experience of drawing workshops with all ages. At the end of the year, the work would be exhibited, printed as postcards, leaflets, and a book. I would host a series of workshops, discussions.

Amount: £15,900
Funder: The Wellcome Trust
Recipient: University College London
Amount: £12,000
Funder: The Wellcome Trust
Recipient: University College London

University College London/Birkbeck Interdisciplinary Programme in Structural, Computational and Chemical Biology 30 Sep 2016

University College London/Birkbeck Interdisciplinary Programme in Structural, Computational and Chemical Biology

Amount: £133,252
Funder: The Wellcome Trust
Recipient: University College London

UCL - Neuroscience 30 Sep 2016

Not available

Amount: £133,252
Funder: The Wellcome Trust
Recipient: University College London

The role of the blood nerve barrier in peripheral neuropathies. 30 Sep 2016

The nervous system in maintained in a protective environment by a specialised vasculature. In contrast to the Blood Brain Barrier (BBB), the Blood Nerve Barrier (BNB) is poorly characterised despite having an important role in protecting peripheral nerves and its disruption being associated with neuropathies associated with pathologies such as diabetes and cancer. We have initiated a characterisation of the BNB in the sciatic nerve and have found that it is distinct from the BBB both in its permeability and cellular make-up. Moreover, we have developed a unique transgenic mouse in which ERK signalling in Schwann cells (SCs) in the nerve can reversibly open the barrier, which mimics the normal injury response. This provides a powerful model system for studying in a temporal manner how the BNB can be broken down and reformed. The aims of this proposal are threefold. 1. To characterise the nature of the BNB throughout the PNS and correlate differences with structural changes 2. To determine the role of SC-secreted Semaphorin 3A in the regulation of the BNB. 3. To analyse the expression and role of BBB transporters in the BNB.

Amount: £34,680
Funder: The Wellcome Trust
Recipient: University College London

The role of the gut microbiota in systemic immune responses and autoimmune arthritis 18 May 2016

Alterations in gut microbial composition, termed dysbiosis, are associated with the development of autoimmune arthritis. However, the mechanisms by which intestinal bacteria influence immune responses at distal sites have not been identified. Recent studies showed that bacterial metabolites, retinoic acid and short-chain fatty acids, modify CD4 T-cell fate through epigenetic mechanisms. Based on these findings I propose that bacterial species produce key microbial products that act on cis-regulatory elements to alter the differentiation potential of immune cells as they migrate through the gut. My project will address whether transient dysbiosis can permanently influence the differentiation potential of mature CD4 T cells and their precursors, favouring a pro-inflammatory phenotype during subsequent antigen encounters. My experiments will use state-of-the-art techniques and sophisticated animal models to address three key goals: 1. To assess the effects of transient dysbiosis on CD4 T-cell regulatory elements, their lineage potential and pathogenicity 2. To explore the mechanisms by which commensals regulate CD4 T-cell fate 3. To translate my findings into a causal link between dysbiosis and human autoimmune arthritis. Understanding how variation in gut microbial composition influences CD4 T-cell pathogenicity will provide the rationale for therapeutic targeting of the microbiota to modulate immune-mediated inflammation.

Amount: £441,138
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

The cellular basis of information processing in a cerebellar microcircuit 05 Jul 2016

Our ability to interpret sensory input and to coordinate movements is often taken for granted, but impairment in these functions during neurological disorders has debilitating effects. How neural circuits perform these functions is poorly understood. The aim of this research is to elucidate how the synaptic and cellular properties of a circuit enable populations of neurons to represent, transform and distinguish sensorimotor information, which is critical for understanding how downstream neurons learn sequences, interpret sensory input and coordinate movements. We will use the powerful new methods that we have recently developed to study information processing in the cerebellar cortex, a well-defined neural circuit involved in coordinating movements. By combining dual-channel 3D acousto-optic lens two-photon imaging with genetically encoded indicators, we will measure signalling in identified populations of synaptic inputs, inhibitory interneurons and granule cells during sensory stimuli and behavioural tasks. We will then identify the biophysical properties of the synapses and neurons involved with optogenetic approaches, imaging and electrophysiology in vitro. Using network models, we will quantify how the cellular properties underlie the network input-output relationship measured in vivo. This will advance the field by linking synaptic and cellular properties to population coding and processing in neural circuits.

Amount: £2,628,685
Funder: The Wellcome Trust
Recipient: University College London

The functional architecture of cerebellar computation 05 Apr 2016

The goal of this proposal is to define the fundamental units of computation relevant to behaviour in an accessible and important neural circuit of the mammalian brain, the cerebellar cortex. We will use an unprecedented combination of tools – including multiple patch-clamp recordings, high-throughput electron microscopy, 2-photon population imaging and optogenetics – to make decisive tests of longstanding theories of computations carried out by the circuitry of the cerebellar cortex. We will identify and functionally characterize connectivity motifs within mouse cerebellar cortex, investigate how these motifs are engaged by sensory and motor inputs, and test how they can serve as building blocks for computations required for sensorimotor integration. In parallel, we will examine how these circuit motifs are engaged in the intact cerebellar network in awake, headfixed animals, using novel quantitative behavioural assays in order to link circuit activity patterns with sensorimotor integration and plasticity. Finally, we will forge causal links between engagement of specific circuit elements and behaviour, using a novel ‘all-optical’ approach for reading out and manipulating activity in cerebellar circuits to regulate cerebellar plasticity and behavioural performance in both wild type mice and in cerebellar ataxia and autism mutants.

Amount: £3,514,421
Funder: The Wellcome Trust
Recipient: University College London

Material Anxieties: The Perceived Health of Materials in Medical Products 11 Jan 2016

This project will study the dynamic trajectories of materials like stainless steel, silicone rubber and PVC that make up clinical and direct-to-consumer healthcare products. I will follow materials as they move from manufacturing to the marketplace and beyond, exploring their perceived risks and rewards, and examining how the choices of materials scientists and designers influence users’ experiences of health and wellbeing. The project’s innovative tripartite method will afford a uniquely holistic understanding of human experiences of materials, combining ethnography, design research and psychophysics to allow for a simultaneous focus on the physical, sensory, aesthetic and cultural affordances of materials. My key goals are to firmly establish this new interdisciplinary approach, thereby providing a bridge between the laboratory, design studio, care environment and society, with the potential to influence design practice, research directions in materials science and practices and experiences of healthcare. In bringing together materials producers, designers, clinicians and users this project encourages dialogue and enables translation between isolated disciplinary and professional communities. It therefore takes crucial first steps towards the identification and development of materials that accord with clinical and societal needs.

Amount: £200,556
Funder: The Wellcome Trust
Recipient: University College London