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Results

Volunteering Matters 06 Nov 2014

Piloting Engage and Transform, a scheme to break down cultural barriers and develop a long-term partnership of mutual benefit between public and social sector organisations.

How does nonsense-mediated decay contribute to gene regulation in developing neurons? 31 May 2018

Nonsense mediated decay (NMD) is a quality control mechanism used by eukaryotic cells to destroy messenger RNAs containing incorrectly positioned translation termination codons [1]. NMD, in combination with alternative RNA splicing (AS), also provides a potent mechanism for natural changes in gene expression in developing brain [2-5]. The main goal of my summer project will be to test the hypothesis that progressive down-regulation of an RNA-binding protein called PTBP1 during mammalian neurogenesis promotes neuronal identity by changing AS patterns and triggering NMD of multiple neural precursor-specific transcripts. I will first follow up on the RNA sequencing screen carried out in the Makeyev lab and validate bioinformatically predicted AS-NMD targets using Reverse Transcription PCR and quantitative PCR analyses of developing nervous system samples and embryonic stem cells undergoing neuronal differentiation in vitro. I will then analyse AS-MND regulation for one example showing the most robust regulation. This will be achieved by designing minigene and CRISPR-Cas constructs specific for AS-NMD promoting exons and testing these reagents in mouse ES cells undergoing neuronal differentiation or treated with siRNA against PTBP1. The results of this work should improve our understanding of the AS-NMD pathway and evaluate its contribution to neuronal differentiation.

Amount: £0
Funder: The Wellcome Trust
Recipient: King's College London

Investigating mitochondrial metabolic signalling in the nervous system 31 May 2018

Mitochondria generate the majority of ATP, but have key additional roles in cellular metabolism. Mitochondrial dysfunction causes neurodegeneration, but the underlying molecular mechanisms are poorly understood. Recent studies in cultured cells have shown that mitochondrial dysfunction leads to an increase in production of the oncometabolite 2-hydroxyglutarate (2HG), which plays important roles in signalling and modification of the epigenome. The host lab has recently shown that reducing 2HG levels improves neuronal function in a Drosophila mitochondrial disease model. This project will use Drosophila to study the effects of increased 2HG levels in the nervous system. We hypothesise that mitochondrial dysfunction causes increased 2HG levels in neurons, which results in neuronal dysfunction and neurodegeneration. The key goals of the project will test this hypothesis: 1. To determine whether Drosophila L2HGDH mutants, which have increased 2HG levels, have reduced locomotor activity and lifespan. 2. To determine whether Drosophila L2HGDH mutants have increased neurodegeneration. 3. To test whether increasing 2HG levels exacerbates neuronal dysfunction and neurodegeneration in a Drosophila mitochondrial disease model. Overall, this project will provide the first evidence that mis-regulation of mitochondrial metabolism contributes to neurodegeneration. It will also show that 2HG is a potential novel therapeutic target for neurodegenerative disease.

Amount: £0
Funder: The Wellcome Trust
Recipient: King's College London

‘To live or die: early fate decision of cortical interneurons.’ 10 Jul 2018

My vision is a project, which uses digital portraits created by an artist ‘in residence’ and the portrait subjects together. The work on the portraits is digitally recorded and an animation is created, showing how the artist saw the person and what input the person had on the portrait during the day. A podcast is recorded throughout the day by an experienced podcaster, who himself has ADHD. The portraits and the podcasts are a foundation for a round-table consultation between autistic individuals, their carers, clinical and basic neuroscientists, and students studying for a relevant degree, and we record podcast summaries of the conclusions drawn during the round-table discussions. All the portraits and podcasts are brought into the Science Gallery for a one day exhibition to inspire school children, their teachers and families who have members with autism along with the research scientists to think about what living with autism is like, what is needed from science to best serve the community and how we can all work together to create an open and inclusive environment for all. All the contents will be hosted on Autistica UK’s website as well as permanently exhibited in spaces with high footfall in both Denmark Hill and Guy’s Campus at King’s College London to have a wider range and longer lasting impact on the followers of Autistica; students, staff and visitors at KCL.

Amount: £32,742
Funder: The Wellcome Trust
Recipient: King's College London

Transformations: Encountering Gender and Science 16 Jun 2018

The Rethinking Sexology team’s historical research has uncovered important material on the relationship between medical authority and ‘patient’ experience and the development of diagnostic categories/treatment protocols. We propose a public engagement programme that invites young trans people (age 16-25) to explore this material, co-conduct new research, including an oral history project, and develop an ambitious programme of creative responses leading to a performance and exhibition in four relevant high-profile venues across the UK. The plan of action has been developed during an extensive consultation period with key stakeholders, in which ideas and methodologies have been fully tested. The programme is led by the Rethinking Sexology (RS) team who has an outstanding track record in field-leading engaged research and public engagement. The team’s experience will be complimented by collaborating with a uniquely qualified group of writers, performers and youth-facilitators, known for their pioneering and award-winning work with the trans community, with whom the RS team already has long-standing collaborative relationships. The programme will deliver a set of exceptionally innovative activities that will empower young people to: contribute to and enhance health and humanities research and public engagement practices; investigate clinical and diagnostic protocols and transform clinical dialogue; shape public debate through high-quality creative outputs (exhibition/performance) that promise to be intellectually, artistically and emotionally powerful and stimulating. The co-production model at the heart of the programme will feed systematically and continually into ongoing research activities, enabling the project to stand as a beacon of good practice in engaged research and public engagement.

Amount: £147,315
Funder: The Wellcome Trust
Recipient: University of Exeter

High-throughput cellular assays to find a small molecule inhibitor of the TrkA receptor 31 May 2018

This project aims to identify novel TrkA receptor antagonists that in the future might be developed into drugs to reduce chronic pain symptoms upon the binding of NGF. NGF levels have been shown to be elevated in injury, inflammation and chronic pain states. Sequestering of NGF with anti-NGF antibodies has been shown to reduce hyperalgesia. However, antibody therapies are costly due to manufacturing and purification processes. To find novel TrkA receptor antagonists, a virtual screen against a novel allosteric site within the catalytic domain of the TrkA receptor has identified 125 compounds with potential to dock into the site and inhibit receptor function. I will test these compounds on a cellular assay using NFAT-bla CHO-K1 reporter lines that have had human TrkA, TrkB or TrkC genes stably transfected into them and overexpressed. Using reporter gene b-lactamase, activated upon neurotrophins binding to the Trk receptors, the substrate CCF4-AM (directly loaded onto the cells) is cleaved. This can be measured by changes in the cell FRET value from 530nm to 460nm. This will allow us to test if any compounds identified in the virtual screen inhibit TrkA function, and whether they show selectivity for TrkA over the other two Trk receptors.

Amount: £0
Funder: The Wellcome Trust
Recipient: King's College London

Serio Seed Grant 06 Sep 2018

Amyotrophic Lateral Sclerosis (ALS) is an incurable fatal disease that affects principally Motor Neurones (MNs). Interestingly, spinal MNs have extremely long axons, which makes them particularly reliant on efficient decentralized protein translation and axonal transport. We have evidence that ALS presents characteristics of distal axonopathies, with defects in axonal transport, protein homeostasis and changes in local axonal translation reported. Moreover, most ALS-mutations often directly affect RNA processing. Against this background, understanding the links between axonal length and RNA compartmentalisation could highlight new potential therapeutic avenues. Induced pluripotent stem cells (iPSCs) have proven extremely useful in studying ALS; however, the question of how axonal length affects RNA compartmentalisation in MNs cannot be systematically addressed with current in vitro paradigms, as they do not provide efficient ways to control axonal length. I will develop a platform to study how axonal length in iPSC MNs influences local mRNA translation and RNA compartmentalisation, combiningimaging and transcriptomic analysis with bioengineered alignment substrates that allow to obtain ordered arrays of very long axons in vitro.With this platform I will conduct a pilot study on axonal compartment -specific transcriptomics in MNs and analyse the effect of ALS-mutations on local translation in long motor axons

Amount: £99,987
Funder: The Wellcome Trust
Recipient: King's College London

Unravelling the physics of the pressure drop in blood flow constrictions 28 Nov 2017

A blood flow obstruction introduces an additional burden to the heart, currently characterised by the pressure drop through the obstruction. The pressure drop is only available through catheterised sensors, with associated costs and risks, or through Doppler echocardiography with limited accuracy and robustness. This programme investigates the causes of the additional cardiac burden in those conditions that experience an obstruction of the blood flow. The idea is to examine the physics of the blood flow and unravel the three components of the pressure drop (i.e. unsteady, advective and viscous). The enabling technology, to be further developed within the programme, combines advanced medical imaging and computational technologies. The goals are (1) to identify the pressure biomarkers that best predicts adverse events, and thus guide the optimal choice of therapy options; (2) to enable an easy, robust and non-invasive access to the key pressure biomarkers in clinical practice.

Amount: £1,097,073
Funder: The Wellcome Trust
Recipient: King's College London

Towards a quantitative comprehension of the Spindle Assembly Checkpoint 28 Nov 2017

My aim is to complete a quantitative analysis of the dynamic signalling pathways that control mitosis. By combining mass spectrometry with cutting-edge microsopy I intend to measure the number of active molecules of the key mitotic regulators and determine how and where they interact to generate a highly responsive signal transduction network that ensures genomic stability by controlling sister chromatid separation and mitotic exit. I have four main aims: 1) Measure the numbers of the mitotic regulators controlling chromosome separation and analyse how they are modulated by post-translational modifications (PTMs). 2) Determine the dynamics of the spindle assembly checkpoint (SAC) in living cells by measuring the generation of the SAC effector complex and the flux of its components through the pathway. 3) Determine how changes to a kinetochore affect its ability to catalyse the generation of the MCC. 4) Determine how a defined change in the number of molecules of specific regulators alters the dynamics and strength of the SAC, and in consequence their effect on genomic stability. Together, these studies will be used to inform and discriminate between models of mitotic control to determine how the SAC combines the properties of potency and responsiveness.

Amount: £2,249,139
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

In silico functional assessment of pleiotropic cancer risk loci 31 May 2018

Genome-wide association studies (GWAS) have identified greater than 450 common low-penetrance susceptibility single nucleotide polymorphisms (SNPs) for various cancers. Approximately one third of these SNPs map to genomic regions harbouring multiple cancer-SNP associations. This project aims to investigate the properties of "pleiotropic" cancer risk SNPs and derive insights into their effect on tumour development. We will initially extract all reported cancer risk-SNP associations with P -8 and use linkage disequilibrium metrics between risk SNPs at nearby genomic locations (e.g. within 1Mb) to determine if they represent distinct or shared association signals. Where available we will make use of tumour and normal tissue mutation, epigenomic, Hi-C and expression data to determine the likely molecular mechanism underlying cancer risk associations, for example regulating target gene expression. Combining all these analyses we aim to classify regions with multiple cancer associations as those exhibiting a) genuine pleiotropy, where the same association signal is shared by multiple cancer types; b) shared molecular mechanism but distinct disease-specific signals, suggestive of tissue-specific regulation; c) shared location by chance, where both disease-association signal and molecular mechanism appear distinct.

Amount: £0
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Elucidating allosteric processes in immunoglobulin E 31 May 2018

Immunoglobulin E (IgE) is thought to be the first line of defence against parasitic pathogens, mediating immune reactions by binding to either of its two receptors, either the high-affinity FcepsilonRI receptor or the low-affinity CD23 receptors. While the IgE molecule was previously thought to exist in a primarily acutely bent conformation in solution, Drinkwater et al. (2014) found that IgE was able to exist in a fully extended conformation while Davies et al (2017) showed that omalizumab (XolairTM by Novartis) trapped IgE in a partially bent state to block its action on its FcepsilonRI receptors. The McDonnell Laboratory has derived a series of anti-IgE antibody Fab fragments, selected for their ability to affect IgE’s overall structure and dynamics and consequently to allosterically affect the binding to IgE’s receptors. In this proposed study, we will investigate how observed ligand-mediated changes in conformational dynamics manifest themselves as entropically-driven allosteric modulation. As a complement to NMR studies of ligand-mediated changes in protein dynamics, currently ongoing in the McDonnell Laboratory, direct measurements of the thermodynamic parameters of ligand binding will be performed using isothermal titration calorimetry.

Amount: £0
Funder: The Wellcome Trust
Recipient: King's College London

Cellular and molecular regulation of early brain development 16 Jun 2018

Brain-waves is an enrichment project-based targeting children and adult audiences at the Sidmouth Science Festival (https://www.sidmouthsciencefestival.org). It is also a pilot for a new kind of laboratory retreat, where the entire team is engaged in the devising and delivery of an engagement project. We will engage experienced communicators and advisers as part of the development. The project will deliver a professional and highly interactive public event in three parts: a beach-based exploration of brain function and development for primary school classes, an adult pint of science style evening science conversation and a longer-term engagement with local schools through a legacy of project work and materials. The Clarke research team will have developed a new understanding of the science research in which they are engaged and have experienced reconfigured roles within the group. Younger lab members will feel empowered and the enrichment benefit of the exercise will extend into their ongoing research. We will have boosted confidence and developed definable transferrable skills. Finally, we will have developed a model for an "engagement retreat" that capitalises on the strong UK network of local science festivals. Our approach will contribute and capitalise on a burgeoning national conversation on science that exists within the patchwork of local events that gives valuable space to different viewpoints and exchanges. https://www.britishscienceassociation.org/uk-science-festivals-network https://www.big.uk.com/festivals/

Amount: £8,900
Funder: The Wellcome Trust
Recipient: King's College London

Predicting disease progression in cognitive impairment using a brain ageing biomarker 06 Sep 2018

Earlier detection of the neurodegeneration that precedes dementia is needed if we are to address the rising burden that dementia places on our ageing global population. While cognitive impairment is an important risk factor, alone it is insufficient to identify who will experience pathological deterioration and subsequent dementia. Here, I aim to harness the power of neuroimaging as an objective and sensitive index of brain structure, using an ‘ageing biomarker’ framework to measure so-called ‘brain-age’ in people with mild cognitive impairment (MCI) or subjective cognitive impairment (SCI). This project aims to 1) validate the utility of brain-age for predicting future health outcomes in people with MCI or SCI, and then 2) implement a software pipeline to convey these individualised predictions directly to clinical settings. I will meet these goals by taking advantage of the large existing MRI database of memory clinic patients and linked electronic health records available at King’s. Collaborations with memory services across King’s Health Partners NHS Trusts will enable trial clinical deployment of my software pipeline. Using brain-age in combination with clinical expertise in memory services will enable optimal and cost-effective allocation of resources, moving towards the application of precision medicine to detect dementia risk earlier.

Amount: £83,104
Funder: The Wellcome Trust
Recipient: King's College London

The development of insulin resistance and anabolic resistance during muscle disuse: what is the role of fuel integration? 08 Nov 2017

Skeletal muscle atrophy, which occurs during short-term disuse, is thought to be due to the development of anabolic resistance of protein metabolism and insulin resistance of glucose metabolism, although their cause is currently unknown. The primary research aim of this fellowship is to establish the role of muscle fuel availability and integration in disuse-induced insulin and anabolic resistance. In collaboration with the Medical School, I will perform two randomized, placebo-controlled studies in which young, healthy participants undergo 2 days of forearm immobilisation with placebo, Acipimox (to decrease plasma lipid availability), Formoterol (to stimulate glycolytic flux), or dietary branched-chain amino acid (BCAA) manipulation, to alter substrate availability. I will combine the arteriovenous-venous forearm balance technique, that I have recently established in Exeter, with stable isotope amino acid infusion and repeated forearm muscle biopsies to quantify muscle glucose, fatty acid, and BCAA balance, oxidation, and intermediary metabolism (including muscle protein synthesis), both fasted and during a hyperinsulinaemic-euglycaemic-hyperaminoacidaemic clamp. Two periods of research at the University of Texas Medical Branch will enable me to develop skills in mass spectrometry tracer analyses and develop a network of collaborators in the USA, both crucial for my future career investigating disuse-induced muscle atrophy.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Exeter

Genes to networks - insights into dynamic brain pathology from genetic epilepsies 08 Nov 2017

Genetic mutations cause the majority of severe childhood epilepsies. Many 'epilepsy-genes' play a direct role in synaptic transmission, such as SCN1A (coding for voltage-gated sodium channels) and GRIN2A (coding for NMDA-receptor subunits). Some mutations also induce seizures in zebrafish larvae, a novel vertebral model of genetic epilepsies. Furthermore, long-term functional neuronal recordings of large neuronal networks using light sheet microscopy are now possible in these larvae, allowing unique insights into the pathophysiological of the epileptic brain. My proposal will utilise computational network modelling to identify mechanisms leading from synaptic dysfunction to whole-brain epileptic dynamics. I will (1) analyse patients' EEG recordings and light-sheet imaging in zebrafish with corresponding genetic mutations to evaluate whether there are shared abnormal network dynamics, (2) use Bayesian inversion of generative neuronal models to understand how microcircuit dysfunction leads to these abnormal dynamics, and (3) test the predictive validity of the generative models against empirical measurements of anti-epileptic drug effects. This work will provide insights into multi-scale mechanisms underlying devastating childhood epilepsies. The computational analyses will provide novel strategies to translate observations between animal models and patients, and thus in the future will increase the potential of these models to help the development of novel therapies.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: King's College London

Deciphering mechanisms of altered neurodevelopment in BAF complex intellectual disability disorders 06 Dec 2017

Intellectual developmental disorder (IDD) is a common yet poorly understood condition. Recent advances in genomic diagnostic technologies have revealed that disruption of genes involved in transcriptional regulation is a leading cause of IDD. Genes encoding the chromatin remodelling BAF swi/snf complex are among the most commonly mutated. Filling the knowledge gap between mutation and disease will contribute to improved patient care and to our overall understanding of human brain development. To that end, I will bridge the clinical and neurodevelopmental biology fields using patient-phenotype informed cellular models to investigate the molecular underpinnings of disease. I will perform deep-phenotyping of a cohort of patients with BAF-complex mutations, and correlate clinical and psychometric features with gene expression and epigenetic signatures in primary tissues. Alongside this clinical study, I will investigate the specific role of ARID1A, an essential BAF complex subunit, in neurodevelopment. Those investigations, performed in induced pluripotent stem cell (iPSC) models of human neurodevelopment, will inform subsequent studies in iPSCs generated from patients. Detailed understanding of clinical outcomes will improve patient management, and integrating the cellular and molecular defects in in vitro models with clinical and molecular phenotypes in patients will help establish predictive preclinical models for translational research.

Amount: £486,911
Funder: The Wellcome Trust
Recipient: King's College London

Neurobiological mechanisms of emotional relief in adolescents with a history of sexual abuse 06 Dec 2017

Adolescents who experienced childhood sexual abuse (CSA) engage in non-suicidal self-injury (NSSI) more frequently than peers exposed to other forms of abuse or no abuse. NSSI serves an important function of relief from acute negative affect. Despite providing temporary relief from distress, NSSI is also linked to higher rates of suicide and hospitalisations and the effectiveness of current clinical interventions is limited. This may be attributed to a lack of understanding the neurobiological and behavioural mechanisms that underlie NSSI as a relief function in particular in youth who experienced CSA. To address this gap, the study aims (1) to model brain activity during distress and emotional relief (i.e., NSSI) in adolescents with and without a history of CSA using functional magnetic resonance imaging and (2) to examine if adolescents with CSA select actions to 'escape' an aversive context more quickly and often compared to non-abused peers. The ultimate goal of this translational research is to understand the neurobiological and behavioural mechanisms that confer vulnerability to NSSI following CSA (Stage 1) in order to develop effective intervention and prevention strategies to keep vulnerable teenagers safe (Stage 2) . Keywords: sexual abuse, non-suicidal self-harm, relief, functional magnetic resonance imaging, translational research

Amount: £230,048
Funder: The Wellcome Trust
Recipient: University of Exeter

Replication through structure-prone DNA – mechanism and impact on genome stability 21 Feb 2018

This proposal is aimed at understanding how repetitive and structure-prone sequences are replicated accurately. Repetitive DNA comprises over half of the human genome. Repeat instability due to unusual DNA secondary structures causes many neurodegenerative diseases and is a diagnostic and prognostic cancer marker. While genetic studies revealed that repeats impair DNA replication and that replication can induce repeat instability, mechanistic insight is lacking. It is therefore crucial to understand how repeats are accurately replicated in normal tissues and how they become unstable in disease. First, I will determine the nature of replication-dependent DNA structures. Building on my recent advances in sequence-specific in vitro replication, I will delineate the effects of DNA secondary structures on replication dynamics, including DNA unwinding, DNA synthesis, Okazaki fragment maturation and replisome stability. Finally, I will discover factors that enable faithful replication of structure-prone DNA using a combination of biochemistry, candidate genetics and proteomics. As a long-term goal, I aim to elucidate the interplay between replication and repair pathways, such as mismatch repair. Altogether, these aims will define the relationship between DNA sequence, structure and replication and may lead to identification of novel factors that modulate the formation and resolution of toxic DNA structures.

Amount: £1,283,217
Funder: The Wellcome Trust
Recipient: Institute of Cancer Research

Thick filament-based mechanisms for the dynamic regulation of contraction and relaxation in the heart 21 Feb 2018

Recently it has become clear that, whilst the canonical calcium/thin filament-based pathway provides a start signal for contraction in skeletal muscle, its strength and speed are largely controlled by structural changes in the myosin-containing thick filaments. I now propose to test the hypothesis that thick filament regulation plays a similar key role in the dynamic control of contractility in heart muscle, by adapting and extending the methods I successfully applied to study thick filament-based regulation in skeletal muscle. I will use a fluorescence-based approach to characterise the structural dynamics of thin and thick filaments during activation and relaxation of isolated cardiac trabeculae and cardiac myofibrils. I will investigate the role of thick filament regulation and mechanical stress in determining the physiological rate of force generation and of relaxation in the heart, and how these rates are modulated in response to its functional requirements, including the stronger contraction observed after increased venous filling (the Frank-Starling law of the heart). The results of these studies are likely to lead to a new paradigm for the physiological control of contractility in the heart that will underpin future studies of the changes in that control in heart disease and potential therapeutic corrections.

Amount: £891,301
Funder: The Wellcome Trust
Recipient: King's College London

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £58,344
Funder: The Wellcome Trust
Recipient: University of Exeter