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Recipients:
University College London

Results

Inhibition in the Periaqueductal Gray 30 Sep 2018

Deciding which action to take, such as whether to cross a busy road, is a critical survival skill. Making decisions requires integrating complex information and identifying the cellular mechanisms of this process is critical for understanding how the brain computes decisions. In this project will investigate neurons that control defensive decisions in mice and focus on inhibitory neurons in the midbrain Periaqueductal Grey (PAG), which have the ability to veto defensive behaviours.The first main goal of the project is to use electrophysiological and advanced molecular techniques, such as RNA sequencing and gene knock-down, to identify the genes and ion channels that control the firing of PAG inhibitory neurons. The second goal is to determine key regulators of the activity of these neurons, in particular neuromodulators and long-range synaptic connections from other brain areas, using techniques such as optogenetics in combination with behavioural assays that exploit the innate defensive behaviours of mice. The results of this work will reveal new the biophysical principles that drive firing in a key population controlling a critical behavioural decision, and provide an entry point for understanding how pathological states such as anxiety lead to maladaptive decisions.

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

Non-local computations in hippocampal circuits: neural mechanisms 17 Jul 2018

The overall goal of this proposal is to build a neural-level understanding of how non-local cortico-hippocampal communication mediates memory consolidation and spatial computations. The well-studied network of spatially modulated neurons in the hippocampus and associated regions provides the pre-eminent cellular-model of memory for events and places. However, the activity of these neurons mainly encodes local information, that is, the current configuration of an animal in its environment. Work conducted by us, and others, have identified transient reactivations of hippocampal neurons and cortical counterparts as a key mechanism supporting systems consolidation and spatial planning. These brief ‘non-local’ events provide a means by which remembered experiences can gradually update memory networks, equally they are theorised to support the calculations necessary for route planning. Our aims are: 1) to understand how hippocampus and cortex interacts during reactivations; 2) determine how reactivated information affects existing representations; 3) precisely define the spatial computations that guide navigation; 4) investigate how neuromodulation controls the occurrence of reactivations. To this end, our approach is to combine computational modelling, machine learning, and state-of-the-art experimental techniques. Developing a basic understanding of these processes opens the way to understand how they fail in disease and may ultimately deliver tremendous therapeutic benefits.

Amount: £1,670,136
Funder: The Wellcome Trust
Recipient: University College London

Investigating the energy homeostasis of cellular calcium signalling 31 May 2018

Cellular calcium signalling is a ubiquitous and fundamental mechanism driving many processes in cell physiology. However it carries a significant energetic cost: calcium that enters the cytosol must be removed or sequestered by ATPases. In this project we propose to explore the mechanisms involved in maintaining energetic homeostasis in the face of this energy demand. The transfer of calcium signals to mitochondria is thought to support energy production, as it upregulates the rate limiting enzymes of the TCA cycle, increasing the rate of ATP production, although extrusion of calcium from the mitochondria also carries an energetic cost. The recent development of new targeted fluorescent reporters allows detailed exploration of compartmental ATP generation, making these questions accessible. We will therefore use fluorescence microscopy and imaging of a novel mitochondrial targeted ATP reporter to measure changes in cytosolic and mitochondrial ATP in response to changes in cytosolic and/or mitochondrial calcium signals to address these fundamental questions in cell biology. It is important to understand the fundamental mechanisms of cellular energy homeostasis so that we can better understand how mitochondrial dysfunction, associated with many disease states, undermines the ability to match energy demand with energy production.

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

New methods to predict gene function in fission yeast 30 Sep 2018

Computational biology aims to answer some of biology’s most complex questions using computational and statistical methods. The field has successfully identified genes involved in disease and has helped to discover drugs for their treatment. My PhD research takes this approach to understand the processes by which we age. Aging is a complex disease — characterised by the progressive loss of function in an organism over time — with huge social and financial cost. Faced with an aging population, breakthroughs in this area are desperately needed. I am attempting to do this using data collected from experiments that measure the lifespan of yeast in different environmental conditions. Whilst we are only distantly related to yeast, it is a useful model of human aging as it shares many cellular processes, but lives for a fraction of the time. Ultimately, I aim to use these data to predict the genes that cause yeast to age. Whilst a handful of aging genes have been identified, more genes are likely to contribute. I use networks and machine learning approaches to make my predictions. Going forward, these will help to deepen our understanding of aging and aid the development of treatments to eventually cure this disease.

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

Predicting the Strength of Zinc Metal Binding Sites in Proteins 30 Sep 2018

Many proteins bind to metal ions, and rely on these interactions in order to properly carry out their function - indeed failure to do so is responsible for a number of diseases. Understanding the details of how these metal-protein interactions work and developing tools to predict their occurence in newly discovered proteins, as well as predicting sites that are created when proteins interact with one another, will aid our understanting of these diseases. Such knowledge would also allow us to engineer metal binding sites into synthetic proteins, which would have enormous benefits in biosensing, novel pharmaceuticals, and developing synthetic biological circuits. This project will focus specifically on zinc-protein interactions - creating a publicly accessible database resource of known zinc binding sites, and developing sophisticated tools for predicting the location and strength of zinc binding sites in a given protein structure, including sites that occur when two protein chains come together. Ultimately the project seeks to allow a researcher to modify a protein without zinc binding ability, to enable it to bind zinc and to reveal sites for drug design to modify zinc binding.

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

Investigating the effect and impact of binding RSV-G protein on pneumococcal growth and antibiotic sensitivity 21 May 2018

The pneumococcus (Streptococcus pneumoniae) is a global pathogen associated with high mortality rates in young children and the elderly. My research has shown that pneumococci rapidly increase their virulence by binding to the G protein encoded by human respiratory syncytial virus (RSV), the leading cause of viral pneumonia. This is thought to be mediated by the pneumococcal receptor for RSV, penicillin binding protein 1a (PBP1a), an important protein involved in bacteria cell wall synthesis and cell division. However, the mechanism behind the increase in virulence remains unknown. This proposal builds on my recent observations and brings together world-leaders in the fields of virology and bacterial cell wall biosynthesis to determine the immediate phenotypic and genotypic consequences of the pneumococcus binding to RSV-G protein. To do this I will: Determine whether binding RSV-G protein affects pneumococcal growth and increases pneumococcal cell lysis. Determine the effect of RSV-G on PBP1a gene expression and the enzymatic activity of pneumococcal PBP1a. Determine whether binding to RSV-G protein increases pneumococcal antibiotic sensitivity. These findings will help direct a larger study to determine the mechanisms of virulence enhancement during co-infection and the impact this has on inflammation, the host cell response and, importantly, antimicrobial therapy.

Amount: £99,958
Funder: The Wellcome Trust
Recipient: University College London

Personalising the pharmacological treatment of bipolar disorder 23 May 2018

Background Prescribing for bipolar disorder is a major clinical dilemma as long-term pharmacological treatment is often necessary. Lithium is the most effective mood stabiliser. However, only 30% of individuals have a good therapeutic response. Presently, there is no reliable way to predict response or adverse event risk, or if an alternative treatment would be better for that patient. Aim To personalise prescribing for people with bipolar disorder via prediction models that quantify potential benefits and risks of existing treatments based on clinical phenotypic characteristics of the individual. Objectives Identify individualised clinical predictors of lithium and second-generation antipsychotic response. Determine clinical predictors of chronic kidney disease in individuals taking lithium. Determine clinical predictors of pathological weight gain in individuals taking second-generation antipsychotics. Methodology Data sources Swedish population registers, Hong-Kong health registers, Taiwanese health insurance database, UK primary care data linked to secondary care admission records, and UK mental health care data. Analyses Traditional epidemiological and machine learning methods; drawing on the strengths of each approach. Prediction model generation I will combine predictors from different datasets; resulting in models predicting drug response, chronic kidney disease and weight gain. Application Prediction models will be presented as online and smartphone application clinician decision aids.

Amount: £460,704
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

Visualising the spatial range of neuropeptide action 21 May 2018

Our moods and our memories arise from a form of chemical communication in our brain termed neuromodulation. Neuromodulators are diffusible neurotransmitters, such as monoamines and neuropeptides, that can act at a distance and potentially reach many different circuits in the brain. Traditionally, neuropeptides have been thought to act on all receptor-expressing neurons within the brain. However, the fact that these molecules convey very specific information and that this information depends on the source of release, indicates that their spatial range of action must be actively regulated. The aim of this proposal is to develop a system for the in vivo visualisation of neuromodulation and the identification of mechanisms that regulate neuropeptide spatial range of action. For this we will exploit the advantages of C. elegans: transparency, single-cell resolution and amenability to genetics. We will first generate a reporter strain to visualise neuropeptide receptor activation upon controlled neuropeptide release, based on the TANGO assay. The novelty of our approach is to apply this tool to the study of neuropeptide target reach. Second, we will perform a forward genetic screen to identify regulators of neuropeptide spatial range of action by isolating mutants with changes in the pattern of neuropeptide receptor activation.

Amount: £99,949
Funder: The Wellcome Trust
Recipient: University College London

Characterising the neural mechanisms of human memory at high resolution 10 Apr 2018

Our past experiences are captured in autobiographical memories that serve to sustain our sense of self, enable independent living and prolong survival. Despite their clear importance and the devastation wreaked when this capacity is compromised, the neural implementation of autobiographical memories has eluded detailed scrutiny. My goal is to understand precisely how autobiographical memories are built, how they are re-constructed during recollection and how these memory representations change over time. My aim is to identify the mechanisms involved in these processes and thereby establish a theoretically enriched account of their breakdown in pathology. This endeavour will be enabled by cutting-edge, multi-modal technology that includes a new wearable MEG system and ultra-high-resolution MRI. The ventromedial prefrontal cortex and hippocampus are heavily implicated in autobiographical memory. I will test a novel hierarchical model that specifies their distinct roles and how they interact to produce the seamless encoding and recollection of our lived experiences. Overall, this new extension of my work will expose autobiographical memories as never before, revealing the millisecond temporal dynamics, and the laminar-specific and hippocampal subfield processing that supports their evolution from the point of inception, through initial sleep cycles and then over longer timescales.

Amount: £2,359,757
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

NMR structural studies of protein folding during biosynthesis on the ribosome 30 Sep 2018

Proteins must fold into their tertiary structure in order to function. This complex process has been well studied over recent decades. However, most of these studies rely on small isolated proteins; protein folding inside of cells can be very different. In cells during translation, the ribosome synthesises proteins by adding amino acids to the growing polypeptide chain, this eventually extends out of the ribosome tunnel and can can begin to fold while still being synthesised; representing a major difference between historical folding studies and the real picture inside cells. In our lab we aim to characterise the process of protein folding on the ribosome. We are especially interested in how the ribosome may aid proteins to fold efficiently. To do this we use Nuclear Magnetic Resonance (NMR) spectroscopy to generate structural information of proteins attached to ribosomes alongside Cryo Electron Microscopy and Molecular dynamics computer simulations. This PhD project will aim to fully characterise the structure and dynamics of a nascent chain attached to the ribosome using a variety of NMR experiments. We will then analyse a variety of proteins to try and understand why they fold at different points during translation.

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

Control and enzymatic activation of the APC/C ubiquitin ligase system 30 Nov 2016

CDK1 and APC/C are two key regulatory enzymes controlling the cell division, growth, differentiation and death, through phosphorylation and ubiquitylation, respectively. Although it has long been apparent that phosphorylation modifies APC/C function, the challenges posed by the need for functional assays to study this control puts the elucidation of the molecular basis of phosphorylation control beyond our grasp. We have recently overcome these limitations with a pipeline that uses reconstituted recombinant APC/C in Xenopus cell free extracts to show how CDK1 activates the APC/C through coordinated phosphorylation of Apc3 and Apc1. We will now extend this pipeline with targeted assays that will determine how phosphatases regulate these phosphorylation events. Because we have found that the disordered loop domains of APC/C subunits are targets for both post-translational modifications (PTMs) and interacting partners, including protein phosphatases, we will study how the loop domain controls the APC/C. Cell cycle specific and stress-dependent PTMs and binding proteins will be identified and we will determine their impact upon APC/C-dependent ubiquitylation. This approach of combining high throughput reconstitution mutated apo-APC/C in extracts from which any component of interest can be depleted offers a unique opportunity to gain an unprecedented insight into APC/C function and control.

Amount: £1,547,248
Funder: The Wellcome Trust
Recipient: University College London

Complex Urban Systems for Sustainability and Health (CUSSH) 06 Oct 2016

The CUSSH programme will deliver strategically vital global research on the complex systemic connections between urban development and health. Based on transdisciplinary methods, it will develop critical evidence on how to achieve the far-reaching transformation of cities needed to address vital environmental imperatives for population and planetary health in the 21st century. Its core components include: a systematic review of evidence on potential solutions; the development and application of methods for tracking the progress of cities to towards sustainability and health goals; the development and application of models to assess the impact on population health, health inequalities, socio-economic development and environmental parameters of alternative urban development strategies to support policy decisions; iterative in-depth engagements with stakeholders in partner cities in low-, middle- and high-income settings, based on participatory methods, to test and deliver the implementation of the transformative changes needed to meet local and global health and sustainability objectives. Through these steps, the project will provide transferable evidence on how to accelerate actions essential to achieving population-level changes in such areas as energy provision, transport infrastructure, green infrastructure, water and sanitation, and housing. Associated public engagement and training, based on principles of co-generation of research, will be embedded throughout.

Amount: £149,988
Funder: The Wellcome Trust
Recipient: University College London
Amount: £2,814,500
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

Vision, decision and navigation in mouse parietal cortex 31 Jan 2017

Posterior parietal cortex (PPC) in humans and other animals is considered to be a nexus of sensory, motor, and cognitive functions. The underlying circuits and computations are increasingly studied in mice, a species that affords unparalleled resources such as genetic tools and behavioral tasks. Studies of mouse PPC, however, have focused on distinct functions: visual processing, decision making, and spatial navigation. It is not clear whether the same neurons and populations participate in these three functions, and whether they play similar roles in different behavioral contexts. We will first establish how the anatomical definition of mouse PPC used in studies of decision and navigation relates to functional maps of visual cortex established in studies of vision. We will then train head-fixed mice to perform two visual decision tasks: one of which involves navigation in virtual reality, and we will use two-photon calcium imaging to track the activity of populations of PPC neurons over weeks. These data will reveal whether the activity of the same PPC neurons stays fixed or varies to meet the variable demands of these two tasks, and thus establish the role of mouse PPC in functions that are typically combined in daily life: vision, decision, and navigation.

Amount: £27,400
Funder: The Wellcome Trust
Recipient: University College London

Explaining Language Outcome and Recovery After Stroke (ELORAS) 30 Nov 2016

My aim is to develop a theoretical model of language processing that explains inter-patient variability in outcome after stroke. My hypotheses are that the same language task (e.g. describing a picture) can be sustained by different sets of brain regions (and neuronal pathways) and that inter-subject variability in neuronal pathways for the same language task reflect an individual’s inherent potential and prior experience. My investigations will (1) use functional neuroimaging to characterize inter-subject variability in neuronal pathways in a range of language tasks; (2) cluster healthy individuals and stroke patients into different groups according to the neural systems used for the same task; and (3) compare the identified groups on a multitude of demographic, behavioural and structural imaging measures. The results will identify the factors that distinguish which neuronal pathways a subject typically uses and which neural pathways are available to support recovery. The work will provide: (i) greater understanding of the neuronal pathways sustaining recovery; (ii) improved accuracy and precision in our prognoses for whether and when patients with aphasia will recover after stroke, and (iii) a new patient stratification system that can be used to design effective, individualised therapeutic interventions.

Amount: £2,701,886
Funder: The Wellcome Trust
Recipient: University College London