- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 30 Sep 2017
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
In this fellowship I plan to investigate whether mutations in hereditary neuropathy genes affect endosomal sorting of proteins and receptors to the plasma membrane of motor neurons and whether this leads to aberrant activation or inhibition of specific cellular pathways that can be targeted as potential therapies. In order to answer this question I will investigate a model of hereditary neuropathy due to mutations in BICD2. This fellowship has the following five aims. 1. To generate and charact erise a mouse embryonic stem cell-derived motor neuron model of neuropathy due to mutations in BICD2. 2. To analyse changes in the cell surface receptor landscape induced by mutations in BICD2. This will be performed using Stable Isotope Labelling of Amino-acids in Culture (SILAC) and mass spectrometry. 3. To validate in vitro the signalling pathways revealed in aim 2. 4. To validate in vivo alterations in the cell surface proteins identified and validated in aims 2 and 3. 5. To validate the changes in cell surface protein expression in human tissue. As almost all hereditary neuropathy mutations can impact on endosomal sorting and recycling to the cell surface, the techniques learnt during the fellowship may be applied to other forms of hereditary neuropathy.
Perinatal brain injury remains a significant cause of neonatal mortality and is associated with long-term neurological disabilities including cognitive impairment, mental retardation and accounts for 15 to 28% of children with cerebral palsy. There is an urgent clinical need to detect as early as possible those neonates at most risk and who may benefit from adjunct therapies and/or redirection of clinical care for effective rehabilitation. Early detection and assessment of brain neurological sta tus and outcome requires sensitive, robust and easy to measure biomarkers. The aims of my fellowship are to: (1) develop new methods for assessing neonatal brain injury and deliver early bedside biomarkers of atypical cognitive and neurological development; (2) inform and access efficacy of targeted interventions and clinical management for long-term neurological outcome in brain injured neonates through a clinical evaluation program. For several years now I have been developing instrumentati on and methodology that can non-invasively measure brain tissue oxygenation, haemodynamics and uniquely assess mitochondrial oxygenation through measurement of the oxidation status of cytochrome-c-oxidase (oxCCO). We have shown recently that, utilising our novel multimodal measurements that combine optics and magnetic resonance spectroscopy, in the neonatal animal model, the oxCCO measurement is a good indicator of the biochemical status of the brain and is directly related to recovery and outco me following brain hypoxic-ischaemia. This Fellowship will enable me to build upon my previous achievements and embark on an ambitious program of research to clinical evaluate and establish the brain optical measurement of oxCCO as a neuromonitoring biomarker.
Loneliness is the distressing subjective feeling one’s social relationships do not meet one’s social needs. Its adverse impact in physical health and mortality is established. I will investigate its impact on relapse in acute psychiatric crises, and its potential mediating role between neighbourhood social deprivation and relapse. Objectives 1) Test hypothesis that loneliness is associated with: a. increased relapse rate at twelve months follow-up (primary hypothesis) b. reduced time to relapse c.increased service use and cost 2) Test if loneliness is associated with neighbourhood-level deprivation and social isolation Test if loneliness mediates any association between neighbourhood-level deprivation and relapse 3) Discovery replication: second acute psychiatric care cohort Methods Analyse data from multicentre cohort (UCL ‘CORE’) study of acute psychiatric patients with serious mental illness. Validate results in different cohort. I will use logistic regression, with adjustment for relevant confounders/modifiers, to test the hypotheses. I will use survival analysis, (Kaplan-Meier curves and Cox hazard ratios) for ‘time-to-relapse,’ and structural equation modeling to investigate whether loneliness mediates any relationship between deprivation and relapse. Key goals Establishing how loneliness affects outcomes should inform the development of future loneliness interventions. These may reduce relapse, and incorporate both individual and area-level elements.
Background: Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disorder associated with haemorrhage and malignant potential. 70-80% also suffer severe inflammatory complications. Despite excellent survival post stem cell transplant, 30% of children have ongoing autoinflammation. Emerging evidence indicates that the actin cytoskeleton has an important role in autophagy, and inflammasome activity is intricately linked. Aims: Define the molecular role of Wiskott-Aldrich syndrome protein (WASp) in autophagy and inflammasome activation and investigate the impact of potential therapies. Methods: WASp knockout macrophage cell lines will be generated using CRISPR technology and GFP-tagged WASp introduced using lentiviral transduction. ATP, starvation and infection will be used to stimulate autophagy/ inflammasome activation. Cellular events will be followed by qPCR, western blotting and flow cytometry. Cellular localisation will be investigated by high resolution microscopy (epifluorescent, confocal, super resolution). Transcriptomics will be used to identify the impact of WASp deficiency on cellular gene expression. Implications: Inflammasome dysregulation has been implicated in a wide range of disease processes. Investigation of inflammasome dysfunction mechanisms in WAS will facilitate better understanding of the actin cytoskeleton role in the autophagy-inflammasome axis, providing therapeutic implications far beyond WAS.
The consequences of, and relationship between, amyloid deposition, grey matter microstructural change and atrophy in the MRC NSHD 1946 birth cohort 19 Nov 2015
The development of disease modifying therapies to delay the clinical onset of Alzheimer’s disease (AD) is of the highest public health importance. Robust biomarkers of the long pre-symptomatic period between the first appearance of the histopathological hallmarks of AD and the onset of clinical symptoms will be crucial for recruitment and monitoring in drug trials and clinical practice. I will analyse the multi modal MRI and amyloid PET imaging data of 500 individuals from the MRC National Survey for Health and Development (NSHD; the British 1946 birth cohort) to address the following key objectives: 1. Investigate whether amyloid deposition leads to microstructural grey matter change utilising diffusion based MRI and a new and novel multi-shell acquisition technique (NODDI).2. Investigate the extent and pattern of grey matter atrophy associated with amyloid deposition and compare sensitivity of diffusion based/NODDI metrics with measures of grey matter atrophy.3. Evaluate the sensitivity of tests of cognition, audition and olfaction in assessing early impairment of cortical function and the relationship with the the neuroimaging data.4. Investigate the relationship between neuroimaging metrics and cognitive trajectory throughout life.
The neural circuits of social preference 01 Jun 2016
Social preference requires the ability to recognize and approach individuals of the same species (conspecifics). In humans, these behaviours are present from birth and are thought to be impaired in developmental disorders, such as autism, that are characterized by aberrant sociality. The innate brain circuitry that underlies human social preference is conserved in other social vertebrates, including the genetically accessible zebrafish. I have recently shown that larval zebrafish exhibit social preference from just two weeks post fertilization. At this developmental stage, larvae are transparent and thus amenable to the full range of modern optical techniques for single cell resolution circuit analysis. I will first use reporters that integrate neural activity to highlight the anatomical correlates of the social preference circuit. Two-photon calcium imaging during the presentation of virtual social stimuli will then be used to characterize the functional properties of the identified circuit elements. Finally, given that fish development occurs ex utero, I will monitor the development of this essential circuit and precisely document the impact of environmental and genetic manipulations that have been implicated in models of human disease.
Development of a novel bioartificial liver device for the treatment of patients with liver failure 30 Sep 2016
In the UK, over 16,000 patients a year die of liver failure. Their livers have the capacity to repair and regenerate, but do not have time to do so. A device temporarily replacing liver function would save lives and reduce the necessity for liver transplantation worldwide. Dr Clare Selden and her team at UCL have developed a prototype 'bio-artificial liver' (BAL) to address this unmet need. Its key element comprises functioning liver cells in an external bioreactor. Plasma from a patient with liver failure will be passed through the bioreactor, contacting the alginate encapsulated liver cells, so that the cells replace those functions that the sick liver cannot perform. The machine will buy time for a patient's liver to improve or, if damage to the liver is irreversible, may buy time until liver transplantation can be arranged. The technology combines alginate encapsulation of a human liver cell line and subsequent culture of the encapsulated cells in a fluidised bed bioreactor - providing a convenient, manipulatable biomass in a form which maximises mass transfer between cells and perfusing plasma. The team have Translation Award funding to complete the design, specification, performance characterisation and manufacture of this fully biocompatible BAL.
Ultrasound at high intensities can cause tissue damage, therefore knowing the intensities used in clinical application is paramount. Ultrasound source outputs are calibrated using hydrophones, following a primary standard calibration at the National Physical Laboratory (NPL) in the UK. Yet uncertainty in the primary calibrations is surprisingly high: around 10% and growing with frequency (NPL 2014). The primary calibration uses optical interferometry for the measurements. This project will investigate one source of uncertainty in this procedure: the effect of the tension in the optically-reflecting membrane. The rig for these experiments will be designed and built following the design shown in Figure (1). There are three key goals: a) Create a measurement rig that can measure the normal incidence acoustic pressure transmission coefficient of a stretched mylar membrane as a function of frequency, membrane tension, and membrane thickness. b) Based on previous work in the literature (Thomas 1976; Romilly 1969; Lamb 1957; Ingard 1954; Chen et al. 2014), construct a mathematical and/or numerical model of the motion of a membrane under tension when a sound wave is incident, and make for comparison with the measurements. c) Formulate advice to the National Physical Laboratory on how to minimize this uncertainty.
The research project represents an initial investigation into the role of the diverse components of the ventral hippocampal circuitry in the context of social interaction. The aim is to explore a potential correlation between complex behavioural patterns observed during social interaction tasks and degree of activation of ventral hippocampal neurons. Behavioural assessment will only be carried out on single housed male mice to avoid sex-specific differences. During my experiments I will compare two contexts. First, as a control, mice will be placed in a test chamber with a novel object. Second, social interaction will be tested by introducing a juvenile male. The behavioural patterns generated will be scored and compared both qualitatively and quantitatively. After 90 minutes, the degree of activation of distinct ventral hippocampal areas (CA1, CA2, CA3, Dentate Gyrus and Subiculum) will be tested in each of these groups of mice using expression of the immediate-early gene c-fos (which is correlated to neuronal activation), by optimising immunohistochemical detection in the lab. I will then aim to establish the involvement of the ventral hippocampus in social interaction by using fluorescent microscopy analysis, followed by appropriate statistical testing between the control and social groups.
The Neuroscience of Nudge 01 Apr 2016
Nudges are simple behavioural methods designed to influence decision making by taking advantage of people’s implicit biases. One important type of nudge is known as "anchoring." The simple presentation of an irrelevant number affects people’s decisions by shifting estimations towards that number. This behavioural effect is well understood although the mechanism behind the unconscious bias remains unclear. The brain bases of this effect has received surprisingly little attention in the literature. One study found that the medial prefrontal cortex played a crucial role in anchoring theory-of-mind decisions in a social context, suggesting that activity within cortical networks intrinsic to the task is shaped by this extrinsic information. I propose to initiate this investigation by piloting an fMRI experiment to investigate the neural correlates of anchoring in reasoning about uncertainty. The aim is to collect a preliminary data set from a small sample of healthy adults (n=12) to explore whether the experimental paradigm: yields robust behavioural anchoring effects, identifies brain regions whose activity is affected by these anchoring effects, and tests whether these effects are parametric modulated. I predict that within prefrontal regions engaged by the task, I will observe parametric modulation based on the amplitude of the behavioural anchoring effect.
Liposomal delivery of therapeutic agents, and/or imaging agents, is an important and rapidly emerging area which will have considerable impact on many disease areas including respiratory diseases, vaccine delivery and cancer. These liposome-based formulations are increasingly important for delivery and imaging of small molecule therapeutics, and for the delivery of plasmid DNA encoding for imaging agents or toxic genes, as they offer the benefits of cell-selective delivery with minimal off-target effects. However, to date it has not been possible to formulate both small molecule therapeutics and plasmid DNA in the same nanoparticle delivery system. The aim of this research is to develop multifunctional nanoparticles for liposomal delivery of both a small molecule therapeutic and plasmid DNA. This will have the advantage of delivering two different therapies to the same diseased cell, ensuring more rapid therapeutic effect and minimising the development of resistance to each individual therapeutic intervention.
Background The mechanisms driving ketamine’s efficacy in treatment-resistant depression are unknown, but this treatment has been shown to elicit changes in the brain’s reward system. Together with the observation that anhedonia is specifically alleviated by ketamine, this finding has prompted the hypothesis that changes in brain and behavioural processes related to motivational processing may be important in the antidepressant action of ketamine. Main hypotheses Changes in motivational processes underlie the anti-anhedonic effect of ketamine in depression. Depressed patients experiencing a greater antidepressant response should exhibit greater neurocognitive changes in motivational processes following treatment. Research and educational goals - Method: Simultaneous fMRI+EEG imaging pre-, during, post- repeated ketamine administration and at 4 week follow-up. - Educational outcomes: Multimodal scanning, computational modelling, establishing task psychometrics. - Method: Behavioural testing in healthy and depressed individuals pre- and post- ketamine infusion combined with high-resolution fMRI. - Educational outcomes: fMRI data collection and connectivity analyses. Potential time line of proposed research Year 1 UCL: Develop behavioural tasks and neuroimaging methods; initiate tasks at the NIMH. Year 2 NIMH: Run tasks in healthy and depressed individuals during ketamine infusion and concurrent fMRI+EEG imaging. Year 3 NIMH : Retest patients at phase 3 and 4. Year 4 UCL: Neuroimaging analyses and writing thesis. Year 4 UCL: Neuroimaging analyses and writing thesis.
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.
Thanks to the Wellcome Trust and other leading international institutions, we have developed and proved the viability of a new generation of recording probes that will transform electrophysiology. These "Neuropixels" probes transcend past approaches, recording hundreds to thousands of neurons simultaneously. Several key steps are now necessary to maximize the impact of this new technology, enabling its widespread use in the neuroscience community. We must develop radically new recording equipment and software, provide training, and build a collaborative community of users (Aim 1). To allow this community to fully exploit the potential of this technology, we must extend it to a larger range of applications: multi-shank probes, wireless recording for freely moving animals, and optrodes for use with optogenetics (Aim 2). Meanwhile, we will obtain ground-truth data to calibrate error rates, and begin the development of a tool to automatically identify brain regions based on electrophysiological characteristics (Aim 3). This project integrates software and hardware engineering, fabrication efforts, neurophysiology tests, and behavioral and anatomical techniques. It thus requires a collaboration between laboratories with different skill sets, and a unique nanoelectronics research partner, IMEC. The results of this collaboration will transform the field of neuroscience.
My current and previous Wellcome Trust Fellowships (Henry Wellcome, 2009-13; Henry Dale 2014- present) focus on important aetiological questions about psychotic disorders, using epidemiological data. Psychotic disorders are a debilitating set of mental health disorders, characterised by hallucinations, delusions and cognitive deficits. My research demonstrates that these disorders have a robust, replicable social aetiology, with higher incidence rates observed in young people,1–3 men,1–3 ethnic minorities2–7 and people exposed to greater social disadvantage.8–11 In my previous fellowship, I established the largest epidemiological study of first episode psychosis [FEP] in England since 1999, to demonstrate that these substantial mental health inequalities also exist in more rural populations (East Anglia)3,12; rates are over twice as high as expected,3,13 with deprived rural communities experiencing the highest psychosis incidence. This study has generated new Page 5 of 18 aetiological clues, for example by showing that people at "ultra-high risk" of psychosis are exposed to similar social and spatial markers of social disadvantage as FEP patients,14 implicating an aetiological role for social adversities prior to onset. I have also demonstrated that migrants face greatest FEP risk when immigrating in childhood,15 an important period of sociocognitive development. I am attempting to replicate this in my current Fellowship, in a larger longitudinal cohort using Swedish national register data. Using this data, I have already shown that refugees are at elevated psychosis risk compared with other migrants from the same region of origin,7 providing further insights into the possible social determinants of psychosis. Epidemiological data can also inform mental health service planning. In England, Early Intervention in Psychosis [EIP] services assess and treat people with suspected FEP, offering evidence-based multidisciplinary care to improve downstream clinical and social outcomes, shown to be highly costeffective.16 Unfortunately, original policy implementation guidance17 made no provision for the heterogeneity in incidence described above, with services commissioned on a uniform expectation of 15 new cases per 100,000 people-per-year. This was at least half the true incidence,1,3 and over three times lower than the overall referral rate for all suspected FEP, including "false positive" (nonFEP) referrals,3 who still require appropriate psychiatric triage and signposting, and consume additional EIP resources not factored into original guidance. In response, I demonstrated that epidemiological estimates of psychosis risk could be used to better predict the expected FEP incidence in the population at-risk in England,13 nationally and regionally. The tool, known as PsyMaptic, has had substantial impact on policy and commissioning since it was freely-released in 2012 (www.psymaptic.org).16,18–22 Most recently, it has been used to inform national EIP workforce calculations23 following the introduction of Access and Waiting time standards,19 as part of the Department of Health’s commitment to achieving parity of esteem between mental and physical health by 2020.24 Whilst I have demonstrated, via PsyMaptic, that it is possible to translate epidemiological data into effective public mental health,25 some vital methodological limitations require empirical attention. I therefore seek Wellcome Trust enhancement funding to answer four empirical questions to develop and apply novel statistical prediction methodologies to generate sustainable, dynamic populationbased models of future mental health need.
Mechanisms and Regulation of RNAP transcription 11 Jul 2017
This grant focuses on four lines of scientific enquiry converging on RNAP function Characterisation of the molecular mechanisms underlying RNA polymerase and basal factors that facilitate transcription initiation, elongation and termination by using multidisciplinary approaches in vivo and in vitro. This includes using bespoke transcription assays, structure elucidation and a global characterization of the occupancy and transcriptomes. Identification of novel gene-specific factors and characterization of the proteomes of transcription preinitiation- and elongation complexes in vivo. Identification and characterization of RNAP-associated proteinaceous- and RNA regulators. Characterisation of the structure and function of archaeal chromatin formed by A3 and 1647 histone variants. A biophysical characterization of protein-DNA interactions and a whole-genome view of histone occupancy. Focus on the impact of chromatin on RNAP as it progresses through the transcription cycle, and the role of elongation factors to overcome the inhibitory effect of chromatin. Characterisation of factors that modulate RNAP during virus-host interactions. Virus (RIP)- and host (TFS4)-encoded RNAP-binding factors function as global inhibitors of transcription and their mechanism is reminiscent of antibiotics. Using two virus libraries of we want to screen for novel RNAP-binding regulators and use them as molecular probes to dissect RNAP function.
LRG1 and dysfunctional vessel growth 05 Apr 2017
Neovascularisation plays a key role in the pathogenesis of diseases such as cancer and diabetic retinopathy. Neovessels are frequently disorganised, poorly perfused and leaky resulting in hypoxia, oedema and ineffective delivery of therapeutics. Until recently, most therapeutic strategies have focused on the inhibition or ablation of these vessels but recent evidence suggests that re-directing abnormal vessel growth towards normality is clinically beneficial. Vascular normalisation has gained traction as a therapeutic concept, but its application to human disease is severely hampered by our limited understanding of the factors that subvert normal angiogenesis. A fundamental conundrum is that many of the molecular drivers of normal vascular development are also responsible for pathogenic angiogenesis, indicating that in disease there are additional factors corrupting this process. We recently discovered a secreted pro-angiogenic factor, leucine-rich alpha-2-glycoprotein-1 (LRG1), that is up-regulated in pathogenic settings and disrupts vessel growth, and we have shown that inhibition of LRG1 results in vessel normalisation. In this study, we will investigate the mechanisms that drive pathological angiogenesis, and test the hypothesis that LRG1 subverts endothelial-mural cell interactions by interfering with or redirecting key signalling pathways. The work will increase our understanding of pathological angiogenesis and pave the way towards new therapies.
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.
Using new evidence synthesis techniques to explore health and care inequalities among Lesbian, Gay, Bisexual and Transgender people 24 May 2017
This proposal will utilise a developing approach to synthesising existing quantitative data in order to substantially enhance the evidence-base around health, wellbeing and care inequalities among Lesbian, Gay, Bisexual and Transgender (LGBT) people. The aims of this project are to: Review the potential of nationally representative UK datasets for individual participant data meta-analysis on the health, wellbeing and care states of LGBT people in the UK Apply individual participant data meta-analysis, to develop robust estimates around LGBT health, wellbeing and care needs and inequalities. The analysis will first focus on four target measures of general health, alcohol consumption, mental wellbeing, and provision and receipt of social care among older LGBT people. Develop policy and research recommendations arising from the modelling. By combining evidence from multiple datasets we expect to show representative findings for LGBT outcomes (including statistically significant differences) that we would otherwise not have sufficient power to detect if modelling within individual datasets alone. Develop a network collaborators to expand the approach trialled above, creating a stronger evidence base of LGBT health and care needs across different age groups, intersectionalities, and also across international settings including low and middle income countries.