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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

Microtubule organisation and role of LL5-beta in lymphoid stromal fibroblasts 27 Apr 2017

The lymph node is a meeting point for lymphocytes with antigen-presenting cells, and rapidly expands during immune responses. Lymph node structure is highly compartmentalised, and the complex internal architecture is maintained during lymph node expansion. Therefore, mechanisms must exist to balance lymph node integrity with the need to remodel very rapidly. Fibroblastic reticular cells (FRCs) are the most abundant lymphoid stromal cell population, and span the full volume of the tissue. They provide structural support and are highly contractile. FRCs ensheathes bundles of extracellular matrix, termed the conduit, which filters draining lymph. The Acton lab works to understand how lymph nodes are remodeled during expansion and has shown that interaction between FRCs and dendritic cells change FRC behaviour. This project asks how the microtubule networks within FRCs are reorganised as the FRC network expands. Phosphoproteomic screening has revealed that LL5-beta, a protein targetting microtubules to adhesion sites is regulated by interactions between FRCs and dendritic cells. This may provide a mechanism by which FRCs uncouple from underlying matrix, and target secretion of proteases or new matrix to the expanding network. This project will investigate whether LL5-beta coordinates organization of microtubules in FRCs and whether dendritic cell contact changes LL5-beta activity.

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 (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

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

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: £796,863
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

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

Created Out of Mind: Shaping perceptions of dementia through art and science 07 Mar 2016

Created Out of Mind will shape public and professional perceptions of dementia through a dynamic fusion of scientific and creative experimentation. Our Hub residency will support the active connection and collaboration of previously disparate cultures (scientists, artists, commissioners/policymakers) and infuse the insights and skills of people living with dementia, communications professionals and collaboration experts. Common (mis-)conceptions of dementia will be challenged through integrated artistic and scientific investigation of less recognised symptoms associated with typical and rare dementias. The project will investigate the neuroscientific, artistic and social bases of artistic engagement, enjoyment and change across multiple art forms. Interdisciplinary discussion, disagreement and creativity will also challenge and develop thinking regarding the principles, priorities, practice, health benefits and methodologically-robust evaluation of arts in dementia. Our inspiration comes directly from the intriguing experiences, heart-rending questions and puzzling uncertainties of people living with dementia. Team members will become creative collaborators whilst maintaining their professional ‘essence’, yielding a richly and meaningfully interconnected network of multi-skilled science/arts researchers, practitioners and communicators. We will also enrich understanding about dementia by raising provocative questions about the healthy brain, our emotional reactions to change in ourselves and others, and the attributes by which we value and define humanity.

Amount: £715,199
Funder: The Wellcome Trust
Recipient: University College London

Bangles and Bindhi’s:Engaging communities about child marriage in southern Nepal 27 Apr 2016

Child marriage is a major determinant of physical and mental ill health and affects educational and economic attainment. Despite being illegal, it is common in Nepal, having been ingrained over generations, with strong social and financial incentives. Attempts to reduce this have been unsuccessful. Rather than mere education, we plan to work with adults who have married young. We will engage with couples (both men and women) to think deeply about how child marriage has affected their lives and how to tell their story through film. We will create a film together, take it to communities where child marriage is common and show it in large public screenings. A trained facilitator will engage the audience in discussions and help them to reflect on the issues presented. The community members will then have the opportunity to discuss the issues at length in smaller meetings and think about how they may address the issue locally. We hope that by engaging the public in this process, we can help communities take action to prevent child marriage and help both them and us understand the barriers to change.

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

A drug target for common ocular inflammatory diseases 13 Jan 2016

Epithelia form cellular barriers such as the corneal epithelium, protecting the eye’s surface, and the retinal pigment epithelium (RPE), a barrier between the blood and the retina. Epithelial defects are major components of common diseases, such as inflammation, infections, diabetes and age-related conditions. Professors Maria Balda and Karl Matter, UCL Institute of Ophthalmology, have developed inhibitors targeting a central regulator of a mechanism activated in such diseases to prevent epithelial and endothelial inflammation, malfunction, and loss of or reduced vision. These pathological conditions are integral components of chronic inflammation and ageing; hence, they become increasingly more common. There are few treatments available and they are not very effective. Therefore, their project addresses an unmet, clinically relevant healthcare need and will potentially benefit a wide range of patients suffering of inflammatory and age-related conditions that become increasingly more common. Balda and Matter research programme thus has a high future potential healthcare impact and directly supports the strategic aim of Moorfields Eye Hospital and the Institute of Ophthalmology to develop new therapies with High-Patient-Impact. (172 word)

Amount: £143,976
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

Analysis of cytomegalovirus pathogenesis in a human challenge system 30 Nov 2016

Our research has made major contributions to understanding the natural history and pathogenesis of human cytomegalovirus (HCMV) in allograft recipients. Critically, we have demonstrated that biomarkers can be applied to stratify patients most at risk of HCMV disease and thus inform clinical practice to reduce HCMV end-organ disease. This clinical approach of administration of antivirals to individuals with elevated viraemia above designated levels provides a unique opportunity to gain fundamental insight into disease processes in a human challenge model of HCMV infection. A multi-disciplinary consortium has been recruited to apply next generation DNA sequencing, molecular virology and functional immunological assays to identify virus and host cell determinants of disease susceptibility. Whole genome sequencing of virus in organ donors (live and cadaveric) and recipients will be used to track the source, replication kinetics and evolution of HCMV strains in seronegative and seropositive recipients. We will then define in vitro humoral, cell-mediated immunity and natural killer responses against HCMV that correlate with protective immunity against primary infection, reinfection and reactivation in these patient groups. This approach has the potential to provide unique insights into the natural history and pathogenesis of HCMV and identify innovative therapeutic approaches against it.

Amount: £2,669,767
Funder: The Wellcome Trust
Recipient: University College London

International Brain Laboratory 30 Sep 2017

Understanding mechanisms of brain function is a scientific frontier with enormous potential benefits which is now within reach, thanks to recent exciting technical innovations. However, given the brain’s extraordinary complexity, effectively harnessing these tools is beyond the reach of single laboratories pursuing problems in isolation. This initiative - the International Brain Laboratory - will focus the efforts of 20 laboratories to understand the neural mechanisms supporting decision-making behavior in mice. As in real-world foraging contexts, mice will combine information from sensory stimuli with internal estimates of evolving reward availability. To understand how sensory signals are integrated across the brain and combined with an internal, dynamic understanding of reward structure, we will measure brain-wide neuronal activity using 2-photon imaging and high-yield electrophysiology with Neuropixels probes. Theorists and experimentalists will work closely together to interpret data, making use of standardized data processing pipelines and immediate cloud-based data sharing. This is a paradigm-shifting approach in terms of its large-scale collaborative structure and its aim to provide a mechanistic explanation of decision-making behavior across brain structures. Further, by harnessing strategies for sharing data and analyses to ensure tight collaboration and improved reproducibility, we aim to provide a new template for global neuroscience collaborations.

Amount: £1,998,000
Funder: The Wellcome Trust
Recipient: University College London

Human Immune Response Variation in Tuberulosis 11 Jul 2017

I aim to discover novel mechanisms by which differences in human immune responses influence the outcome of Mycobacterium tuberculosis (Mtb) infection. I hypothesise that host-genetic polymorphisms lead to variation in immune responses that determine the clinical outcome of Mtb infection by affecting host-cell restriction of mycobacterial growth. We will use transcriptional profiling at the site of tuberculin skin tests (TST) to make comprehensive molecular and systems level assessments of in vivo human immune responses to a standardised mycobacterial challenge. In order to identify human immune responses that increase risk of disease in people exposed to Mtb, we will test the hypothesis that the TST transcriptome will reveal immune phenotypes associated with progression of LTBI to active TB. We will test the role of host genetics by identifying genome-wide expression quantitative trait loci (eQTL) associated with variation in the TST transcriptome. We will then recall participants by genotypes associated with selected traits to undertake in vitro mechanistic studies in primay immune cells. We will validate the causal association between genetic and phenotypic variations, and test their impact on Mtb restriction by macrophages. The findings will inform clinical risk stratification, vaccine design and development of host directed therapies for TB.

Amount: £1,660,537
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

Investigating the role of RNA interference in retinal development and as an agent of degeneration 31 Jan 2017

Genetic diseases affecting the retina, are the leading cause of blindness in the developed world. Despite the wide knowledge of the genetic factors which result in retinal dystrophies, (more than 200 genes have been identified as playing a role) such conditions remain untreatable. In monogenic retinal dystrophies the age of onset of photoreceptor cell death and rate of sight loss varies, yet the pathogenic gene mutation is present throughout life. Why some cells die at a given point in time and others do not, is unknown. This project aims to investigate the role of endogenous micro RNAs (miRNA) in retinal development and the relationship between miRNA dysregulation and retinal dystrophy. Specific miRNAs will be inactivated using the CRISPR/Cas9 system and the effects on photoreceptor differentiation and optic cup lamination determined. Furthermore, retinal organoid cultures derived from Type I Usher (a syndromic retinopathy) patient induced-pluripotent stem cells (iPSC; derived by reprogramming skin fibroblasts), will be used to establish whether miRNA dysregulation is indicative of an early disease state and whether CRISPR/Cas9-based gene correction can return dysregulated miRNA levels to normal. Finally, the effects of delivering certain miRNAs to a mouse model of retinal dystrophy on early disease phenotype will be established.

Amount: £24,581
Funder: The Wellcome Trust
Recipient: University College London

Local control of ventral subicular circuitry and its alteration by social isolation 31 Jan 2017

The overall aim of this project is to use viral tracing, electrophysiology and optogenetics to investigate the local circuitry of the ventral subiculum (vS), and how this circuit is altered by social isolation stress – a common route to affective disorders such as depression and anxiety. I will first investigate the anatomical distribution of neurons in vS that project to the prefrontal cortex or the NAc. These have been shown to be distinct parallel populations with unique circuit functions, but very little is known about their detailed local circuit organisation. Next I will use optogenetics, electrophysiology and viral tracing to determine the functional connectivity of the local circuit that defines the differential activity of these projections. Despite strong hypotheses that local control is key in this circuit, how this is acheived mechanistically remains unknown. Finally, I will determine how this detailed projection-specific circuitry is altered by social isolation - a manipulation that drammatically alters vS circuitry - and aim to provide more specific targets for in vivo manipulations aimed at reversing isolation-induced behavioural deficits. Overall, these experiments will provide for the first time mechanistic insight into the function and organisation of vS circuitry, from individual synaptic connections, to circuit function.

Amount: £30,524
Funder: The Wellcome Trust
Recipient: University College London