- 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
Central to the activity of all living systems is the need for polypeptide chains to acquire their biologically-active structures and avoid the competing events of misfolding. It is well established that the majority of proteins begin to acquire structure as highly-dynamic nascent chains during biosynthesis on the cell’s protein biosynthesis machinery, the ribosome. A detailed molecular understanding of how this native structure is acquired and how misfolding is avoided during biosynthesis is sparse. We will build on our capacity to derive structural and dynamic mechanistic information of the fundamental process of co-translational folding: we will produce a multi-scalar analysis extending from in vitro to in vivo to provide a comprehensive, high-resolution description of emerging nascent chains (NC) during biosynthesis. Our research will integrate NMR and cryo-EM to answer emerging questions regarding the observation that the ribosome itself can modulate folding processes, and also act as a hub for the recruitment and co-ordination of auxiliary proteins that can assist NC folding and modification processes. Structure-based design, incorporating protein engineering and ribosome modification will dissect NC folding mechanisms and understand how misfolding is avoided. This underpins aims to reshape co-translational folding, targeting the ribosome and NC at the earliest stages of protein-biosynthesis.
Investigating the role of RNA interference in retinal development and as an agent of degeneration 31 Jan 2017
Genetic diseases affecting the retina, are the leading cause of blindness in the developed world. Despite the wide knowledge of the genetic factors which result in retinal dystrophies, (more than 200 genes have been identified as playing a role) such conditions remain untreatable. In monogenic retinal dystrophies the age of onset of photoreceptor cell death and rate of sight loss varies, yet the pathogenic gene mutation is present throughout life. Why some cells die at a given point in time and others do not, is unknown. This project aims to investigate the role of endogenous micro RNAs (miRNA) in retinal development and the relationship between miRNA dysregulation and retinal dystrophy. Specific miRNAs will be inactivated using the CRISPR/Cas9 system and the effects on photoreceptor differentiation and optic cup lamination determined. Furthermore, retinal organoid cultures derived from Type I Usher (a syndromic retinopathy) patient induced-pluripotent stem cells (iPSC; derived by reprogramming skin fibroblasts), will be used to establish whether miRNA dysregulation is indicative of an early disease state and whether CRISPR/Cas9-based gene correction can return dysregulated miRNA levels to normal. Finally, the effects of delivering certain miRNAs to a mouse model of retinal dystrophy on early disease phenotype will be established.
Investigating the role of microglia in shaping dorsal horn pain circuitry during normal development and after early postnatal injury 31 Jan 2017
The neonatal CNS is highly responsive to noxious stimulation and early pain exposure, such as neonatal surgery or routine clinical procedures, cause persistent changes in somatosensory processing. It has been therefore been proposed that early life pain experience may determine adult pain sensitivity. Thus, an understanding of the postnatal development of the somatosensory and nociceptive system, and how it is influenced by early pain experience is an important neurobiological question. This project focusses upon developing nociceptive circuits within the dorsal horn of the mouse spinal cord and the interaction between microglia and neurons in this process. I plan to investigate how microglia shape nociceptive synaptic connections during normal postnatal development and their role in altering nociceptive circuitry after early life injury. The following questions will be addressed How do nociceptive and tactile afferents become structurally and functionally organized in the postnatal dorsal horn (dorsal horn sensory connectome)? What role do microglia play in the development of dorsal horn sensory connections under normal conditions and after neonatal injury? How do microglia change over postnatal development under normal conditions and after neonatal injury? Is injury-induced priming of microglia due to changes in the dorsal horn environment, changes in microglial properties, or both?
Utilising electronic health records and Mendelian randomisation to investigate the relationship between liver function biomarkers and gastrointestinal disease; an example of bilirubin 30 Sep 2017
Liver function tests (LFTs) are commonly performed in clinical practice and are often associated with malignant and inflammatory diseases. Bilirubin has an anti-oxidant, cytoprotective function, and reported inverse associations with conditions including cardiovascular disease, inflammatory bowel disease, colorectal cancer and overall mortality. We will use linked primary care, hospitalisation, disease registry and mortality data in England (the CALIBER programme),  and include people aged 18 or older with no underlying gastrointestinal disease at baseline. We will use Cox models to estimate cause-specific hazard ratios (HRs) for the association of baseline bilirubin with onset of gastrointestinal disease. We will further compare outcomes in gastrointestinal disease and malignancy cohorts including hospitalisation rates, relapse-free survival, net survival and mortality. Finally, we will determine whether the associations detected (with serum bilirubin) are likely to be causal by utilising a Mendelian randomisation approach.
This fellowship will explore the impact of arts and cultural engagement on health and wellbeing at a population level, using the outstanding longitudinal cohort data that have been collected in the UK. Research will examine the effects of (i) cultural engagement (e.g. attending concerts/museums/galleries/cinemas/theatre); (ii) active arts participation (e.g. music/dance/crafts/drama); (iii) passive arts consumption (e.g. music listening/watching TV/reading) on: Diagnosed mental health conditions, self-reported mental health and wellbeing Diagnosed physical health conditions, self-reported health and somatic symptoms (such as pain) Physiological measures (e.g. stress hormones/inflammation/lung function/cardiovascular measures) Cognitive measures (e.g. memory/mood/reasoning) Psychosocial measures (e.g. self-esteem/social support/quality of life/life satisfaction) A key focus will be on how different populations within society, including people of varying ages, socioeconomic status, ethnicities and education attainment, might be differently affected. In order to maximise the impact of this research on society, there will be a four-pronged engagement programme, including: Peer-reviewed papers and conference presentations aimed at academics Presentations at industry conferences for cultural organisations to explain the implications of findings for practice Reports and meetings with stakeholders in public health, politics and commissioning to explore the implications for policy A suite of activities to raise awareness amongst the public of the effects of arts engagement.
The complex causal chain between a gene and its effect on susceptibility cannot be unravelled until the casual changes have been localised in the DNA sequence. By exploiting high-resolution population-specific genetic maps, we have recently identified 111 additional disease-susceptibility locations, 93 of which are cosmopolitan (in Europeans and African-Americans) and 18 are European specific. We also refined previously identified T2D signals and showed that many of these are also risk loci in African-Americans. The novelty of our results is two-fold: 1) We obtain a precise location for the implicated functional variant(s) and 2) We were able to identify that the majority of the disease locations appear to confer risk of T2D by acting as expression quantitative trail loci (eQTL) that regulate adipose expression levels of a large number of cis-regulated genes. Our aim is to further characterise in detail all the 111 novel and previously found loci by effectively integrating all our causal location estimates together with cell-specific regulatory annotation and chromatin modifications. In addition, we will investigate all our disease and co-localised eQTL locations for tissue specificity (so far we have only used adipose) by performing gene expression analyses in other tissues relevant to T2D.
Exploring the epidemiology of respiratory syncytial virus in young children in the community using sparse serological survey data 12 May 2017
Bronchiolitis caused by respiratory syncytial virus (RSV) leads to over 30,000 hospital admissions annually in infants in England. RSV infection only confers transient immunity, and early RSV infection is associated with asthma in later childhood. Several vaccine candidates are currently in clinical trials. We currently know very little about how age at first infection is affected by, for example, the number and age of siblings, or what factors influence protection from maternal antibody. We will carry out the first community serosurvey of RSV in the UK using a unique collection of serial baby blood samples linked to maternal, family and symptom data from the Born in Bradford study. We will develop novel statistical methods to estimate the age at first and subsequent RSV infection in the first two years of life, and validate our findings against parent questionnaires and routinely collected primary care data. This study will provide important information about who to vaccinate, and when, to ensure babies are protected from early RSV infection, novel methods to estimate age at infection from sparse serological data, and validated methods for a larger, pan-European study of the role of RSV infection in early life and respiratory health in later childhood.
During this fellowship I will use high throughput sequencing (HTS) and novel analytical methods to develop a framework for the investigation and diagnosis of infectious diseases. The focus will be on complex and difficult to diagnose diseases, such as encephalitis and meningitis, where pathogen detection rates remain poor. I will first optimise my existing Bayesian mixture model approach1–7 to ensure its wider application to a range of infections and suspected pathogens. I will then analyse metagenomic RNA-seq data from brain biopsy, cerebrospinal fluid (CSF) and whole blood samples towards pathogen detection. For selected samples where the cause of the disease is known, I will investigate whether host transcript signatures can distinguish infectious or autoimmune encephalitis, motivated by successes in other infectious diseases8–12. I hypothesize that diagnosis will benefit from the joint analysis of pathogen and host genomic data. A distinct but related problem is to characterize single pathogen mixed infections and to better understand their effect on disease phenotype and severity. This proposal goes beyond diagnostics to provide a platform for discovery research including novel virulence determinants, tropism, association of genotype and phenotype, description of novel pathogens, host gene expression patterns and characterization of co-infections and mixed infections.
Towards an individualised, mechanistic understanding of resilience to mental illness during development: the role of affective processing in adolescence 19 Apr 2017
This project examines how individual differences in affective processing contribute to the development of psychiatric traits in adolescence. My two-pronged approach tackles this question from complimentary angles: 1) applying sophisticated statistical methods to currently-available large-scale data to understand individual differences in affective processing and 2) developing more sensitive measures of these individual differences. I will build upon statistical techniques for large-scale data analysis utilising two existing cohorts of adolescents/young adults (Objective 1). Using Structural Equation Modelling, I will investigate how individual differences in multi-level longitudinal measures of affective processing map onto risk for the development of mental illness. Second, I will use computational and psychophysics approaches to build upon established computational models of face perception. I will develop a facial emotion-processing task to quantify individual differences in emotion perception and assess the degree of variability in an individuals’ emotion perception (Objective 2a). I will then relate this variability to individual differences in behavioural traits associated with common mental health difficulties including anxiety and conduct problems (Objective 2b). Together, these approaches link large-scale investigation of mechanisms (Objective 1) with a more refined way of measuring individual differences in these mechanisms (Objective 2) to understand vulnerability to mental illness in adolescence.
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.
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.
The putative propriospinal contribution to feedforward control mechanisms during skilled grasp 27 Apr 2017
The corticospinal pathway is the major direct pathway contributing to hand and motor function, after stroke or spinal cord injury this pathway can become irreversibly damaged. However, other parallel pathways may still function and are accessible to the motor system. The propriospinal network is an interneuronal system that is located at the mid-cervical levels (C3-C4), which transmits and alters descending commands for targeted reaching and grasping. Lesion studies have illuminated the role of this system in the recovery of reach and grasp movements.The aim of this project is to investigate the role of this connection in healthy humans. Specifically, our objective is to show the contribution of this system in feedforward grasping mechanisms. We will employ a motor task that involves grasping an object between the index finger and thumb where the task demands change prior to contact. Paired low-intensity peripheral nerve stimulation (PNS) and transcranial magnetic stimulation (TMS) will be used to probe the propriospinal modulation of corticospinal output during the task. Studying the propriospinal system in healthy humans will show how motor commands are updated at a spinal premotoneuronal level and could provide a novel pathway to target for neurorehabilitation after lesions of the central nervous system.
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.
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.
I am an undergraduate Neuroscience Msci student studying at the University of Bristol. I am undergoing an industrial trainee year, with Alzheimer’s Research UK University College London drug discovery institute (AR-UK UCL DDI), as part of my course. The AR-UK UCL DDI is a newly established unit in UCL, with core funding from Alzheimer’s Research UK. Its goal is to discover new approaches and therapies for dementia, a core symptom of a number of important diseases ("neurodegenerative diseases" of the brain such as Alzheimer’s disease). With the increasing aging population these neurodegenerative diseases are becoming a huge individual, societal and economic problem. The AR-UK UCL DDI currently has 12 scientists and will increase to about 24, and is equipped to enable the scientific experiments and studies to be performed.My industrial trainee year with the AR-UK UCL DDI will allow me to experience neuroscience in the research setting with an opportunity to use techniques commonly used in the field. The placement will provide a very practical learning in a professional environment, challenging me both personally and academically. It will also expose me to the process of working towards developing new therapies. I will be able to develop my interpersonal skills alongside vital experience working in lab with experienced colleagues. I will take the confidence and skills built during the placement into my final year and in my future studies and career as I hope to do a PhD after my undergraduate course.Project details: Neurons are key cells of the brain. Synapses are the key points that neurons communicate to each other, and are thought to be the basis of learning and memory. In neurodegeneration the neurons and the synapses decrease in number and ability to function, leading to progressive memory loss, dementia and eventually, death. Therefore ways of protecting the neurons and synapses, and maintaining their function, could be useful therapeutic approaches. The project will involve growing neurons in a cell culture dish; it is possible to do this by obtaining the neurons from mouse brains. The neurons are able to form synapses in the culture dish, which mimic the synapses that would be naturally formed in the mouse brain. I will use these cultured neurons to develop ways of measuring the number of synapses. It will be possible to measure the number of synapses by using fluorescently tagged antibodies that bind specifically to neuronal proteins that localise to synapses, and then use microscopy to count the number of those synapses. Once I have set up this system, I will be able to add various small molecules (compounds) and drugs and identify any that are able to increase the number of the synapses. Such small molecules or drugs could be the starting point for developing new therapies for dementia.
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
The overall goal of this proposal is to elucidate the cellular and molecular mechanisms that regulate natural glia-to-neuron cell-fate switches. Stably differentiated cells can sometimes display a remarkable degree of plasticity and switch fates to another differentiated cell type, in a process termed transdifferentiation. In the vertebrate nervous system, radial glia act as neural progenitors during embryogenesis. Suprisingly, stably differentiated glia can also act as neural progenitors during adult neurogenesis. We have recently discovered two cases in which stably differentiated glial cells undergo a glia-to-neuron cell-fate switch during sexual maturation in the nervous system of C. elegans, allowing us to study these events at the single-cell level in a genetically tractable system. We will combine classic genetic approaches with state-of-the-art molecular and next-generation sequencing approaches to characterise the molecular and epigenetic changes that occur during natural glia-to-neuron transdifferentiation. We will elucidate the role of cell division in this process, identify novel molecular regulators and determine the reprogramming abilities of the factors we identify. Unleashing the neurogenic potential of glia offers tremendous therapeutic possibilities.
Vacation Scholarships 2017 - University College London
CoAlation is a novel post-translational modification to proteins whereby Coenzyme A is covalently attached to proteins. It occurs as part of the oxidative stress response as an alternative mechanism to protein glutathionylation. It is specifically a modification of enzymes involved in cellular metabolism and protects catalytic thiol groups on active site cysteine residues from irreversible damage by reactive oxygen species and reactive nitrogen species. Applying oxidizing agents to cells results in induction of apoptosis. Such agents also induce protein CoAlation. The aims of this project are to monitor induction of apoptosis in HEK293 cells in response to treatment with oxidizing agents using anti-PARP3 and anti-Caspase 3 Western blot and Fluorescence-activated Cell Sorting and to analyse the pattern of CoAlation at different stages of apoptosis using anti-Coenzyme A Western blot.
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.