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Recipients:
University College London
University of Cambridge
Currency:
GBP
Award Year:
2017

Results

Dynamical modelling of somatic genomes 28 Nov 2017

Cancers are complex and chaotic systems. It is becoming apparent that no two cells in a cancer are genetically identical or follow the same evolutionary trajectory. Chromosomal instability (CIN) is one way that cells generate this complexity and is a hallmark of all cancer and ageing. In cancer, it increases the level of variation available to cells and gives rise to intra-tumour genetic hetereogeneity, which makes the disease more agressive, drug tolerant, and harder to treat. We are still far from a complete understanding of how cells undergoing CIN evolve over time, in particular, we do not know how populations of cancer cells evolve and how selection acts to change these properties. Understanding this normal evolutionary behaviour will be key to separating the functional and non-functional aspects of intra-tumour heterogeneity. We will tackle this problem by understanding cancer as an emergent complex system, and use simple dynamic stochastic models to capture the essential biological features of the processes underlying CIN, including chromosome gain and loss, structural change, and genome doubling. We will use the vast amount of NGS data already available to fit these models using Bayesian inference and infer the evolutionary aspects of CIN in healthy and cancerous tissues.

Amount: £1,273,968
Funder: The Wellcome Trust
Recipient: University College London

Molecular mechanisms of alternative splicing regulation 28 Nov 2017

Alternative pre-mRNA splicing (AS) is a widespread regulatory mechanism enabling individual genes to generate multiple protein isoforms. We have investigated the mechanisms controlling AS events that are regulated during the transition of smooth muscle cells (SMCs) between contractile and proliferative phenotypes. We have shown how the widely-expressed RNA binding proteins (RBPs) PTBP1 and MBNL1 regulate SMC splicing events. Recently, we identified RBPMS as a potential "master" regulator of SMC AS. RBPMS is sufficient to switch AS events to the SMC pattern and its activity is strongly modulated by its own AS and by phosphorylation. Critically, RBPMS is sufficient to switch AS to the SMC pattern in vitro. This offers a unique opportunity to determine the molecular anatomy of regulated splicing complexes. We will carry out detailed mechanistic analyses of RBPMS-regulated splicing using a combination of biochemical, proteomic, single-molecule, and structural approaches including Cryo-EM. We will identify critical regulatory interactions between regulatory RBPs and core splicing factors, and test their importance by genome editing and mRNA-Seq. In a complementary aim, we will investigate how peptide-ligand interactions equip PTBP1 to regulate AS and a range of other post-transcriptional processes, and whether a family of such peptide-mediated interactions extends to related RBPs.

Amount: £1,503,005
Funder: The Wellcome Trust
Recipient: University of Cambridge

Somatic adaptation and sex differences in human endocrine development and disease 28 Nov 2017

Our work focusses on new genetic mechanisms affecting human adrenal and reproductive function. We have recently described a multisystem growth restriction disorder caused by gain-of-function of SAMD9, where somatic adaptation can modify phenotype and mask detection of the genotype. In parallel, we developed a transcriptomic atlas of human adrenal and gonad development, mapping out sex-specific effects of organogenesis. We now plan to develop these insights to address several related fundamental questions: 1) How extensive is SAMD9 variability in endocrine and growth phenotypes and does dynamic somatic adaptation play a wider role in human disease mechanisms; 2) What are the dynamic roles of sex chromosomes and sex hormones in development (focussing on brain, adrenal gland and genital tubercle), and how does genetic variability of the X-chromosome contribute to phenotype in Turner syndrome (45,X); 3) Can we apply these concepts to discover new genetic mechanisms underlying adrenal and reproductive disorders. This work would provide novel disease models and approaches to analysis, could link the dynamics of development and sex-differences to common conditions (e.g. neurodevelopment, stress, early-onset hypertension), and would continue to elucidate the causes of human adrenal and reproductive disorders, with important implications for personalised management and development of new therapies.

Amount: £1,561,134
Funder: The Wellcome Trust
Recipient: University College London

Principles of human development and germ cell program 28 Nov 2017

Specification of human primordial germ cells (hPGCs) occurs around gastrulation, a critical juncture when the specification of the primary somatic lineages also occurs. In combination with human preimplantation embryos, in vitro models and hPGCs from aborted fetuses, our objective is to elucidate the origin and properties of the early human germline. For the mechanism of the hPGC fate, we will use experimental models that simulate early human development. We aim to investigate how cells gain competence for germ cell fate, and then respond to combinatorial effects of the critical transcription factors, which induce hPGC specification. Altogether, this study will reveal the organisation of the very early human embryo, and mechanisms of hPGC and somatic outcomes, which is essential for advances in regenerative medicine. Following hPGC specification, epigenetic resetting of the early human germline leads to extensive erasure of DNA methylation and epimutations in response to the critical regulators of chromatin organisation and nuclear architecture towards the epigenetic ground state. Some conserved resistant loci ('escapees') evade reprogramming. We will explore if some escapees have been exapted to function as regulatory elements. If so, this may have a crucial influence on human development, including brain development and neuronal diseases.

Amount: £2,750,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Metabolic magnetic resonance imaging across the human heart 18 Oct 2017

During my fellowship, I proved the feasibility of measuring cardiac energetics in volunteers and patients using ultra-high field (7T) MRI scanners. The sensitivity and the separation of signals from different metabolites both improved significantly compared to standard research scanners. I recently secured £340k funding to fit a new phosphorus coil on the Oxford 7T scanner, which I am now testing in volunteers. Theory predicts that this coil will have several complementary technical advantages. These will enable mapping of cardiac energy metabolism across the whole heart, with sufficient spatial resolution to distinguish signals from healthy from diseased tissue. It will also enable quantification of cardiac energy metabolism with high precision to study single subjects rather than groups. I request funding to validate these new whole-heart methods, proving their value in three carefully-targeted groups of patients, via an extension of my fellowship. My goals are (A) to study patients in which the metabolic pattern is known by other means; (B) others where the metabolic pattern will reveal previously-inaccessible aspects of disease mechanism; and (C) to prove I can resolve metabolic changes in single patients. Success in each of these studies will give me the pilot data needed for competitive Senior Fellowship applications.

Amount: £584,259
Funder: The Wellcome Trust
Recipient: University of Cambridge

Assessment of placental function in complicated pregnancy using advanced MRI 04 Dec 2017

Placental insufficiency underlies the major obstetric syndromes of fetal growth restriction (FGR) and pre-eclampsia and accounts for one third of stillbirths in high-income countries. There is an unmet clinical need for a method to properly characterise placental perfusion and determine if and when a placenta is likely to fail. The objective of this work is to develop an imaging method to assess placental function in complicated pregnancy. This work will help us to better understand placenta function in FGR. This project will compare placenta properties from appropriately developing and early-onset growth-restricted pregnancies to understand the differences in the appearance of the placenta in FGR. The key goals of this work are to assess a novel Magnetic Resonance (MR) Imaging method to measure fetal and maternal placental perfusion. This technique describes an MR signal that models the blood flow properties as they change between the maternal and fetal sides of the placenta. to link this to relevant clinical information including clinical ultrasound markers and fetal MRI. to use these results to establish a comprehensive imaging project for the placenta by providing an in vivo measurement of placenta function to complement information from ultrasound imaging and ex utero microCT.

Amount: £99,804
Funder: The Wellcome Trust
Recipient: University College London

Virus remodelling of host-cell endomembranes 18 Oct 2017

Enveloped viruses appropriate host-cell membranes to assemble their progeny. Large DNA viruses achieve this by dramatically remodelling the host-cell endomembrane system. I work at the intersection of virology and membrane trafficking, exploiting the intimate connection between viruses and their host cells to gain insights into both virus biology and the dynamic regulation of cellular membranes. I will combine biophysics, biochemistry and cell-based infection assays to investigate the conserved mechanisms by which human herpesviruses change the composition and architecture of intracellular membranes, addressing two questions: What is the role of ceramide transport in the biology of enveloped viruses? We have identified a direct interaction between a conserved herpesvirus protein and a cellular ceramide transporter. This suggests that herpesviruses actively modify the ceramide composition of intracellular membranes during infection, a new paradigm in virus:host interactions. How do enveloped viruses bend membranes during assembly? We have identified a conserved protein complex that promotes herpesvirus membrane wrapping, potentially via palmitoylation-dependent sensing and/or stimulation of membrane curvature. A detailed molecular understanding of how viruses subvert host-cell membranes not only expands our knowledge of host and virus biology, but it provides the basic underpinning science for the next generation of vaccines and antiviral therapies.

Amount: £599,947
Funder: The Wellcome Trust
Recipient: University of Cambridge

The chemical biology and function of natural modified DNA bases in genomes 28 Nov 2017

I aim to elucidate the function of natural, chemically-modified DNA bases in the genomes of model organisms, using chemical biology and physical science approaches on genomic DNA. Modified bases are of fundamental importance to transcriptional programming and cell identity during and after development. The role of the cytosine derivative 5-formylcytosine and its influence on nucleosome formation, active enhancers, transcription and cell identity will be one area of focus to build mechanistic understanding, following on from hypotheses derived from our prior work. There will also be an investigation of 5-carboxycytosine and 5-hydroxymethyluridine and their potential links with transcription regulation. For other modified bases, such as N6-methyladenine, we will develop and use new chemical mapping/sequencing methods to elucidate their function in mammalian systems. The programme will include a systematic discovery of other natural DNA base modifications, building on and augmenting chemical methodologies I have developed to discover and profile modified bases in RNA. The function of newly identified base modifications will be investigated during the programme. The insights provided from these fundamental studies may have far-reaching consequences for normal biology and disease states. Keywords: chemical biology, nucleic acids, DNA, modified bases, epigenetics, sequencing

Amount: £2,198,391
Funder: The Wellcome Trust
Recipient: University of Cambridge

Building and breaking epithelial integrity in the neural tube: an optogenetic approach 18 Oct 2017

Using an innovative optogenetic approach within the zebrafish neural tube, I will directly explore how the polarity of individual cells drives the tissue organisation of a whole organ. In combination with 4D live imaging and functional abrogation, I will use light to specifically and reversibly manipulate apicobasal polarity, cleavage furrow formation and PI3K pathway signalling on a subcellular level. I will assess how apicobasal polarity and division are interrelated during morphogenesis of vertebrate epithelial tubes and how this relationship contributes to tissue integrity. Early zebrafish neuroepithelial divisions are highly predictable and coincident with de novo apicobasal polarisation. This provides a tractable model to assess a potential feedback loop between apical protein localisation and cleavage furrow positioning during epithelial establishment. The PI3K pathway is likely key to integrating apicobasal polarity with division. Within established epithelia, PI3K pathway defects are prevalent in cancers. I will manipulate PI3K pathway signalling within individual cells or groups of cells within an otherwise normal zebrafish neural tube. This in vivo method for manipulating cancer-linked signalling will allow me to test whether apicobasal polarity dysregulation is a cause or consequence of tissue disruption, providing clues to the cellular mechanisms of disease initiation.

Amount: £977,448
Funder: The Wellcome Trust
Recipient: University of Cambridge

A multi-disciplinary approach to understanding and improving hearing by cochlear implant users 28 Nov 2017

Cochlear implants (CIs) restore hearing by electrically stimulating the auditory nerve. This allows many CI users to understand speech well in quiet, but even the most successful have poor pitch perception and struggle in noisy situations. We believe there are two main reasons for these limitations.(i) Although it is possible to elicit different pitches by stimulating different electrodes, the selectivity of this place-of-excitation cue is much worse than in normal hearing (NH). (ii) It is also possible to increase pitch by increasing the pulse rate applied to each electrode, but use of this temporal cue is also much worse than in NH. We will study both of these limitations by performing analogous experiments in cats and humans, using some of the same measures in the two species. This will allow us, for the first time, to link the limitations that occur perceptually to their underlying physiological bases, and to do so even for novel stimulation methods that are not possible with existing clinical CIs. The knowledge gained wiill allow us to propose and test modifications both to implant design and audiological practice.

Amount: £1,727,476
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

Fractionating the human frontoparietal cortex: combining meta-analytic and real-time optimization approaches 08 Nov 2017

Disruptions in the same set of frontal and parietal brain regions are seen across a striking range of psychiatric and neurological conditions. This network of regions has been referred to as multiple-demand (MD) system and can be divided into at least two closely coupled subnetworks. However, despite extensive research efforts, the specific functional mechanism each subnetwork supports remains poorly understood using available neuroimaging technology. To overcome these limitations, I have recently developed a novel technique based on real-time neuroimaging and machine learning: Neuroadaptive Bayesian Optimization (NaBO). The key goal of this fellowship is to develop a complementary approach that leverages the strength of large-scale, automated meta-analyses and NaBO to obtain a fine-grained functional mapping between MD subnetworks and the cognitive processes they support. This approach will exploit the wealth of data generated by neuroimaging to date (meta-analysis) for defining a prior model of how cognitive functions relate to MD subnetworks and then refine this model in unprecedented detail (NaBO). The resulting model will be validated using behavioural assessment. Advancing our understanding of these subnetworks in normal brain function is an important first step for developing targeted clinical interventions and informing the design of sensitive diagnostic test batteries.

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

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

Timestamping Integrative Approach to Understand Secondary Envelopment of Human Cytomegalovirus 28 Nov 2017

The mechanisms facilitating the assembly of Human cytomegalovirus (HCMV) in the cytoplasm of infected cells, a complex process termed ‘secondary envelopment’, are poorly understood. Our goal is to identify in-situ the identity, position, and interactions of all the essential proteins involved in this critical stage of the viral ‘lifecycle’. Despite decades of research, it has been difficult to dissect the complexity of secondary envelopment, as bulk assays only show ensemble averages of populations of viral particles. To study these intermediates that are formed when cytoplasmic capsids acquire tegument proteins and their envelope membrane, we will develop a novel approach that separates these intermediates in time and space. We will provide their spatio-temporal models by integrating complementary cutting-edge techniques and expertise within this collaboration, including flow-virometry, correlative (fluorescence and electron cryo) microscopy, crosslinking and ion-mobility mass spectrometry-based proteomics, and computational modelling. Specifically, we aim to: -Identify key players in tegument assembly on capsids/membranes. -Elucidate the order and spatial organisation of tegument assembly. -Validate the interactions in vivo and analyse capsid tegumentation in vitro. -Integrate the information into a spatiotemporal model. This will significantly improve our understanding of herpesvirus assembly in general, a crucial step towards identifying new therapeutic targets.

Amount: £705,137
Funder: The Wellcome Trust
Recipient: University College London

Development of likelihood-based methods in structural biology 28 Nov 2017

I propose to build on our development of new likelihood-based methods for structural biology, transposing approaches that have had great impact in macromolecular crystallography to the new area of cryo-EM. 1) In crystallography we will enable the solution of difficult structures (poor data or poor starting models) that still evade current methods. New statistical innovations will automate the clustering of alternative molecular replacement models into sensible ensembles representing different conformations. 2) We will exploit a promising new approach to the determination of substructures for SAD phasing, based on our SAD likelihood function. 3) In cryo-EM we will investigate the propagation of errors in reconstructions, building on this understanding to devise improved likelihood-based methods to dock atomic models into cryo-EM maps, particularly those challenging cases determined at low resolution such as sub-tomogram averages. The implications of multi-variate cryo-EM likelihood targets will be explored, with potential applications in the angular deconvolution of cryo-EM maps. 4) Finally, we will develop a new approach to modelling macromolecular structures at low resolution, using interactive molecular dynamics flexible fitting to combine high-quality potential functions with likelihood targets.

Amount: £1,916,285
Funder: The Wellcome Trust
Recipient: University of Cambridge

Crafting Qualitative Health Research for the Future 04 Dec 2017

Healthcare environments across the globe are encountering new challenges as they respond to changing populations, global austerity, rapid technological advances, personalised medicine, and demands for more patient involvement. We believe that qualitative health research (QHR) can contribute to our understanding and responses to these challenges, and we have developed a proposal which aims to expand and improve the work of this field. This proposed work will be conducted through our UCL Qualitative Health Research Network (QHRN) and will include the following activities: 1) a networking and brainstorming event to create a forum for the critical analysis and improvement of QHR; 2) the fourth QHRN symposium, a two-day event with 200 delegates, 20 oral presentations and 40 posters; and 3) our quarterly seminar series, which showcases presentations from leading scholars in QHR. The main outputs generated through these events and activities will include: A position paper detailing recommendations for the improvement of QHR, publication of our proceedings from the symposium in a peer-reviewed journal, workshops and other training opportunities at the QHRN Symposium, the continuation of communication channels for members of the network (website, email listserv, and Twitter account), and dissemination of findings of QHR to patient organisations, practitioners and policymakers.

Amount: £29,198
Funder: The Wellcome Trust
Recipient: University College London