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Recipients:
University College London

Results

Understanding sex-linked disease mechanisms in Hirschsprung's disease 15 Jul 2013

Hirschsprung's disease (HSCR) is a congenital disorder causing obstruction of the large intestine as partial or total innervation of the gut fails to occur in development. It is one of the most common causes of neonatal intestinal obstruction with incidence rates of up to 1.4/5000 live-births in China and 1/5000 in Caucasians. The most common form of the disease, short segment HSCR (S-HSCR), comprises 80% of HSCR cases and exhibits a strong sex bias with a 5:1 male to female ratio (Badner et al., 1990; Amiel et al., 2008; Garcia-Barcelo et al., 2009). This project aims to answer the disparity in HSCR incidence between males and females, and provides a tractable model to begin to investigate and understand sex bias in numerous diseases. We will focus on a number of mouse models with S-HSCR-like phenotypes for malebias and carry out genetic crosses utilising the "four core-genotype model" (De Vries et al., 2002). The two models showing the most robust sex bias will be chosen for further study. We will then investigate whether sex bias is sex chromosome-specific or gonad/hormone-specific, identifying HSCR-associated variants, genes and/or pathways that are significant in one gender and exploring differences in their activity and function.

Amount: £163,023
Funder: The Wellcome Trust
Recipient: University College London

Biomechanics of collective chemotaxis 15 Jul 2013

Collective chemotaxis (CCT), whereby groups of cells collectively migrate in response to chemotactic signals, is a fundamental mode of migration in development and metastatic cancers. The biomechanics of this process has been largely overlooked, with most work focusing on spontaneous migration of epithelial sheets despite evidence that strong cell-cell adhesions are not required for collective migration. Additionally, chemotactic signals are important for directional migration in vivo. We propose to use neural crest (NC) cells, a highly invasive mesenchymal cell population that extensively migrate throughout the embryo, to address the biomechanics of CCT. We will perform high-resolution time-lapse imaging of Xenopus NC to assess physical properties of CCT such as velocity and viscosity. Traction force microscopy, FRET tension sensors and atomic force microscopy shall be used to measure the physical forces required for CCT. Finally, the molecular mechanisms necessary for the biomechanics of this process shall be identified, in particular through chemical and mechanical manipulation of the actomyosin cytoskeleton tounderstand how it contributes to providing forces for CCT. Collectively, theseresults will provide a novel insight into the biomechanics of CCT which could have important implications for morphogenetic processes, regeneration and diseases like invasive tumours.

Amount: £163,023
Funder: The Wellcome Trust
Recipient: University College London

Developing Novel Antimicrobials by Synthetic Biology 24 Jun 2013

Current problems with increasing antimicrobial resistance mean the discovery of novel antimicrobials is becoming increasingly important. Therefore, antimicrobial drug discovery has been selected as a model to investigate the feasibility of using synthetic biology to create azol(in)e modified peptide libraries and select mutants with biological activity. The library of azol(in)e modified peptides will be created by engineering Escherichia coli to express; heterocyclisation enzymes and a mutated array of substrate peptides. The library will undergo a selection methodology to detect mutants which show antimicrobial activity against a target bacterial overlay e.g. Mycobacterium tuberculosis. Once identified, the large scale biological production and potency optimisation of discovered antimicrobial compounds will be conducted.

Amount: £163,023
Funder: The Wellcome Trust
Recipient: University College London

Characterisation of genes regulated by S-nitrosylation of HDAC2 during radial neuron migration. 11 Feb 2013

The generation of the laminar structure of the cerebral cortex relies on the radial migration of post mitotic neurons. This proceeds under the control of extremely precise regulatory networks requiring input from multiple extracellular signalling pathways and the co-ordinated expression of nuclear factors that result in specific programmes of gene expression. Recently, in the Riccio lab, we have shown that S-nitrosylation of HDAC2 is required for polarization and radial migration of cortical neurons during the formation of the cerebral cortex. A screen was carried out to identify genes regulated by S-nitrosylation of HDAC2 during cortical neuron migration. Druing this project, 2 candidate genes identified by this screen will be selected and their role in cortical development will be characterised. Key goals which have been set in order to achieve this include the following: 1) Verifying that these genes are upregulated in response to HDAC2 S-nitrosylation. 2) Characterisation of candidate genes expression in vivo 3) Analysis of candidate gene promoter and interaction with HDAC2 4) Characterisation of the function of the candidate genes in cortical neuron polarization and migration, which will include the generation of 2 knockout mouse lines.

Amount: £33,208
Funder: The Wellcome Trust
Recipient: University College London

Redirecting T cells with a Chimeric Antigen Receptor against ROR1 to target Chronic Lymphocytic Leukaemia. 26 Jun 2013

Our overriding aim is to demonstrate the safety & efficacy of adoptive immunotherapy for patients with chronic lymphocytic leukaemia (CLL) with T cells engineered to express chimeric antigen receptors (CAR) targeting the tumour associated antigen ROR1. CARs comprise an extracellular single-chain antibody fragment coupled with intracellular signalling domains sufficient for cytotoxicity, independent of MHC, when bound to their cognate antigen. This approach is necessary as CLL remains incurable i n the vast majority of patients. The key goals of this proposal are designed to establish the preclinical feasibility of our strategy with the intention of generating data to support a future clinical trial in poor prognosis CLL patients: 1. Demonstrate cytotoxicity of ROR1CAR-T cells against ROR1 expressing cells in a xenograft model. 2. Assess off target toxicity by analysing interaction of ROR1CAR-T cells with primary human tissues representing vital organs and undertaking safety assessm ent in a syngeneic mouse model. 3. Develop a good manufacturing practice compliant protocol which allows generation of sufficient numbers of human ROR1CAR-T cells for future clinical use whilst minimising manipulation and maximising efficacy. We would use the results of this project to gain regulatory approval for a future trial aimed at benefiting patients.

Amount: £260,322
Funder: The Wellcome Trust
Recipient: University College London

Establishing the Role of the FoxG1 transcription factor in normal and glioma-derived neural stem cells. 16 Sep 2013

Glioblastoma (GBM) is the most common and lethal primary brain tumour. GBMs contain a population of cells that display characteristics of neural stem cells. Understanding the action of the lineage specific transcription factors responsible for orchestrating self-renewal in this population and in their normal stem counterparts offers promise in identifying therapeutic targets. Through pilot studies comparing gene expression in normal NS cell cultures with GBM-derived NS (GNS) cells we have ident ified FOXG1 as a brain-specific transcription factor that is consistently overexpressed in GNS cells. Previous studies have implicated FOXG1 in control of cell cycle and differentiation pathways (p21 and Bmi-1). The aim of this project is to define the function and transcriptional targets of FOXG1 in these malignant and non-malignant contexts. I will make use of established and well characterised NS and GNS cell lines as the model system and use intracranial xenotransplantation as an in vivo a ssay of tumour formation. The objectives are: 1) Monitor the changes in FOXG1 mRNA and protein during differentiation. 2) Perform gain-of-function studies using 'tuneable' overexpression. 3) Perform loss-of -function studies using the latest genome editing technologies (TALENs). 4) Define genome-wide transcriptional targets of FOXG1 using chromatin immunoprecipitation and deep sequencing (ChIP-Seq).

Amount: £13,325
Funder: The Wellcome Trust
Recipient: University College London

Psychosis risk over the life course: A multilevel, longitudinal investigation of social, economic and physical environmental risk factors at different stages in life. 29 May 2013

I propose four multilevel, spatial and longitudinal epidemiological studies to answer my research question. Study 1 will examine the spatial distribution of non-affective and affective psychotic disorders and symptoms over the life-course (i.e. birth, 5 years, 15 years, onset) to determine whether, and if so when, these outcomes show different socio-spatial patterning. I will apply Bayesian spatial latent structure models to two datasets (ALSPAC birth cohort, Swedish Register data) in order to t est this question. Study 2 will investigate the relative roles of social, economic and physical environmental factors on psychosis risk over the life course. I will investigate different theoretical models by applying survival-based spatial SEM to Swedish longitudinal data to investigate the direct and mediating pathways through which social and physical environment factors influence psychosis risk over the life course. Study 3 will investigate whether moving between neighbourhoods in childhood is associated with psychiatric symptomatology in adolescence, using latent class analysis to model neighbourhood trajectories in relation to psychiatric symptoms in two cohorts (ALSPAC; National Longitudinal Survey of Children and Youth, Canada). Study 4 will use Swedish data to investigate whether timing of maternal immigration is related to offspring psychosis risk, as reported for autism spectrum disorders.

Amount: £700,322
Funder: The Wellcome Trust
Recipient: University College London

From vision to action: Systems analysis of sensorimotor circuitry controlling visually-guided behaviour. 29 May 2013

My overall goal is to produce a comprehensive structure-function model that describes the complete sensorimotor circuit mediating visually-guided prey-capture behaviour in larval zebrafish. The small size and optically transparency of larval fish will enable me to perform two-photon functional imaging with genetically-encoded calcium indicators to examine neural activity throughout the brain whilst the tethered animal performs hunting-specific behaviours directed towards synthetic visual cues. C orrelation-based analyses will be used to define the response properties of neurons throughout the brain and identify population-level representations of sensory and motor parameters. Gain and loss of function approaches will be used to test the contribution of observed activity patterns to neural processing and behaviour. These include optogenetic methods to optically manipulate the activity of distributed neuronal assemblies, and laser ablations to precisely eliminate candidate neurons. Techni ques including single-cell electroporation, electrophysiology and immunohistochemistry will be used to relate functional data with underlying circuit anatomy. In this way, combined structure-function models of the entire sensorimotor circuit will be constructed and tested. Finally, virtual reality environments will be used to evoke extended behavioural sequences that incorporate the natural variation of the hunting. This will provide a rich dataset for understanding the neural basis of a complex , adaptive behaviour.

Amount: £1,118,346
Funder: The Wellcome Trust
Recipient: University College London

Bridging microscopic and macroscopic measures of reward-guided decision making. 23 Nov 2012

I propose a series of experiments targeted at understanding the role of prefrontal cortex in valueguided choice. All experiments will be conducted by recording single-unit activity from multiple regions of prefrontal cortex simultaneously in an animal model, and also bycollecting magnetoencephalography data in healthy human volunteers. This will facilitate comparison of neural responses across species, and across microscopic and macroscopic spatial scales. The key goal of this research is to bridge these spatial scales using a common mechanistic framework, by making use of biophysically realistic spiking network models to explain neural activity. In my first experiment I will use a paradigm that has been closely studied in the domain of perceptual decision-making - a working-memory guided discrimination paradigm - adapted for reward-guided decision making. This bears the advantage that several biophysical models are readily available, simplifying the process of comparing neural activity to a biophysically realistic model. In subsequent experiments I will develop more elaborate biophysical models to account for decisions made in different and competing decision spaces, and to explain neural response heterogeneity and inter-regional communication. This will support my broader goal of enabling future systems neuroscience experiments to be performed in more formal predictive frameworks.

Amount: £200,000
Funder: The Wellcome Trust
Recipient: University College London

Neural network analysis using a novel multichannel "SMART" neuroprobe 12 Oct 2012

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: £212,460
Funder: The Wellcome Trust
Recipient: University College London

A computer assisted system to reduce auditory hallucinations unresponsive to antipsychotic medication 19 Nov 2012

About 25% of people with schizophrenia continue to suffer with persecutory auditory hallucinations despite drug treatment. Their capacity to work and make relationships is grossly impaired, often for the rest of their life. Professor Julian Leff from University College London and colleagues at Speech, Hearing and Phonetics, UCL have developed and evaluated a novel therapy based on computer technology which enables each patient to create an avatar of the entity (human or non-human) that they believe is talking to them. The therapist promotes a dialogue between the patient and the avatar in which the avatar progressively comes under the patient's control. This translation award aims to refine the system, streamline the technology to make it more user-friendly and evaluate the system by a randomised controlled trial conducted by an independent team of researchers at the Institute of Psychiatry, King's College London.

Amount: £382,405
Funder: The Wellcome Trust
Recipient: University College London

Biomedical Vacation Scholarship 24 Jun 2013

Not available

Amount: £30,780
Funder: The Wellcome Trust
Recipient: University College London

Human Developmental Biology Resource (HDBR): an embryonic and fetal tissue bank for the new genetics technologies. 22 May 2012

The Human Developmental Biology Resource (HDBR; www.hdbr.org) is unique, being the only tissue-bank that provides the international scientific community with access to: -High-quality materials from human embryonic and early fetal stages, including tissues for cell culture, RNAs from sub-organ specific regions and slides for spatial gene expression studies; -An in-house gene expression service (IHGES) that undertakes studies for registered researchers; -A un ique web-based database for dissemination of human gene expression data spatially mapped to 3D models. To develop HDBR activities, and extend them to meet new challenges and opportunities, our key objectives are: -increase sample collection with a focus on intact specimens; -expand the range of IHGES studies, to include studies of non- coding RNAs and alternative spliced products, and to develop techniques to maximize expression information obtained from rare human tissues; -expand the range of materials provided, e.g. RNA, DNA and protein, from specific tissues to support sequencing, transcriptomics and proteomics projects; -interact strategically with large-scale initiatives focusing on human development and disease. By also improving our engagement with current and potential users, we will adapt the HDBR to meet the needs of functional gene characterisation, for the new genetics technologies.

Amount: £725,374
Funder: The Wellcome Trust
Recipient: University College London

How well do web panel surveys measure behaviour in the general population and can they be improved? A comparison with a national probability sample. 06 Oct 2011

Despite the dramatic growth in the use of online/web surveys for market research and opinion polling, web methods are not widely used in the UK for collecting epidemiological or surveillance data (or for academic research)(1). Most web surveys rely on quota sampling from volunteer web panels (WPs) run by market research companies.* While volunteer WPs will increase in importance (5,6,12-15), there are well-founded concerns about their representativeness. Research in the US and Europe has shown that WPs have problems with coverage, sampling and non-response (1-8). There has been little UK research comparing results from WPs with high-quality probability samples to explore how WPs can be used to make inferences about the general population and/or to develop estimation methods to use WP data (1,4,6,8,9-11,12,16-21). This enhancement grant aims to exploit an ideal opportunity to compare results from WPs with Natsal3, and to address deficiencies in the literature, eg: comparing a WP with a CASI probability sample; using WPs for asking about sensitive behaviours (most studies have focused on political attitudes and consumer behaviour). This new work was not envisaged or costed in the original Natsal grant; it has in part arisen from an experiment in the development phase to offer a short web questionnaire to Natsal respondents who declined the main interview. We are requesting funds to commission WP samples from three leading UK survey organizations, which will be carried out in two stages alongside two waves of Natsal3 fieldwork.

Amount: £252,403
Funder: The Wellcome Trust
Recipient: University College London

Novel multimodality imaging techniques for neurosurgical planning and stereotactic navigation in epilepsy surgery 02 Dec 2011

Successful neurosurgery for epilepsy depends on removing the parts of the brain that give rise to seizures, and avoiding damaging areas undertaking vital functions such as language, movement and vision. Current techniques to direct surgery are based on MRI scans to show brain structure, but do not show areas needed for vital tasks, and do not permit interactive simulations of placement of recording electrodes in the brain.A research group headed by Professor John Duncan at University College London and Dr Sebastien Ourselin of UCL Centre for Medical Image Computing has implemented methods to identify critical areas of brain function, connections and blood vessels and display these in 3D. They plan to develop this system to enable the neurosurgeon to plan the best operative approach for inserting recording electrodes and for planning surgical resections. This information will be made available in the MRI scan guidance system in the operating room so that operations are more precise. They will produce a new system that will result in epilepsy surgery being planned more effectively, resulting in a higher cure rate and fewer complications.

Amount: £523,615
Funder: The Wellcome Trust
Recipient: University College London

The development, plasticity and pathology of myelinated CNS axons. 18 Jul 2012

CNS white matter transmits information rapidly between grey matter computational nodes. Its function depends on oligodendrocytes wrapping myelin around axons to speed action potential propagation. Myelinated axons are poorly understood, which is surprising, given that: (i) the white matter is half of the human brain, (ii) development of myelin is crucial for normal brain function, (iii) white matter plasticity is increasingly invoked as a learning mechanism, and (iv) myelinated axon dama ge disrupts cognitive and motor function in cerebral palsy, multiple sclerosis, stroke, spinal cord injury and age-related vascular dementia. We will address the following key problems in our understanding of CNS myelinated axons. How is oligodendrocyte development regulated to set axonal conduction speed? The roles of neurotransmitter- and voltage-gated ion channels in oligodendrocyte precursors, provision of N-acetyl-aspartate from neurons (a pathway revealed by human mutations), and mole cules assembling the node of Ranvier, are poorly understood. What are the mechanisms of white matter plasticity? Diffusion tensor imaging has demonstrated structural plasticity of myelinated axons during learning, perhaps reflecting addition of myelin to adjust axonal conduction speed and thus promote synchrony of action potential arrival at target neurons. Simulations suggest that altering node geometry and periaxonal space width, as well as myelination, could tune conduction speed. We will develop an in vitro model to study white matter plasticity. How is the oligodendrocyte-axonal unit disrupted in pathology? How are the node of Ranvier and the internodal myelin affected, what signalling pathways are involved, and how do microglia survey oligodendrocytes to assess their health?

Amount: £2,005,548
Funder: The Wellcome Trust
Recipient: University College London

Physiological and pathological regulation of calcium-channel and other ion-channel functions by alpha2delta-subunits and their interacting proteins. 15 May 2012

The alpha2delta proteins are voltage-gated calcium-channel auxiliary subunits. We have made very important contributions to the understanding of the properties and mechanism of action of these proteins, which are the therapeutic targets of the gabapentinoid drugs. There are a number of key open questions regarding their function, which form the two main Aims of this research. Firstly, how do alpha2delta-subunits facilitate calcium-channel trafficking, and what are their cellular binding par tners in these processes? Secondly, do alpha2delta-subunits influence other proteins, including ion-channels, evidence for which has recently emerged from our own preliminary studies? We have recently uncovered an interaction between alpha2delta-subunits and the multifunctional trafficking protein, low-density lipoprotein-receptor-related protein (LRP1). In Aim1 our goal is to examine how interaction with LRP1 controls trafficking of alpha2deltas and their associated calcium-channels. We wi ll investigate whether gabapentin disrupts this interaction, as this could be very important for future drug discovery, since alpha2delta-1 is a validated drug target. We will also examine whether interaction with LRP1 can bridge identified associations between alpha2delta-1 with both thrombospondins and prion protein. With respect to Aim 2, we have recently found disruption of specific sensory modalities in alpha2delta-1 knockout mice, and a marked inhibition of action-potential duration fol lowing alpha2delta-1 over-expression in dorsal root ganglion neurons. Both results point to alpha2delta interactions with other ion-channels; association with specific candidate channels will be investigated in Aim 2. My goal is to develop a comprehensive picture of alpha2delta-subunit function, in terms both of calcium-channels, and of other proteins mediating calcium-channel-independent functions.

Amount: £1,754,389
Funder: The Wellcome Trust
Recipient: University College London

High Resolution Retinal Imaging. 22 May 2012

Retinal imaging in patients and animal models of retinal dysfunction advances our understanding of diseases affecting vision and provides a window to the brain to study degenerative central nervous system disease. We request funding to obtain five cutting-edge retinal imaging devices that can visualise cellular and subcellular structures and dynamic processes in living retinal cells ex vivo and permit non-invasive high resolution in vivo imaging at single cell resolution in patients and small an imal models. Each of these devices offers new and unprecedented research opportunities due to recent advances in imaging technology. When combined into a single platform, these devices will afford capability not previously available in the UK and significantly enhance a wide variety of Wellcome Trust-funded fundamental, translational and clinical research programmes. The key objectives of the proposal are therefore to establish high resolution retinal imaging i) in patients to facilitate world-l eading research in retinal disease and therapeutics; ii) in animal models to elucidate disease processes and identify novel therapeutic targets; and iii) in living cells to investigate disease mechanisms. Achieving these objectives will add value to currently funded Wellcome Trust research programmes aimed at understanding the brain and retina and identify new therapeutic strategies.

Amount: £737,353
Funder: The Wellcome Trust
Recipient: University College London

A centralized platform for validation of genomic and epigenomic targets from clinical and non-clinical studies. 22 May 2012

Over 1000 associations have recently been identified in over 100 traits and common human diseases using GWAS/EWAS. To further advance this research towards identification of the underlying causal variations for therapeutic targeting, requires follow-up on several levels. In the first instance, the identified associations need to be validated, ideally by an independent method and in additional samples. Secondly, the haplotypes, hepitypes and other genomic intervals in which the associations were found need to be further analysed for functional variations in as many samples as possible. The main objective, therefore, is to establish a centralized high-throughput facility for validation and targeted functional analysis that is directly compatible with next-generation sequencing, the method of choice for downstream processes. We believe that the requested equipment from RainDance Technologies satisfies all the technical requirements for accuracy, sensitivity and specificity. It also curre ntly offers best value with respect to throughput, flexibility and future integration with GCLP settings which is a requirement for clinical and future personalized medicine programmes. Under the guidance of the lead applicant, the experienced UCL Core Facility (UCL Genomics) will operate and maintain the equipment ensuring fair access to the 20 named co-applicants and collaborators and beyond if capacity allows.

Amount: £352,437
Funder: The Wellcome Trust
Recipient: University College London

Open access award 2012/13. 17 Sep 2012

Not available

Amount: £400,000
Funder: The Wellcome Trust
Recipient: University College London