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Recipients:
University College London

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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

Understanding cellular organisation: from archaea to eukaryotes 05 Jul 2016

We know surprisingly little about the basic logic, topology or origins of eukaryotic cell architecture even though such an understanding is fundamental to most biomedical research. Until recently, the proteins responsible for shaping eukaryotic cells (including Actin/Tubulin/coatamers/ESCRTIII) were thought to be unique to eukaryotes. This changed with the discovery of close homologues in TACK/Loki-family archaea. Despite the important part played by these proteins during eukaryogenesis, we know little about their functions in the context of archaea. To determine how these cytoskeletal systems with origins in archaea contributed to the emergence of internal compartments that define eukaryotes, our team will use metagenomic sampling and phylogenomics to trace their evolutionary history, and a combination of approaches, including live super-resolution microscopy and electron tomography to carry out a comparative analysis of their ultrastructure, dynamics and function in both archaea and eukaryotes. Ultimately, we expect this evolutionary cell biological analysis to make a start towards an understanding of archaeal cell biology, to reveal the likely path of eukaryogenesis, and to reveal underlying principles of eukaryotic cell biology that so far have eluded us. In doing so, we expect this fundamental research to have a signficant impact in the future on human health and disease.

Amount: £1,122,019
Funder: The Wellcome Trust
Recipient: University College London

Characterisation of cell types obtained from mixed cell cultures of the human olfactory mucosa, for the application of central nerve repair 23 Nov 2015

Spinal cord and root injuries are commonly due to road traffic accidents and can result in permanent paralysis with major physical, psychological and economic impacts. Although surgical repair of spinal root and cord injuries can restore some movement, patients seldom report good functional outcome. Olfactory ensheathing cells (OECs) are a promising cell candidate for nerve repair and can be obtained from the olfactory mucosa of the nose, where they normally induce repair of damaged olfactory nerve fibres for the sense of smell. They can be obtained by a simple biopsy of the olfactory mucosa using an endoscope. Through funding from the Health Innovation Challenge Fund, Mr David Choi and colleagues at UCL aim to better understand the cell quality attributes and final product formulation to ensure a robust, well-characterised cell product that is effective in laboratory assay systems and satisfies regulatory requirements. With this information the team can then proceed with production of cells for transplantation and plan to start a phase 1 clinical trial involving transplanting a patient's own OECs during the surgical repair of brachial plexus avulsion, within three years. Positive results would impact not only patients with brachial plexus injuries, but also patients with spinal cord injury or stroke.

Amount: £1,163,250
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

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
Amount: £12,000
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

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

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

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

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

Probing the synaptic mechanisms of human genetic neurological disorders 30 Sep 2016

We are interested in how mutations that lead to human neurological disorders (particularly epilepsy) impact neuronal function. Much of our previous work has focused on how mutations change intrinsic neuronal excitability, but epilepsy is increasingly being associated with genes which are also predicted to perturb synaptic activity, and the aim of this project is to probe whether a subset of mutations linked to similar genetic epilepsy disorders have similar consequences for pre-synaptic properties. We will develop a lentiviral tool that will express a fluorescent protein (e.g. RFP) and a cDNA or shRNA to mimic a genetic disorder in a subset of cultured neurons. Recordings will be from untransduced post-synaptic cells, limiting the possibility of post-synaptic genetic effects contaminating readouts of the impact of mutations on synaptic release. We will also investigate whether incorporation of an activating opsin is sufficient for light based stimulation of the pre-synaptic neurons only. By incorporating cellspecific promoters, this project will also allow us to test the hypothesis that mutations that cause seizures have distinct effects in interneurons and excitatory neurons, including how they couple excitation to transmitter release. This project will dissect the synaptic mechanisms of disease, and correlate them with subsets of neurons.

Amount: £5,805
Funder: The Wellcome Trust
Recipient: University College London

Understanding within-patient Mycobacterium tuberculosis genetic diversity to prevent drug-resistance 29 Jun 2016

Tuberculosis, caused by Mycobacterium tuberculosis (M.tb), is a major public health problem. Drug-resistant tuberculosis (DR-TB) cases are increasing, creating a significant barrier to disease control. DR-TB is difficult to diagnose and treatment often takes years. M.tb was traditionally thought to be genetically homogenous within the human host, but deep whole genome sequencing (WGS) data have revealed evidence of within-host genetic heterogeneity (GH), particularly in drug-resistance genes. Changing GH patterns over time can cause acquired drug-resistance (ADR). However, how and where in the host GH arises, or how important it is for ADR is not known. I hypothesise that GH represents isolated M.tb subpopulations in separate lung lesions within a patient, and that development of GH is related to local pathology or drug penetration. I will investigate this by WGS of M.tb extracted from resected human lung tissue, and comparing GH to pathology type and local drug concentrations. To evaluate whether GH causes ADR, I will follow patients with newly diagnosed MDR-TB and perform WGS of sequential sputum samples over 6 months for WGS. I will evaluate if ADR is related to baseline GH. Understanding the role of GH in ADR could help develop prevention strategies.

Amount: £380,125
Funder: The Wellcome Trust
Recipient: University College London

Understanding and predicting prognosis for adults with depression 02 Mar 2016

Depression is the most burdensome disease world-wide in terms of years of life lost to disability. Approximately 90% of depressed patients receiving psychological therapies in the UK are treated in Improving Access to Psychological Therapies (IAPT) services. Treatment outcomes vary between and within IAPT services, with between 24-71% of patients recovering after treatment, a large proportion improve without fully recovering, but a sizeable number do not improve at all or deteriorate while receiving treatment. This project aims to develop an algorithm that can predict prognosis for patients referred to IAPT services with depression. This is important because we are unable to determine what outcome a depressed patient referred to any given IAPT service will have, or account for the variability in outcomes between IAPT services. Predictions of outcome can inform decisions on whether or not a patient should start therapy, particularly for those most likely to not improve or deteriorate during treatment; help commissioners plan for the costs of treatment therefore saving the health service money, and compare between services while accounting for area-level differences and differences in the characteristics of referred patients; and allow services to focus resources on those likely to improve with treatment, potentially improving outcomes.

Amount: £228,328
Funder: The Wellcome Trust
Recipient: University College London

Efficient and transparent methods for linking and analysing longitudinal population studies and administrative data 05 Jul 2018

The Wellcome Trust LPS Strategy states that research is needed to i) underpin efficient linkage of multiple datasets, ii) quantify potential biases resulting from linkage, and iii) to handle linkage error in data analyses. We propose a programme of methodological research to develop efficient and transparent methods for linkage and analysis, to help maximise the joint potential of existing longitudinal population studies and multiple administrative datasets. Our proposed work packages will focus on linkage of LPS and multiple administrative datasets: WP1: Facilitate development of innovative linkage methods for multiple datasets, by developing shareable software to generate synthetic datasets that are generalisable to a range of research settings. WP2: Develop methods for efficient linkage of multiple datasets by expanding existing probabilistic linkage methods to the setting in which multiple administrative or LPS datasets are to be linked dynamically, and where there are multiple sets of identifiers (e.g. collected at different time-points). WP3: Provide appropriate tools for analysis of linked data by extending existing imputation methods for handling linkage uncertainty and avoiding bias within analysis. WP4: Maximise the value of approaches developed in WP2-3 through evaluation using exemplar linkages and dissemination of methods to the LPS community and other key stakeholders.

Amount: £301,055
Funder: The Wellcome Trust
Recipient: University College London

Exploring glial roles in sculpting brain development 30 Sep 2018

Although two broad cell types, neurons and glia, compose the brain, neurobiologists have tended to focus on neurons, the electrically excitable cells that process information. Glia were thought of primarily as neuronal support cells. Recent work challenges this view and shows that glia play essential roles not just in supporting neuronal function but also in instructing their development. I propose three aims to address how glia regulate two key aspects of brain development, neuronal birth and neuronal identity: (i) A major challenge in neurobiology is defining the origin of neuronal identity (and thus diversity). I will investigate how signals sent by glia to naïve precursors determine the unique neuronal fates that these cells adopt. (ii) Although the brain has little regenerative potential, under restricted circumstances differentiated glia can act as stem cells to generate neurons. I have identified one such example and will probe the signals that reprogramme glia to generate neurons. (iii) I will explore how different glial types differ in their regulation of neural development. I will begin with a systematic survey of the signals released by different glial-subtypes and then manipulate these while evaluating their effect on neighbouring neural precursors and neurons.

Amount: £25,000
Funder: The Wellcome Trust
Recipient: University College London

Gene Editing using CRISPR/Cas9 for Gene Correction in Recessive Dystrophic Epidermolysis Bullosa (RDEB) 31 May 2018

Conventional gene therapy approaches rely on the addition of a corrected gene copy via viral vector transduction. Such strategies are currently being applied to recessive dystrophic epidermolysis bullosa (RDEB) where there is defective collagen type VII protein. However, use of constitutive exogenous promoters in viral vectors results in sustained gene expression that is not subject to the normal regulatory mechanisms of C7 expression. Integrating properties of vectors also pose risk for insertional mutagenic-derived events and efficiency of gene transfer has been challenging given the large size of COL7A1 cDNA. Whereas, gene-editing tools can be designed and engineered to target and repair specific defined regions of DNA, thereby alleviating genomic toxicity and maintaining endogenous gene expression control. Existence of well-known mutation hotspots within COL7A1 allows CRISPR reagents to be designed that would target the mutations found in the UK population with RDEB. Investigations outlined in this proposal aim to identify the most effective CRISPR reagent for a chosen mutation hotspot within COL7A1 gene. In skin, keratinocytes predominantly produce collagen type VII. Therefore, this project will evaluate feasibility of gene editing approaches using CRISPR/Cas9 system in HACAT keratinocytes cell line, and help address critical aspects of CRISPR/Cas9 efficiency at a chosen loci.

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

Irritability, Reward Processing and Adolescent Depression 30 Sep 2018

Depression is a common mental health problem and a leading cause of disability. Rates of depression increase throughout adolescence, with most adult disorders beginning during this time. Despite this, we do not fully understand why depression increases during adolescence or why some people are more vulnerable than others. Depressed adults show changes in processing of reward related information, which potentially contribute to their risk of depression. Children who are more irritable (i.e. more prone to anger in response to frustration e.g. omission of an expected reward) are more likely to develop depression when older. Such children also show changes in processing of reward. Adolescence is a time of significant social, emotional and cognitive development both biologically and environmentally. I hypothesise that irritability in childhood is a consequence of differences in reward processing that lead to depression in adolescence in the context of the developmental and environmental changes. This study aims to investigate these relationships by looking at childhood irritability, reward processing and depressive symptoms. Depression has a complex multi-factorial aetiology; studying childhood risks for depression will improve our understanding of the mechanisms underlying depression, allowing development of more targeted interventions and preventive strategies.

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