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Recipients:
University College London

Results

Appraisal of LRG1 antibody internalisation and as a dual acting antibody-drug conjugate 30 Sep 2018

Abnormal blood vessel formation contributes to diseases such as cancer, and is the result of inappropriate angiogenic signalling. In recent years, it has been shown that in the presence of the transforming growth factor beta1 (TGFbeta1), leucine-rich alpha-2-glycoprotein 1 (LRG1) promotes the formation of new blood vessels, via a process known as angiogenesis. Blocking the activity of LRG1 by using an antibody against it leads to reduced blood vessel growth, and thus, could be exploited to inhibit cancer growth. We aim to combine the blood vessel normalisation achieved by LRG1 blockade with affecting cancer cell deterioration. To do this, we aim to modify the LRG1 antibody vehicle, using state-of-the-art biotechnology, with a suitable fluorophore to evaluate internalisation into a cancer cell (i.e. its ability to deliver cargo), followed by decoration with a suitable toxic drug to evaluate efficiency in cells.

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

Myofibroblast metabolism in tissue repair and fibrosis 31 May 2018

The overall goal of this project is to investigate whether biochemical switching and metabolic reprogramming has a role in the development of myofibroblasts and subsequent scar formation in fibrosis. Therefore my hypothesis is that in scleroderma, fibroblasts reprogram their metabolism to accommodate the enhance demand of energy required to differentiate and produce more scar tissue (ECM). And that altered energy metabolism due to dysregulated signalling networks closely linking metabolism with fibroblast differentiation are critical to the establishment of myofibroblasts and contributes to the development of inflammatory-driven scar formation and tissue fibrosis. I wish to build upon the preliminary studies and determine how energy metabolism influences the behaviour of myofibroblasts in fibrosis and ask if the pathological aspects of cell behaviour be attenuate with specific inhibitors. The three specific aims of my vacation scholarship are to examine: 1. Mitochondrial morphology and mitophagy in cultured control and fibrotic fibroblasts and assess any changes in fission and fusion using mito-tracker dyes. 2. Glycolysis and Mitochondrial Respiration in cultured control and fibrotic fibroblasts using the Seahorse metabolic flux analyser. 3. The impact inhibitors and activators of key profibrotic pathways on glycolysis and mitochondrial respiration in cultures of control and fibrotic fibroblasts.

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

Effects of Rab3a-Interacting Molecule 1a (RIM1a), linked to the enhancement of cognitive function, on presynaptic function and plasticity: a direct link from genes to cognition? 30 Sep 2018

Neurons communicate with each other via specialised junctions called synapses. The brain contains trillions of synapses where information is transferred and processed, which shapes neuronal network and brain function. Synaptic terminals contain small vesicles filled with neurotransmitters. When a nerve impulse invades the synaptic terminal, it triggers fusion of synaptic vesicles with the plasma membrane and release of transmitter molecules. Neurotransmitters quickly diffuse towards the target neuron, where they bind to specific receptors and evoke further electrical or chemical signalling. Very often mutations in proteins that regulate synaptic vesicle fusion lead to neurological disorders and cognitive impairment. RIM1alpha is one of the key proteins that regulate synaptic release of neurotransmitters by bringing together the key components of release machinery. Recently, a novel mutation in RIM1alpha was discovered that enhances cognitive function in humans. This "experiment of nature" represents a unique model to test how alterations in synaptic function shape high-level brain activity and cognition. In this project we aim to understand the effects of this RIM1alpha mutation in mouse neuronal model on synaptic transmission and use-dependent synaptic plasticity. We anticipate that our results will provide novel unparalleled insights into the cellular mechanisms that underlie cognitive processing in the brain.

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

Exploring the role of Genome Architecture in Neuronal Development using an in vitro model system 31 May 2018

The research aim is to explore the role of genome organisation and three-dimensional configuration in regulating transcriptional responses during neuronal differentiation. To do so, expression of co-regulated candidate genes during differentiation from neuronal progenitor cells (NPCs) to post-mitotic neurons (PMNs) will be identified with qRT-PCR. NPCs will be dissected from E12.5 mouse cortices and cultured in basic Fibroblast Growth Factor (bGFG). Differentiation into PMNs will be induced by adding neurotrophin-3 (NT-3). The nuclear localisation of pairs of co-regulated genes will be detected using double fluorescence in situ hybridisation (D-FISH), assessing whether these genes relocate to transcriptionally active regions, like transcription factories, or transcriptionally repressive regions, like the nuclear periphery. Results will also compare transcriptional changes in neuronal differentiation with nuclear re-organisation patterns in the expression of activity-regulated genes (ARGs), like c-Fos and Gadd45b. This will allow the identification of genome architecture changes specific to cortical development. Possible gene co-localisation, genomic-wide contacts and loci interactions will be studied with 4C technology, which combines chromosome conformation capture (3C) methodology with high-throughput sequencing.

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

Synaptic Neurology 17 Jul 2018

The overarching theme is to understand how the properties of defined classes of neurons underpin circuit computations and pathological activity patterns in the brain. We will investigate the potential role of NMDA receptor-mediated dendritic supralinearity in parvalbumin-positive interneurons, and how this may help to stabilize neuronal assemblies. We will apply closed-loop optogenetic drive to manipulate gamma oscillations in the visual cortex, and ask whether this can bias perception. Chloride shifts and depolarization block of interneurons have been proposed to underlie seizure perpetuation. We will investigate their roles using closed loop optogenetics, KCC2 overexpression, single unit recordings, and simultaneous imaging of extracellular GABA and glutamate, in awake head-fixed animals. Finally, we will investigate the role of neurogliaform cells, a relatively poorly understood neuronal subtype, in seizures, using Ndnf-Cre mice to target them.

Amount: £1,600,865
Funder: The Wellcome Trust
Recipient: University College London

Wellcome Centre for Human Neuroimaging 10 Jul 2018

The Research Enrichment fund will enable us to embed public engagement (PE) into our Wellcome Centre research process. If funded, we will have achieved the following at the end of the proposed Research Enrichment programme: (1) Established a cultural change within our Centre where PE is integrated into all of our research programmes, with more researchers doing PE than not. (2) Provided a comprehensive tiered training program, that produces world-leading researchers with the skills and experience to readily engage with wider communities. (3) Delivered at least 8 PE team-led activities per year targeted towards empowering five typically under-represented community groups in neuroscience who will contribute to and influence our science: Patients with neurological and psychiatric disorders, Disadvantaged students, Ethnic minorities, Artistic communities and Women in Science, Technology, Engineering and Maths (STEM)). (4) Built sustainable partnerships with UK charities and organisations who lead in PE, such as the Stroke Association and Science Museum, expanding our reach into these substantial networks. (5) Planned a comprehensive PE programme in line with our PE strategy to continue to enrich and develop our engagement programmes in perpetuity. (6) Evaluated the impact of the cultural change, to ensure that the aims of our PE strategy are achieved within our overall vision. (7) Developed and shared our model for integrating PE into the research process at conferences and with other Wellcome Centres across the UK.

Amount: £266,960
Funder: The Wellcome Trust
Recipient: University College London

Lancet Countdown: Tracking Progress on Health and Climate Change 30 Sep 2018

Please see the Executive Summary of the attached document for a summary of the proposal.

Amount: £5,528,492
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

Using modern causal inference methods and general population data to investigate the role of inflammation in the aetiology of eating disorders 08 Nov 2017

Eating disorders are severe psychiatric conditions with typical onset in adolescence and a complex aetiology. Epidemiological studies have shown that inflammation is potentially implicated in the aetiology of several psychiatric conditions. However, although the hypothesis is plausible, robust epidemiological evidence that inflammation is involved in the pathogenesis of eating disorders is largely missing. In this fellowship I will address this knowledge gap and test my hypothesis that inflammation – quantified in terms of exposure to infection, elevated markers of inflammation, and autoimmunity – constitutes an important risk factor in the pathogenesis of eating disorders via four complementary objectives; I will test whether: Prenatal and childhood infections are associated with onset of EDs; Serum markers of inflammation in childhood are associated with ED behaviours in adolescence; The association between inflammation and EDs is likely to be causal using Mendelian randomisation; Genetic risk for autoimmunity is associated with EDs. These studies will integrate the use of biological measurements and large general population samples with novel causal inference approaches for observational epidemiology. Understanding whether inflammation is causally relevant to the aetiology of eating disorders will advance our knowledge of these conditions, and may provide opportunities for new therapeutic and preventative interventions.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

Harnessing pre-clinical lung cancer patient models for precision immuno-oncology 08 Nov 2017

Only 16% of non-small cell lung cancer (NSCLC) patients survive for 5 years. Improvement in survival has been slow as the histological and genomic features of the disease are heterogeneous. Tumour heterogeneity poses a challenge for therapy development and suggests the importance of a personalised medicine approach. One approach is to expand the subset of tumour-infiltrating lymphocytes (TILs) that target neoantigens generated by tumour mutations; however, the lack of model systems that recapitulate the complexity of human disease is a significant barrier to research in this area. Patient-derived xenografts (PDXs) have considerable advantages over murine cancer models and cell lines so I will generate PDX models from patients enrolled in the TRACERx clinical study, which aims to delineate the evolutionary trajectories of NSCLC through multi-region genetic analyses of primary, recurrence and metastatic tumours. My first goal is to establish the extent to which PDX tumours represent patient intratumour heterogeneity using the extensive TRACERx dataset. I will further use these models - along with patient-matched TILs - in in vitro and in vivo assays to investigate the key determinants of the ability of TILs to destroy cancer cells and to investigate the effect of dual checkpoint inhibitor and TIL therapy.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

The Role Of Small-molecule Dietary And Non-dietary Antioxidants In Predicting And Preventing Respiratory Disease 08 Nov 2017

Respiratory diseases caused by smoking and pollution are increasing in prevalence across all continents. At present, there are no simple blood tests for predicting those at highest risk and few molecular targets for primary prevention. This work programme will use pre-collected data to answer the following: do antioxidant molecules found in blood (bilirubin, uric acid, alpha-tocopherol, ascorbic acid and beta-carotene) have any role in the prevention or prediction of respiratory disease? Firstly, I will use conventional risk factors and incident cases of lung cancer recorded for UK Biobank participants to build a risk prediction model. I will then add various combinations of baseline measures of bilirubin, uric acid, their associated genotypes, and respiratory function. The added value of these variables will be assessed using reclassification measures and net benefit analysis. Secondly, I will develop an economic model using UK Biobank and other data sources to evaluate the cost-effectiveness of the risk model combined with different screening strategies (e.g. chest scans). Finally, I will use the new genotype data for the 500,000 participants of UK Biobank to perform a series of instrumental variable analyses (Mendelian randomization) and examine causal relationships between lifelong variation in small-molecule antioxidant exposure and adult respiratory function.

Amount: £284,626
Funder: The Wellcome Trust
Recipient: University College London

Enhancing emotion-regulation in adolescence: A developmental window of opportunity 08 Nov 2017

Adolescence is an emotionally challenging developmental stage. Adolescents frequently experience negative affect and rapid fluctuations in affective states. Difficulty in regulating these emotions is associated with a range of psychopathology. Successful emotion-regulation relies on executive control, the ability to attend and respond to goal-relevant information, while inhibiting responses to distractors. Executive control and its neural substrates in the frontoparietal network develop rapidly during adolescence. Adolescence then may constitute a period of developmental sensitivity to improve emotion-regulation by training executive control over emotional information. Combining population-based experience sampling (Study A), longitudinal functional and structural neuroimaging (Study B) and training studies (Studies C & D), this project will investigate: the association between executive control over emotional information and affective experience in daily life and how it develops across the lifespan (Study A); the biopsychosocial predictors of variation in adolescent emotion-regulation (Study B); adolescence as a sensitive period for training emotion-regulation; and whether training emotion-regulation has preventative potential in adolescents at-risk for depression. The studies will integrate information across behavioural and neural levels of explanation to advance a fuller understanding of adolescence as a potential sensitive period for emotion-regulation and how this developmental sensitivity can be harnessed to improve emotion-regulation through executive control training.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

Computer-based analysis of early fibrosing lung disease 06 Dec 2017

Fibrosing lung disease (FLD) is an idiopathic condition, affecting older patients (median age=65 years) and smokers, accounting for 0.9% of all UK deaths in 2012. Unfortunately, despite newly available treatment options, FLD is typically diagnosed at an advanced stage with patients already markedly functionally impaired. Patient decline is often rapid. A constraint with diagnosing disease at an early stage is that subtle minor CT abnormalities that may evolve into rapidly progressive disease, are hard to identify and yet to be characterised visually. Large population studies may identify those subtle CT features portending progressive disease. Such large-scale analysis of CT imaging would be best suited to advanced computer analytic tools. We therefore aim to develop sophisticated computer tools to evaluate CTs in 20,000 heavy-smoker patients undergoing repeated chest imaging, as part of a lung cancer screening study, to identify early and potentially progressive FLD on CT. GOALS 1.Characterise baseline CT patterns indicative of early FLD and progressive FLD. 2. Predict the trajectory of a patient’s fibrosis progression using computer quantitation of change in an individuals CT features. 3. Generate population-wide quantitative CT metrics (age, gender and race specific) as a reference range applicable to other worldwide lung cancer screening studies.

Amount: £1,034,494
Funder: The Wellcome Trust
Recipient: University College London

Skeletal muscle channelopathies: severe infantile phenotypes and sudden infant death syndrome 06 Dec 2017

Skeletal muscle channelopathies are mainly autosomal dominant disorders that typically cause muscle symptoms of myotonia, periodic paralysis or progressive myopathy. Until now the muscle channelopathy phenotypes described are disabling but not fatal. Pilot data implicates ion channel dysfunction in severe infantile phenotypes with respiratory compromise and some cases of sudden infant death syndrome (SIDS). Aims: Investigate ion channel genetic architecture in new cohorts of infants with life-threatening apnoeas and 300 SIDS cases. Determine if age related differences in ion channel expression and muscle fibre type contribute to disease severity. Build a national SIDS registry with experts and charities to enhance clinical correlation and interpretation of genetic/ in vitro findings. Methods: Whole exome, NGS sequencing and MLPA. Immunohistochemistry, western blotting and RNA analysis of control respiratory, skeletal and cardiac muscle at 0 to 24 months. Questionnaire covering pregnancy and post-natal period for affected patients. Web-based database collecting detailed clinical and genetic data of SIDS, tissue samples collected in biobank. Opportunities: proposes a totally novel mechanism of pathogenesis in SIDS. Inform understanding of normal developmental changes of skeletal and cardiac muscles. A national SIDS registry and biobank will be an invaluable research resource. Key words: ion channelopathies, respiratory, sudden infant death

Amount: £283,711
Funder: The Wellcome Trust
Recipient: University College London

Pre-configured and learned properties of hippocampal circuits 10 Apr 2018

Despite recent advances in systems and computational neuroscience, very little is known about how the brain’s functional complexity arises during ontogenesis and which developmental mechanisms determine the emergence of complex behaviour. The proposed research aims to bridge this gap between developmental neurobiology and systems neuroscience by defining the relative roles of early embryonic events and post-natal learning in the development of spatial and non-spatial coding in the hippocampal formation. Our key goals are to: 1) establish whether the functional diversity in hippocampal place cells is defined by early embryonic divergence; 2) test whether ‘non-place’ coding in the hippocampus is intrinsic to the network (as place coding appears to be), or whether it requires late post-natal learning; 3) discover the relative contributions of experience-dependent and independent processes in creating the specific neural architecture (‘continuous attractor') underlying codes for direction and distance. We will deliver these goals using chronic in vivo recording of neural activity (high density electrophysiology and calcium imaging) in developing animals coupled with neuronal birth tagging, behavioural testing and functional inactivation of crucial targets, to discover which self-organised embryonic events and instructive signals are necessary to organise hippocampal circuits.

Amount: £1,097,310
Funder: The Wellcome Trust
Recipient: University College London

Exploring glial roles in sculpting brain development 21 Feb 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: £1,198,593
Funder: The Wellcome Trust
Recipient: University College London

Using social networks to understand and intervene on HIV epidemic spread 21 Feb 2018

Young people in sub-Saharan Africa are central to ending the HIV epidemic. However, uptake of proven protective interventions is low and evidence on who does/does not engage is limited. Theory predicts that behaviours and intervention uptake cluster within social networks. Interventions in other settings have successfully leveraged social ties to improve intervention impact. I aim to: (1) use novel methods to identify how social networks pattern risk for HIV acquisition; and (2) test the feasibility of using such knowledge to improve intervention uptake. I will undertake this work at the Africa Health Research Institute in rural KwaZulu-Natal, South Africa. Following qualitative interviews with young people exploring their social networks and social norms, we will then quantitatively follow 600 15-24 year-olds, together with their close friends and family, for three years. Using these longitudinal data, we will statistically model how social contacts influence behaviour and HSV/HIV acquisition. We will then quantitatively and qualitatively evaluate the feasibility of using network-selected peer-educators to promote uptake of HIV self-tests and subsequent treatment. We will compare how influential peer-educators differ from randomly selected ones in terms of willingness to be involved, training dynamics and health impact.

Amount: £1,244,577
Funder: The Wellcome Trust
Recipient: University College London

Open Access Award 2017/18 30 Sep 2018

Not available

Amount: £524,262
Funder: The Wellcome Trust
Recipient: University College London

Impact of missense mutations in recessive Mendelian disease: insight from ciliopathies 10 Apr 2018

Background: Over 1,800 autosomal recessive (AR) Mendelian-disease genes have been identified. Missense mutations account for 59% of protein coding region mutations, yet their precise functional effects remain largely uncharacterized. Two important questions in human genetics aim to explain interindividual variation in phenotypic severity and assign pathogenic mechanisms to different disease phenotypes (including independent phenotypes within the same syndrome). For AR disorders, it is thought that many missense mutations cause protein instability. For these hypomorphic mutations, disease phenotypes are defined according to quantitative genetic threshold effects within a protein interaction network. Project: We will focus on a subset of AR ciliopathies which are strongly enriched for missense mutations, where complete gene knockout is thought to be lethal (see Rationale-below). We will use gene-editing and quantitative protein-protein interaction analyses to systematically compare the phenotypic effects of frameshift (likely knockout/null) and missense mutations. We will test our hypothesis that these missense mutations disrupt only a subset of gene functions/protein interactions, using phenomics algorithms we have developed and unbiased phenotyping in cell lines and mouse models, allowing us to assign pathogenic mechanisms to disease phenotypes. In future, this approach could be extended to the estimated 10-20% of > 3,000 Mendelian-disorders enriched for missense mutations.

Amount: £1,706,863
Funder: The Wellcome Trust
Recipient: University College London