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Recipients:
University College London

Results

Identifying Integrative and Conjugative Elements using DLIGHT 27 Apr 2017

Integrative and conjugative elements (ICEs) are mobile genetic elements present in both gram-positive and gram-negative bacteria. They mostly reside in the host chromosome and under certain conditions, will excise and transfer to a new host via the conjugation machinery. ICEs have been found to provide the host with a wide range of phenotypes, including antibiotic and heavy metal resistance and the ability to colonise a eukaryotic host, promote virulence and biofilm formation. The ability of ICE to spread to different species of bacteria through horizontal gene transfer is a major factor in bacterial evolution. Bioinformatics approaches have been increasingly used to identify possible ICEs through sequence similarity. In this project, we aim to find out the effectiveness of using an algorithm, DLIGHT (Distance Likelihood based Inference of Genes Horizontally Transferred) that was originally used to detect lateral gene transfer, to identify integrative and conjugative elements. We will achieve this by assessing DLIGHT's ability to recover already documented ICEs. We will also use DLIGHT to test certain sequences which we suspect to contain ICEs. The predictions of new ICEs will then be vetted through manual analysis and collaboration with experimentalists.

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

Wellcome Trust Centre for Surgical and Interventional Sciences 30 Oct 2016

Image-guided Intervention (IGI) has enabled greater surgical precision resulting in reduced tissue trauma, co-morbidity, complications, and hospitalisation time. However, significant limitations arise from the challenging use of IGI systems, and their predominant reliance on preoperative anatomical images. Disrupting existing IGI, we will deliver pathologically, anatomically, and physiologically optimal surgery by combining diagnostic-quality imaging/sensing with ergonomic smart instruments. The Wellcome Trust Centre for Surgical and Interventional Sciences (WTC-SIS) will launch a new phase in which anatomical cues, which have driven interventional therapies for centuries, are augmented by physiological and pathological insight. Three fundamental research themes will link the WTC-SIS interdisciplinary groups: Physiological navigation, focusing on fusing anatomical, physiological and pathological information for real-time guidance/monitoring. Clinician experience, focusing on optimising the clinical team cognitive/ergonomic workload. Precision instrumentation, focusing on designing interventional devices that both sense physiological/pathological information and interact with tissue. WTC-SIS will serve as a hub-and-spoke translational catalyst for indication-specific externally-funded projects across surgical domains. A single unified Centre (hub) will provide all relevant skills and know-how, from scientific expertise to good manufacturing principles. This will drive rapid translation in our clinical satellites (spokes) and industry engagement through the development of a Health Technology Assessment programme.

Amount: £6,565,142
Funder: The Wellcome Trust
Recipient: University College London

Africa Health Research Institute (GBP record) 6 month partial award 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: £472,230
Funder: The Wellcome Trust
Recipient: University College London

Africa Health Research Institute (USD 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: £25,602,371
Funder: The Wellcome Trust
Recipient: University College London

BRAINEACv2: a resource for the interpretation of genetic variation in multiple regions of the adult human brain 16 Jun 2016

We aim to create BRAINEACv2, a resource for the investigation of the impact of genetic variation on gene expression in adult human brain. This resource will include three types of data: expression quantitative trait loci (eQTL), allele-specific expression and gene co-expression networks. Given the regional, cellular and molecular complexity of human brain, we believe there is a strong case for the creation of a tissue-specific resource. At present no comprehensive resource of this kind exists. However, our own public resource, BRAINEACv1, provides strong evidence for the popularity of such a resource with ~900 users from >80 countries accessing the website monthly. If funded BRAINEACv2 will represent a step-change improvement. It will include all 3 types of data described above (eQTL, ASE and co-expression networks), incorporate RNA-seq based gene expression quantification results and will include data from other major consortia (e.g. the North American Brain Expression Consortium). Given the success we have already demonstrated in creating a brain-specific resource for variant interpretation in human brain, we are well placed to deliver a new, comprehensive resource capable of meeting the growing interest in the understanding of the genetic regulation of gene expression in adult human brain.

Amount: £205,514
Funder: The Wellcome Trust
Recipient: University College London

Moving functional brain imaging into the real world: A wearable, cryogen-free, magnetoencephalography (MEG) system 05 Jul 2016

Functional neuroimaging systems currently comprise cumbersome equipment built around a small bore into which a participant’s head is gently clamped. This artificial environment restricts both the subject groups that can be scanned, and the experimental questions that can be addressed. Here, we aim to develop a new type of magnetoencephalography (MEG) system which will be worn on the subject’s head, allowing them to move freely whilst being scanned. This is possible due to the introduction of new quantum sensors which do not rely on superconducting technology. The new system will offer higher spatial resolution and 5-10 times the sensitivity of current state-of-the-art MEG instrumentation because the sensors can be placed directly on the scalp. This will allow non-invasive electrophysiological measurements to be made with unparalleled spatiotemporal accuracy while participants operate in an unconstrained environment, e.g. navigating in space, or interacting with other people. Importantly, the device opens up the possibility of scanning almost any subject or patient group ranging from children requiring pre-surgical epilepsy evaluation, to patients with movement disorders. The low cost, wear-ability and enhanced sensitivity of the new system will be transformative, offering new opportunities to study ‘real world’ human brain function in health and disease.

Amount: £872,186
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

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

Request for enhancement funding LonDowns 11 Feb 2016

Most studies treat Down syndrome (DS) as a single entity. Our novel aim is to focus on individual differences and subgroups at the cellular, genetic and cognitive levels to explain why the DS phenotype varies so much. For example, despite all DS individuals presenting with Alzheimer's Disease pathology, only a subgroup develops dementia. Is this due to cellular, molecular, genetic and/or cognitive differences? Can we identify these differences not only in adulthood, but also in infancy? If so, early diagnosis and intervention can be targeted. To study DS cognition longitudinally, we will develop comparable assessments for DS infants, adults and mouse models, to characterise deficits associated with hippocampal, cerebellar and frontal regions. Uniquely, we will correlate cognitive/genetic profiles with defects in neurogenesis, neurite/synapse plasticity, mitochondrial dysfunction, A-beta accumulation within participants neurons, differentiated from iPSC. We will create a Biobank and genotype/phenotype database as platforms for add-on pharmacologic/metabolomic/imaging projects, and clinical trials. This project aligns methods with other DS studies globally, but is unique in encompassing different age cohorts, integrating human cognitive development, ageing, neurobiology, genetics, cellular and mouse modelling. It is strategic for improved health, and timely, as therapies for DS cognitive deficits and decline are now realistic.

Amount: £152,400
Funder: The Wellcome Trust
Recipient: University College London

Behavioural role and neural representation of temporal dynamics in sensory stimuli. 02 Dec 2015

The external world is not static but in a constant state of flux. To understand how the brain functions, we, therefore, must investigate how it extracts relevant information from dynamic, highly fluctuating sensory signals. Olfaction is an ideal modality with which to study this question. A key sense for nocturnal and crepuscular animals, such as laboratory rodents, the comparatively simple anatomy of the early olfactory system makes it highly accessible and tractable. Turbulent airflow creates a rich temporal structure in the intensity fluctuations of natural odour stimuli. Yet, how these dynamics are processed by the olfactory system and the extent to which it uses or ignores this information remains unknown. I have recently established quantitative behavioural tools, genetic and optogenetic manipulation of the early olfactory system, electrophysiological and imaging approaches in the awake behaving mouse, and the tools to measure and generate temporally fluctuating olfactory stimuli with high bandwidth. We will now combine these approaches to tackle key questions relating to the significance of natural dynamics for the coding of sensory stimuli. 1: What information is contained in the dynamics of natural olfactory stimuli?2: To what extent do neurons represent such dynamics? 3: How are stimulus dynamics used for behavioural tasks such as navigation? 4: What are the circuits and mechanisms that support, extract information from, or compensate for stimulus dynamics? My guiding hypothesis is that temporal dynamics and coherence of natural smells are decoded by the circuitry of the early olfactory system to extract information about distance, location and the nature of olfactory objects and scenes.

Amount: £1,627,188
Funder: The Wellcome Trust
Recipient: University College London

Complex Urban Systems for Sustainability and Health (CUSSH) 24 Mar 2016

We propose a strategically vital global research programme on the complex systemic connections between urban development and health. We aim to conduct research and improve capacity to guide transformational changes in cities to meet environmental imperatives and to maximize the health and wellbeing of current and future populations by harnessing the benefits of sustainability policies, and minimizing potential adverse consequences of global technological, environmental and social change. The CUSSH programme will formulate innovative, evidence-based examples of healthy urban development, provide underpinning evidence on practical solutions, and identify factors critical to successful implementation. Candidate solutions will be tested in city case studies using participatory methods across Europe, the Americas, Africa and Asia, capitalizing on investments in urban environments. The evidence generated will help decision-makers accelerate population-level changes in such areas as energy provision, transport infrastructure, and housing, as well as to understand the drivers of such change (e.g. demographic change, governance mechanisms, economic factors). Its chief focus is on integrated and implementable solutions to address health, socioeconomic development and environmental sustainability, encompassing both increased resilience to environmental change, and the ancillary effects for health, of measures which reduce the environmental ‘footprint’ of cities. It will include training/capacity building and public/policy engagement.

Amount: £30,000
Funder: The Wellcome Trust
Recipient: University College London

Directed bone marrow homing as a strategy to embed T cells 13 Jan 2016

T-cell therapies are quickly emerging as highly promising candidates for the treatment of infection, cancer and autoimmune disease. Critical for the success of these therapies is the need for T cells to engraft efficiently and then persist long-term. Current clinical protocols have employed ‘conditioning’ with chemo- or radiotherapy, with or without exogenous cytokines, to aid engraftment and survival of transferred cells. But these approaches are associated with significant risks to already sick patients and only have variable success in ensuring the persistence of adoptively transferred T cells. There is an important unmet medical need to develop safer and more effective ‘one-shot’ strategies to promote both the initial engraftment and survival of therapeutic T cells in patients. Professor Ronjon Chakraverty has identified a completely novel strategy to overcome these hurdles. It involves overexpressing using the chemokine receptor CXCR4 to direct the T cells to the bone marrow, where they receive specific niche signals that promote engraftment and survival. Across multiple clinical applications, this strategy is designed to achieve a lasting therapeutic effect with a single dose of T cells.

Amount: £131,502
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

Life history of an organizer: what determins transient orgnaizer function in Hensen's node? 30 Sep 2016

The "primary organizer" of the vertebrate embryo is a group of cells at the gastrula stage which is able to induce a complete patterned nervous system when transplanted to another site. However, the position in the embryo where the organizer is located only has these properties for a short time. This time corresponds to when two particular populations of cells ("central epiblast" and "posterior deep") come together. After this, as cells leave to form the prechordal mesendoderm, organizer ability is lost again. The aim of this project is to find out whether the organizer function of Hensen's node is the sum of properties that exist in separate cell populations or whether new properties are generated by interactions between them, and thus determine how dynamics of these cells contribute to the transient nature of organizer function. Cell dynamics will be studied using carbocyanine dye (Dil and DiO) labelling of the 'central' and 'posterior' populations to identify their contributions and roles in the organizer. These populations, individually and combined, will be assessed by studying their transcriptomes by RNA sequencing. Their organizer function will then be assessed, in time-course, by the gene expression profiles in cells receiving signals from these populations

Amount: £28,350
Funder: The Wellcome Trust
Recipient: University College London

Coordinated neural tube closure: The role of biomechanical properties in directing neuropore 30 Sep 2016

Neural tube (NT) closure is a morphogenetic event of vertebrate development that results in severe birth defects (e.g. spina bifida) when disturbed. The key genes/pathways of neurulation have been studied extensively, but many aspects of the developmental mechanisms remain unclear. This project addresses two questions: (i) how is neurulation linked mechanistically with the process of axial elongation, which accompanies spinal closure in higher vertebrates, and (ii) how/where do tissue-level biomechanical forces arise that drive NT morphogenesis? Neuro-mesodermal progenitors (NMPs) generate both neuroepithelium and mesoderm during axial elongation, and will be fate-mapped in the NT of cultured mouse embryos. Single-cell labelling by photo-conversion of cells expressing the Dendra2 construct will reveal the timing of neural commitment in NMPs. Requirement for NMPs in NT closure will be assessed in embryos mutant for Grhl3, a gene expressed in NMPs and where loss- or gain-of-function causes spina bifida. Biomechanical forces in the closing NT will be detected by electroporating a FRET-based mechanosensor that reports stress in cytoskeleton-linked proteins (e.g. alpha-actinin). Embryo manipulations (e.g. closed NT incision) will be tested for effects on FRET-reporter activity to identify the origin of closure forces, while mutant embryos developing spina bifida will be assessed for altered force distribution.

Amount: £55,346
Funder: The Wellcome Trust
Recipient: University College London

MRF2 National Alliance for Museums, Health and Wellbeing 30 Sep 2017

This project seeks to take forward work begun by the National Alliance for Museums, Health and Wellbeing. Since its establishment in July 2015 the Alliance has engaged with an of audience of 96,000, recruited 400 members, led an All Party Parliamentary Roundtable on Museums and Wellbeing, delivered the first National Museums and Wellbeing Conference and Week, and developed a database of over 600 museum-wellbeing projects. The proposal draws together the shared expertise of a number of allied organisations with interests in wellbeing. By working in partnership we will: share expertise and best practice across our diverse audiences; provide training to help develop the regional workforce; create online virtual training resources for building resilience in museums; provide leadership and advocacy at the highest levels of health and social care policy making; and develop an umbrella organisation across arts and culture to ensure future sustainability and legacy. The Alliance is a consortium led by UCL Museums, National Museums Liverpool, British Museum, Thackray Medical Museum, UK Medical Collections Group, Tyne & Wear Archives & Museums, Manchester Museums and Galleries, University of Leicester Research Centre for Museums and Galleries, Museums Association and National Alliance for Arts, Health & Wellbeing.

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

Mechanisms and Regulation of RNAP transcription 11 Jul 2017

This grant focuses on four lines of scientific enquiry converging on RNAP function Characterisation of the molecular mechanisms underlying RNA polymerase and basal factors that facilitate transcription initiation, elongation and termination by using multidisciplinary approaches in vivo and in vitro. This includes using bespoke transcription assays, structure elucidation and a global characterization of the occupancy and transcriptomes. Identification of novel gene-specific factors and characterization of the proteomes of transcription preinitiation- and elongation complexes in vivo. Identification and characterization of RNAP-associated proteinaceous- and RNA regulators. Characterisation of the structure and function of archaeal chromatin formed by A3 and 1647 histone variants. A biophysical characterization of protein-DNA interactions and a whole-genome view of histone occupancy. Focus on the impact of chromatin on RNAP as it progresses through the transcription cycle, and the role of elongation factors to overcome the inhibitory effect of chromatin. Characterisation of factors that modulate RNAP during virus-host interactions. Virus (RIP)- and host (TFS4)-encoded RNAP-binding factors function as global inhibitors of transcription and their mechanism is reminiscent of antibiotics. Using two virus libraries of we want to screen for novel RNAP-binding regulators and use them as molecular probes to dissect RNAP function.

Amount: £2,029,869
Funder: The Wellcome Trust
Recipient: University College London