- 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
Dravet syndrome is a rare, incurable epilepsy which affects young children. Before two years of age they have seizures, incoordination and cognitive impairment. They carry mutations in the SCN1A gene, which codes for voltage-gated sodium channel NaV1.1. This protein is expressed in hippocampal inhibitory interneurons. Gene therapy offers several advantages over conventional drugs. It is a treatment which targets the cause of the disease by delivering the corrected copies of the SCN1A directly to brain cells. Our hypothesis is that we can incorporate a promoter to achieve persistent expression specifically in inhibitory interneurons of the hippocampus. We aim to compare two novel promoters against a pan-neuronal promoter, synapsin. The first is a truncated endogenous promoter, Gad67. The second is a synthetic promoter identified by in silico analysis. Before the project commences, we will clone these two promoters into lentiviral vectors. These, and a synapsin vector, will be injected intracranially into neonatal mice. At the start of the project the brains from four mice will be co-stained with antibodies directed against GFP and inhibitory interneurons to assess colocalisation. To measure persistence of expression from these promoters, the four remaining mice will be subject to whole-body bioluminescence imaging twice-weekly.
Optimisation of carrier materials for the delivery of olfactory ensheathing cells in spinal cord injury 27 Apr 2017
Transplant-mediated repair is a promising method in spinal cord injury (SCI) treatment. This involves transplanting therapeutic cells that promote nerve regeneration at the site of injury. For SCI, one promising therapeutic cell type is olfactory ensheathing cells (OECs). These have been shown to remyelinate demyelinated axons and promote new synapses following injury. They are also easily accessible clinically via trans-nasal endoscopic biopsy, and compelling pre-clinical evidence means that they are now close to being formally tested as part of a first-in-man clinical trial. However, currently these cells are delivered as a simple cell suspension, and this is unlikely to be optimal for creating a permissive and optimised repair environment. Thus, the objective of this project will be to develop and engineer optimised biomaterial scaffolds for OEC delivery. In doing so, it is hoped that a permissive 3D extracellular environment can be created, and the phenotype and behaviour of OECs optimised for spinal cord repair. Promising prospective biomaterials include fibrin, collagen and collagen-fibrin blends. To this end, we will investigate the effect of these promising carrier materials on OEC survival and phenotype, particularly with a focus on changes they may cause on 3D cell morphology.
Developing a behavioural task for measuring the ability of listeners to perform auditory scene analysis. 27 Apr 2017
The auditory brain separates simultaneous sounds arriving at the ear into identifiable and localisable sources by a process known as Auditory Scene Analysis (ASA). The two steps that are involved in ASA are i) segregation of the simultaneous auditory information and ii) the integration of the sounds from the same source into one stream. To understand how these two steps are connected and how different auditory cues interact to shape the scene, this project will develop a behavioural task and analyse the performance of human listeners. A target vowel will be presented alongside with a distractor vowel, and human listeners will identify what the target is. Listeners will only be able to identify the target if they can separate the two sounds: changing the location and pitch of target and distractor will help this. In order find out whether the separation of competing sounds is facilitated by the formation of perceptual streams, the vowels will also be presented as part of a sound sequence. Our hypothesis is that the ability to identify a target vowel will be improved by the formation of two perceptual streams. The long-term goal is to develop a behavioural paradigm suitable for humans and animals.
The project's aim is to up and down regulate MafB gene, that is expressed in the Nucleus Laminaris (NL) and Nucleus Angularis (NA), in the developing chick hindbrain and ask questions about: 1) formation of nucleus Laminaris and nucleus Angularis in the dorsal hindbrain; 2) other effects on hindbrain development e.g interfering with fgf8 molecule expression, which in turn would affect the development of the cranial motor nerves VI, VII and nVIa. Such experimental techniques as in ovo electroporation, immunofluorescence and in situ hybridization will be used to look at the genes expressed in the auditory brainstem. The in ovo electroporation constructs used will overexpress MafB and also express a dominant negative version of MafB and immunofluoresce analysis will be carried out to test whether the electroporation was successful. The in situ hybridization analysis will be performed to establish the effect of MafB on the expression of such genes like FGF8, Pou6F2, N-cadherin, gamma catenin, cadherin-13 and cadherin-22 in the hindbrain. These techniques would also allow the analysis of the formation of the nucleus Laminaris in the developing hindbrain.
Integrative and conjugative elements (ICEs) are mobile genetic elements present in both gram-positive and gram-negative bacteria. They mostly reside in the host chromosome and under certain conditions, will excise and transfer to a new host via the conjugation machinery. ICEs have been found to provide the host with a wide range of phenotypes, including antibiotic and heavy metal resistance and the ability to colonise a eukaryotic host, promote virulence and biofilm formation. The ability of ICE to spread to different species of bacteria through horizontal gene transfer is a major factor in bacterial evolution. Bioinformatics approaches have been increasingly used to identify possible ICEs through sequence similarity. In this project, we aim to find out the effectiveness of using an algorithm, DLIGHT (Distance Likelihood based Inference of Genes Horizontally Transferred) that was originally used to detect lateral gene transfer, to identify integrative and conjugative elements. We will achieve this by assessing DLIGHT's ability to recover already documented ICEs. We will also use DLIGHT to test certain sequences which we suspect to contain ICEs. The predictions of new ICEs will then be vetted through manual analysis and collaboration with experimentalists.
In this project I will test the hypothesis that oxytocin expression and development of oxytocin-expressing neurons are altered in zebrafish with mutations in the ASD risk genes cntnap2 and chd8. I hope to find evidence for the sleep modulating effects of oxytocin, and posit whether deficiencies in oxytocin signalling pathways may contribute to sleep disorders in autism mutants. I will examine oxytocin mRNA levels across the day/night cycle for both wild-type and mutant fish established in the Rihel lab. I will then analyse the pattern of oxytocin expression in the brains of mutant embryos and their wild-type siblings. From the findings in related studies with cntnap2 mutant mice and the Rihel lab zebrafish models of autism (see references  and ), I expect to see an alteration in the amount of oxytocin mRNA for day/night between the wild-type and mutant embryos, and a change in the number of neurons expressing oxytocin. If such changes are found, they could explain the sleep phenotype observed in cntnap2 autism mutants, and elucidate a link between neuronal circuit dysfunction and behavioural perturbation in this animal model.
Evaluation of antimicrobial resistance and intrahospital transmission of respiratory pathogens in antibody-deficient patients. 27 Apr 2017
I will be studying the respiratory microbiome of antibody-deficient patients to determine whether the number of bacterial species that are resistant to common antibiotics correlates with antibiotic usage, and whether transmission of these bacteria occurs between patients whilst attending hospital for immunoglobulin infusions. Immunocompromised patients provide a highly permissive environment for pathogen evolution as the lack of immune pressure allows resistance to develop without an associated fitness cost. Many of these patients take long-term prophylactic antibiotics together with frequent treatment courses, which we hypothesise acts as a selection pressure to further increase the number of resistant bacterial species in their microbiome. By analysing sputum samples with conventional microbiology techniques and MALDI-TOFF mass spectrometry, I will identify the bacterial species present in each sample and determine how many are resistant to common antibiotics, comparing this to questionnaires detailing the patients’ antibiotic usage. Additionally, for any resistant species identified in multiple patients, I will compare the antibiograms from each sample and extract DNA for 16S next generation sequencing to determine whether the presence of these species is due to intrahospital transmission. This project could inform clinical management of these patients as well as other situations where immunocompromised patients share hospital facilities.
To attack cells in our body, bacteria make use of toxins that drill holes in the cell membranes. Following a similar strategy, our immune system makes use of such pore forming proteins to target cancerous, virus-infected and bacterial cells. In the course of their action, pore forming proteins are first secreted as monomers, bind to the membrane, and next self-assemble into oligomeric pores. Some of the various open questions are how these pore assembly processes take place on more complicated, composite membranes such as bacterial envelopes. This project will aim to contribute to answering these questions, while providing the student research expertise in nanoscale microscopy methods applied to process that is essential for bacterial attack and immune defence. More precisely, the student will image live bacteria (E. coli) as they are attacked by the membrane attack complex. This is part of on-going atomic force microscopy experiments in the supervisors lab, which offer the possibility to visualise bacterial cell wall degradation in real time. Time permitting, the student will also be exposed to computational approaches to analyse such new data as well as past data on assembly and membrane insertion of immune effector perforin.
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.