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Results

Strategic Partnership Project pilot 12 Oct 2012

Funding under Sport England's National Programme - Market Development funding programme for a Mixed project titled 'Strategic Partnership Project pilot'. This project lists its main activity as Sports Development. This funding has contributed towards a Multi Facility - Canoeing (Pontoons/Moorings),Cycling (Mountain Bike track),Public Rights of Way (Cycleway),Public Rights of Way (Footpath (Local))

Amount: £1,700,000
Funder: Sport England
Recipient: National Trust
Region: North East
District: Northumberland

Fell Foot Improvement and Development Project 25 Jul 2016

Funding under Sport England's Improvement Fund funding programme for a Capital project titled 'Fell Foot Improvement and Development Project'. This project lists its main activity as Multi Sports.

Amount: £500,000
Funder: Sport England
Recipient: National Trust
Region: North East
District: Northumberland

National Cycle Trails Programme 14 Sep 2015

Funding under Sport England's National Programme - Market Development funding programme for a Revenue project titled 'National Cycle Trails Programme'. This project lists its main activity as Cycling.

Amount: £2,000,000
Funder: Sport England
Recipient: National Trust
Region: North East
District: Northumberland

Bounts Pilot 03 Dec 2015

Funding under Sport England's National Programme - Market Development funding programme for a Revenue project titled 'Bounts Pilot'. This project lists its main activity as Multi Sports.

Amount: £28,361
Funder: Sport England
Recipient: National Trust
Region: South West
District: Wiltshire

Fell Foot Flood Repairs 03 Oct 2017

Funding under Sport England's Emergency Flood Relief funding programme for a Capital project titled 'Fell Foot Flood Repairs'. This project lists its main activity as Athletics. This funding has contributed towards a Flood Relief - Flood Relief (Repair/Defence)

Amount: £1,800
Funder: Sport England
Recipient: National Trust
Region: North East
District: Northumberland

Quantifying the development of neural progenitor polarisation 27 Apr 2017

Apicobasal polarity plays a fundamental role in the defining functional features of neural progenitors during the early stages of embryonic development. The apical pole in neural progenitors is specialized for multiple rounds of progenitor divisions, resulting in brain growth, where as the basal pole forms the environment where neuronal differentiation will occur. However, it is not well understood how the apicobasal polarity of neural progenitors is established. During the project, we will test a hypothesis which suggests that apicobasal polarity is progressively generated and can be monitored by quantifying a Cdh2 protein gradient along the apicobasal axis in neural progenitors. A key goal will be to determine the distribution of the Cdh2 protein over time during neural progenitor polarization. To do this we will make three-dimensional time-lapse movies of developing neural primordium in zebrafish embryos that express a transgene Cdh2-GFP. The transgene containing GFP will make it possible to visualize the distribution of the Cdh2-protein during progenitor polarization. Quantification will be done using FIJI image analysis software.

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

Can factors secreted by MUC1-ST educated monocytes influence breast cancer stem cell growth? 27 Apr 2017

Aberrant glycosylation of glycoproteins expressed by cancers can lead to tumour:immune cell interactions that are cancer specific. One such interaction is the binding of a tumour-associated glycoform of the mucin, MUC1-ST, to the sialic binding lectin, Siglec-9, expressed by monocytes and macrophages. The engagement of Siglec-9 by MUC1-ST, leads to the secretion of factors by monocytes associated with tumour-progression. Interestingly, one such factor that has been identified is growth hormone and the growth hormone receptor has been found to be associated with normal mammary stem cells. To investigate if growth hormone or other factors secreted by MUC1-ST educated monocytes can influence breast cancer stem cells we will examine the extent to which breast cancer cells lines show cancer stem cell properties by: 1. Determining the expression of the breast stem cell markers (CD44 and CD24) using flow cytometry, in the presence or absence of media from MUC1-ST educated monocytes. 2. Looking at mammosphere growth in the same medium, where we will also take into account the production of GH by blocking the GHR using specific blocking antibodies.

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

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

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

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

‘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

Mechanotransduction in the intestinal epithelium - a role for RhoA in mediating innate immune system - microbiome interactions 30 Sep 2018

To have a ‘gut feeling’ is more than an idiom, as the intestine not only digests food and excretes waste, but helps the micro-organisms in our gut interact with the white immune cells in our blood. I will study how these three units interact in real life by creating a replica ‘intestinal immune-system in a dish’, which consists of 3D mini-guts called organoids (1) that I will inject with disease-associated microbiome strains (2) and surround with innate immune lymphoid cells (3), which protect us from infection and help keep the intestinal epithelium healthy. I am interested in improving the culture conditions necessary for the maintenance of this system, using novel hydrogels and bioengineering techniques to make it as similar to the human body as possible. I will then use this model to study why the composition of the microbiome has such a dramatic impact on human health and well-being. More specifically, I will use it to understand how environmental and genetic causes act together to cause inflammatory bowel disease, creating a platform to look for new drug targets for the treatment of this severe and incurable disease.

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

The role of miR142 in mucosal immunity 30 Sep 2018

ICF extension - The role of miR142 in mucosal immunity

Amount: £255,699
Funder: The Wellcome Trust
Recipient: King's College London

Characterizing Mesp1-Eomes interaction in cardiac progenitor cells 31 May 2018

The embryonic bHLH transcription factor, Mesp1, is a master regulator of cardiac progenitor cell (CPC) fate. Upregulation of Mesp1 in mouse embryonic stem cells induces cardiac cell fates. However, depending on the conditions, Mesp1 can also induce hematopoietic or skeletal muscle fates. Many bHLH factors, including Mesp1, require dimerization partners for their activity. However, few Mesp1 interacting partners have been identified, and whether such factors control Mesp1’s ability to regulate cardiac versus other fates has not been investigated. Further characterisation is required to understand how CPCs form and improve methods of generating cardiac cells for regenerative medicine applications. This proposal aims to confirm preliminary data that suggest Mesp1 and Eomes physically interact during CPC formation.

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