- Total grants
- Total funders
- Total recipients
- Earliest award date
- 24 Jan 2017
- Latest award date
- 06 Dec 2017
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
We propose to establish Global Health 50/50, a new initiative seeking to advance action and accountability for gender-equality in global health. Gender is a key driver of power to exercise the right to health, including exposure to risks of poor health, health seeking behaviours, and access to quality health care. Gender inequalities continue to define and drive career pathways and opportunities for people working in global health organizations. While some progress has been made, major gaps and challenges remain. We seek to raise awareness of persistent inequality and identify pathways to change. We will establish a network of experts in gender and global health, working with an advisory body drawn from the realms of politics, development, management, advocacy, human rights, social justice. Global Health 50/50 will publish an annual report on the state of gender-related policies and practices of 150 major organizations working in the field of global health.
Jeevan Shakti Mela - Funfair for lifeforce 28 Nov 2017
Type 2 Diabetes mellitus (T2DM) is often not well understood among marginalized populations, but its prevalence is increasing, particularly in low-income countries. We will address this challenge in rural plains Nepal, enabling female Maithil artists from the Janakpur Women’s Development Centre (JWDC) to engage with communities about T2DM through research, drama, and a funfair. First, a research skills workshop will bring JWDC artists and researchers together to plan and implement discussions with community members, people with diabetes, healthworkers, and pharmacists about local understandings and effects of T2DM. Building on these discussions, JWDC and independent artists will work together during three workshops to produce traditional Maithil paintings, props, interactive displays, and games for a funfair. The fair will run for 2 days in a large public park, with one ‘women and children only’ day to enable culturally acceptable participation. JWDC artists will develop and perform a drama at the fair and in 15 marginalised communities. A local and a national advisory committee will advise on content, quality, and reach of our activities at quarterly meetings. Through this engagement process, we hope to increase knowledge, understanding, and motivation to prevent diabetes among both JWDC artists and community members.
Our new UCL Unit for Stigma Research (UCLUS) will be a hub for innovative high quality research and theory production in the field of stigma research. UCLUS brings together research across diverse fields, including intellectual disability, mental health and dementia, and explores cross-cutting themes and opportunities for research. We are seeking funding to support UCLUS activities and explore areas for new research on stigma resistance and disclosure decision making, two novel areas in which we are piloting work. A better understanding of what makes some members of highly stigmatised groups more vulnerable/resistant to stigma, and how they manage disclosure offers the potential for innovative contributions to broader theorising on responses to adversity. It can also inform the development of interventions that enhance wellbeing via capacity to resist stigma among members of highly stigmatised groups. Funding will allow us to (a) explore this area further, (b) develop a research agenda, (c) build capacity for high quality research, and (d) extend existing and form new partnerships to take this work forward through the public launch of UCLUS, a seminar series, development of the research unit's social media presence, a UCLUS led session at the 2018 IASSID European Congress, and international collaborative visits.
Investigating mechanisms involved in retinal signalling in health and disease through detailed in vivo human electrophysiological investigation 25 May 2017
Retinal imaging investigates structure, but not cellular function. Electrophysiology allows direct assessment of the latter. The electroretinogram (retinal electrical response to light) can be recorded non-invasively. As understanding of retinal processing improves, with refinement of mathematic models of current flows, light and dark adaptation, there is scope to probe retinal signalling in great detail. Findings from animal and in vitro studies can be specific to species or laboratory conditions. This project uses in vivo human recording. Novel stimulus protocols will be used in patients with largely monogenic disease (including natural "knock-outs"), and in genetically characterised twins (both using the classic twin study and by exploring further genetic associations including the retinal functional significance of myopia-associated genetic loci). Project goals include the following: 1. A more integrated model of sensory signalling pathways in the retina: elucidating roles of specific proteins (in the photoreceptor-RPE complex and in signal transmission to bipolar cells) 2. Elucidation of a myopia signalling cascade: functional effect of variants that confer susceptibility to myopia These will yield insights into neural processing (with wider implications for neuroscience), retinal disease and myopia. As new gene and stem cell therapies emerge, novel functional assessments can provide objective outcome measures.
Migration is a defining political challenge of our time and a global health priority. Internationally there is a lack of epidemiological data on new migrants including the prevalence of high morbidity conditions and estimates of risk factors for disease. The overarching aim of this research is to generate evidence that will improve the health of migrants moving from low and middle-income to high-income countries. Key goals: Million migrant study: Create an electronic cohort that will establish the first national rates of age-specific morbidity and risk factors for disease in migrants. Migrant eCohort: Investigate the migrant exposome and how this changes over time since migration, using digital technologies (smart phones and apps) for data collection. Personalised public health intervention: Develop and test the feasibility of a tailored health advice website to improve migrant health. Outcomes: These studies will transform how we conduct digital cohorts in mobile populations and have wide application for efficient study design. The detailed epidemiological and health service data produced will provide the first national evidence of the health effects of rapid epidemiological transition as a result of UK migration, and a platform from which to carry out digitally enabled personalised public health interventions.
Aim: Investigating the relationship between genotype, gene expression and phenotype of microphthalmia, anophthalmia and ocular coloboma (MAC), which collectively causes one-third of life-long blindness and severe visual impairment in children worldwide. Research questions: What are the pathogenic variants underlying MAC? How do molecular subtypes correlate with phenotype and stratify clinical risk? What molecular pathways are involved in human eye development? What is the relationship between genotype and gene expression in microphthalmia? Key goals and methodology: Whole genome sequencing of 30 parent-offspring trios with isolated MAC and longitudinal phenotyping. Establish an international reference network to stratify a well-defined cohort to improve care pathways and future research. Temporal comparative analysis of DNA methylome (bisulfite conversion and Illumina Infinium EPIC BeadChips) and transcriptome (65 million reads per sample using Illumina HiSeq-2500) in the developing human eye between 4-9 weeks gestation. Model 3D human microphthalmic optic cups using iPSC technology with isogenic controls using CRISPR/Cas9 gene-editing. DNA methylome and transcriptome analysis to assess disruption of molecular pathways. Outcomes: Establish a molecular framework for ocular maldevelopment. Identify drug targets and develop therapeutics. Improve genetic diagnosis, counselling and management. Elucidate shared molecular mechanisms between embryonic tissue fusion defects and late-onset visual sensory disorders.
International Brain Laboratory 30 Sep 2017
Understanding mechanisms of brain function is a scientific frontier with enormous potential benefits which is now within reach, thanks to recent exciting technical innovations. However, given the brain’s extraordinary complexity, effectively harnessing these tools is beyond the reach of single laboratories pursuing problems in isolation. This initiative - the International Brain Laboratory - will focus the efforts of 20 laboratories to understand the neural mechanisms supporting decision-making behavior in mice. As in real-world foraging contexts, mice will combine information from sensory stimuli with internal estimates of evolving reward availability. To understand how sensory signals are integrated across the brain and combined with an internal, dynamic understanding of reward structure, we will measure brain-wide neuronal activity using 2-photon imaging and high-yield electrophysiology with Neuropixels probes. Theorists and experimentalists will work closely together to interpret data, making use of standardized data processing pipelines and immediate cloud-based data sharing. This is a paradigm-shifting approach in terms of its large-scale collaborative structure and its aim to provide a mechanistic explanation of decision-making behavior across brain structures. Further, by harnessing strategies for sharing data and analyses to ensure tight collaboration and improved reproducibility, we aim to provide a new template for global neuroscience collaborations.
Summary: Identifying and implementing appropriate and effective public policy responses for improving the sexual health of migrants and refugees Global challenges are complex, interwoven "wicked problems" whose solutions require systemic thinking, cross-disciplinary collaboration, and engagement with a range of stakeholder opinions and positions. In this proposal we will address the interlinked problems of inequalities, migration/refugees and global health. Using the tracer example of sexual health (sexually transmitted infections including HIV) we will explore rigorous evidence for interventions to address upstream determinants driving poor health outcomes for refugees/migrants from West Asia/Middle East North Africa (WA/MENA). Results from systematic reviews, realist reviews and mathematical modelling will be synthesised to identify effective interventions which can be translated into policy (in a range of sectors). These policy options will be assessed and refined to enhance their ‘palatability’ – i.e. their legitimacy, feasibility and acceptability with a range of key stakeholders in countries in the WA/MENA region as well as in pan-EU and national level (UK) health institutions.