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

Results

Integrative structural biology of protein folding during biosynthesis on the ribosome 05 Apr 2017

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.

Amount: £2,034,461
Funder: The Wellcome Trust
Recipient: University College London

Investigation of the regulatory hot-spots identified for type 2 diabetes 05 Sep 2017

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.

Amount: £99,945
Funder: The Wellcome Trust
Recipient: University College London

Sexy glia: developmental plasticity during glia-derived neurogenesis 11 Jul 2017

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.

Amount: £1,453,931
Funder: The Wellcome Trust
Recipient: University College London

Community interventions for primary and secondary prevention of violence against women and girls: a cluster randomized controlled trial in urban India 05 Apr 2017

In a cluster randomised controlled trial in Mumbai slums, we will test the effects of community mobilisation through groups and individual volunteers on the prevalence of violence against women and girls. One in three women in India have survived physical or sexual violence, making it a major public health burden. Reviews recommend community mobilization to address violence, but trial evidence is limited. Already implemented in other areas, our intervention has been developed over 16 years of programmatic experience and two years of formative research. Guided by a theory of change, we will compare 24 areas receiving support services, community group, and volunteer activities with 24 areas receiving support services only. These community mobilisation activities will be evaluated through a follow-up survey after three years. Primary outcomes will be prevalence of intimate partner violence, and prevalence of domestic violence, in the preceding year. Secondary outcomes will describe disclosure of violence to support services, community attitudes to violence, bystander intervention, gender equality, and prevalence of non-partner sexual violence. Backed by public engagement, advocacy, and open publication, our vision is of a replicable community-led intervention to address the public health burden of violence against women and girls.

Amount: £2,413,112
Funder: The Wellcome Trust
Recipient: University College London

Studying murine behaviour and extending the hippocampal place cell model to 3 dimensions 27 Apr 2017

In previous decades, studies focussing on hippocampal place cell activity have resorted to using 2-dimensional simulation models. I argue that such a paradigm proves to be insufficient when extending it to real-world, heavily 3D-biased, applications. As such, in this project, I propose an alternative approach to the study of place cells in which a rat’s neuronal activity is wirelessly monitored while it is allowed to freely explore a lattice maze in all directions of Cartesian space. Most importantly, I aim to show that receptive fields are of similar sizes in the horizontal and vertical directions; I also hypothesise that concatenating receptive fields (RFs) from several place cells will yield a layered organisation with inter-RF distances being larger in the x-z/y-z planes than the x-y plane. Incidentally, this study will also provide data which I hypothesise will confirm the horizontal bias model in murine behaviour proposed by Jovalekic et al. (2011).

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

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.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

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.

Amount: £0
Funder: The Wellcome Trust
Recipient: University College London

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.

Amount: £1,121,611
Funder: The Wellcome Trust
Recipient: University College London

Public health data science to investigate and improve migrant health. 25 May 2017

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.

Amount: £1,164,786
Funder: The Wellcome Trust
Recipient: University College London

Human Immune Response Variation in Tuberulosis 11 Jul 2017

I aim to discover novel mechanisms by which differences in human immune responses influence the outcome of Mycobacterium tuberculosis (Mtb) infection. I hypothesise that host-genetic polymorphisms lead to variation in immune responses that determine the clinical outcome of Mtb infection by affecting host-cell restriction of mycobacterial growth. We will use transcriptional profiling at the site of tuberculin skin tests (TST) to make comprehensive molecular and systems level assessments of in vivo human immune responses to a standardised mycobacterial challenge. In order to identify human immune responses that increase risk of disease in people exposed to Mtb, we will test the hypothesis that the TST transcriptome will reveal immune phenotypes associated with progression of LTBI to active TB. We will test the role of host genetics by identifying genome-wide expression quantitative trait loci (eQTL) associated with variation in the TST transcriptome. We will then recall participants by genotypes associated with selected traits to undertake in vitro mechanistic studies in primay immune cells. We will validate the causal association between genetic and phenotypic variations, and test their impact on Mtb restriction by macrophages. The findings will inform clinical risk stratification, vaccine design and development of host directed therapies for TB.

Amount: £1,660,537
Funder: The Wellcome Trust
Recipient: University College London

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

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

Amount: £1,561,134
Funder: The Wellcome Trust
Recipient: University College London
Amount: £2,814,500
Funder: The Wellcome Trust
Recipient: University College London

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?

Amount: £21,633
Funder: The Wellcome Trust
Recipient: University College London

Vision, decision and navigation in mouse parietal cortex 31 Jan 2017

Posterior parietal cortex (PPC) in humans and other animals is considered to be a nexus of sensory, motor, and cognitive functions. The underlying circuits and computations are increasingly studied in mice, a species that affords unparalleled resources such as genetic tools and behavioral tasks. Studies of mouse PPC, however, have focused on distinct functions: visual processing, decision making, and spatial navigation. It is not clear whether the same neurons and populations participate in these three functions, and whether they play similar roles in different behavioral contexts. We will first establish how the anatomical definition of mouse PPC used in studies of decision and navigation relates to functional maps of visual cortex established in studies of vision. We will then train head-fixed mice to perform two visual decision tasks: one of which involves navigation in virtual reality, and we will use two-photon calcium imaging to track the activity of populations of PPC neurons over weeks. These data will reveal whether the activity of the same PPC neurons stays fixed or varies to meet the variable demands of these two tasks, and thus establish the role of mouse PPC in functions that are typically combined in daily life: vision, decision, and navigation.

Amount: £27,400
Funder: The Wellcome Trust
Recipient: University College London

How do cells integrate signals? Roles of timing in neural induction 31 Jan 2017

During embryonic development cells have to integrate up to eight molecular pathways in order to choose between alternative fates or behaviours. However, even in combination, these eight pathways cannot provide enough information to specify the many (perhaps as many as 104) cell types that comprise the adult body. Timing seems to be important. One of the earliest fate decisions in embryonic development occurs soon after gastrulation during neural induction when one part of the epiblast is set apart, acquiring neural identity in response to signals from the organiser, Hensen’s node. A recent view is that neural induction is highly regulated in time and that it involves several steps. Competent cells, capable of responding to signals from the organiser, go through different states of specification before committing to the neural fate. Here we aim to understand how timing orchestrates neural induction. Specifically, we will uncover whether competence to respond to inducing signals is regulated by a cell-autonomous clock or by external instructions, how competent cells can sense exposure to signals of different duration and how this signal changes over time to generate an appropriately regionalised neural plate.

Amount: £12,700
Funder: The Wellcome Trust
Recipient: University College London

Water resistance: a study of environmental justice, resilience and citizen science activism in Mexico City 02 May 2017

This research will explore resilience in the context of environmental justice, with a focus on water insecurity in Mexico City. The concept of resilience is central to public health and climate change discourse, but is rarely critiqued. Addressing this omission is crucial: resilience frameworks can conceal social inequalities, uphold political status quo, and overlook local experience. Equally, few anthropological studies have examined resilience and urban water insecurity. In Mexico City these gaps are especially prescient. The third most water-stressed city in the world, low-income neighbourhoods have limited access to water. Communities often protest in response. Drawing together an ethnographic study with the digital participatory methods of citizen science, the goals of this research are to: Understand the meaning and practices of resilience amongst people who experience water insecurity. Investigate the role of digital technology and citizen science in this space. Inform future uses of resilience in environmental justice research, design and policy. Through these objectives, the research acts at the intersection of social inequality, public health and the environment. The outcomes will contribute to anthropological theory and knowledge, open the potential for trans-disciplinary collaborations, and bring a more sensitive and ethical perspective to the overlap of climate change and health.

Amount: £96,532
Funder: The Wellcome Trust
Recipient: University College London

What's in a voice? 30 May 2017

Why do we sound the way we do? "What’s in a voice", is an exhibit which aims to start conversations about voices, and which illustrates the evolution, complexity and meanings associated with the human voice – which is simultaneously a musical instrument without peer in terms of flexibility and range, and also a powerful social instrument with which we express who we are, how we are, and who we would like to be. This project will tell the story of the human voice – from evolution to acoustics, from anatomy to emotion – in novel and engaging ways. We will illustrate this with a strong scientific background into our work on voices, and also with demonstrations of why and how our voices can change, as well as the use of different kinds of vocal performance to allow us to illustrate the different kinds of vocal mechanisms live. The performances will involve voice professionals, including beat boxers, actors, poets, rappers and singers. We are also working with people who have more ‘difficult’ voices, (e.g. people who stammer), and children from a local Camden primary school (St George the Martyr, Camden), with whom we are working to produce some vocal demonstrations.

Amount: £20,000
Funder: The Wellcome Trust
Recipient: University College London

Development of metagenomics-based diagnostics of infectious diseases 19 Apr 2017

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.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

Pathological aversive learning as a mechanism in clinical anxiety 19 Apr 2017

Generalised anxiety disorder (GAD) is a common and debilitating condition. Its core symptoms are strongly related to subjective feelings evoked by uncertainty. This fellowship will build on advances in computational modelling to characterise the role of estimations of uncertainty about aversive events in GAD. The project has three key goals: 1) To develop behavioural tasks, and computational models of these tasks, that allow estimations of uncertainty during aversive reinforcement learning. I aim to achieve this by building on existing reinforcement learning tasks that manipulate uncertainty through changing stimulus-outcome contingencies, combined with models that allow explicit estimation of participants’ perceived uncertainty. 2) To determine whether individuals with GAD overestimate uncertainty, or overestimate the likelihood of negative outcomes in uncertain situations. To do this I will exploit tasks and models developed in phase 1 of the proposal to compare subjects with GAD and healthy individuals on their estimation of uncertainty in aversive environments. 3) In this phase I aim to identify the neural basis of these abnormalities using functional neuroimaging (fMRI), by combining these tasks and models with fMRI to identify neural systems underlying uncertainty estimation in aversive contexts, and examining the differential function of these systems in patients with GAD.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London