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Recipients:
University College London
Award Year:
2017

Results

Crafting Qualitative Health Research for the Future 04 Dec 2017

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.

Amount: £29,198
Funder: The Wellcome Trust
Recipient: University College London

Global Health 50/50: Towards accountability for gender equality in global health 04 Dec 2017

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.

Amount: £29,764
Funder: The Wellcome Trust
Recipient: University College London

Lost&Found: engaging with narratives of ageing 30 Nov 2017

no abstract available.

Amount: £123,300
Funder: The Wellcome Trust
Recipient: University College London

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.

Amount: £2,029,869
Funder: The Wellcome Trust
Recipient: University College London

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

Force Generation during Collective Chemotaxis in vivo 31 Jan 2017

Collective cell migration (CCM) plays an essential role in many developmental and physiological processes. However, much remains unknown about the mechanisms driving this CCM with a limited number of studies focusing on CCM, in absence of external cues, instead of the directional migration observed in vivo. Furthermore, studies have focused mainly on epithelial cells. Another issue relates to the forces involved in moving the cells as studies, to date, have produced contradictory results regarding whether leader or trailing cells generate propulsive forces. In this project, we will analyse the mechanical properties during the collective migration of Xenopus and zebrafish neural crest cells; a mesenchymal cell population which undergoes directional migration during development, giving rise to a range of cell types. Using traction force microscopy and FRET-tension sensors, we will identify which cells generate forces during CCM. Furthermore, we will address whether intercellular mechanocoupling is important for attaining coordination in CCM by measuring traction forces in cell cohorts with varying degrees of adhesion. Finally, we will elucidate the molecular mechanisms of CCM by disrupting proteins implicated in force generation and analysing the effect on generated forces. This study will thereby establish an understanding of the physical mechanisms driving CCM.

Amount: £14,399
Funder: The Wellcome Trust
Recipient: University College London

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.

Amount: £24,581
Funder: The Wellcome Trust
Recipient: University College London

Homeostatic gene networks in Drosophila models of epilepsy and dyskinesia 31 Jan 2017

Transcriptional and translation control in neurons is highly plastic, allowing firing frequency and synaptic output to be regulated with high temporal precision. Recent research has demonstrated that the complement of ion channels within a neuron can undergo homeostatic remodelling in response to altered neuronal excitability. However, the extent to which this occurs in neurological diseases is unknown, as are the alterations in ion channel expression that may buffer disease-linked mutations to the greatest degree. We aim to investigate these questions using the fruit fly, Drosophila melanogaster. Using homologous recombination, we will generate a novel knock-in fly model of Generalized Epilepsy and Paroxysmal Dyskinesia (GEPD). This disorder is caused by a gain-of-function mutation in the KCNMA1 BK potassium channel – the mammalian homologue of Drosophila slowpoke (slo). We will characterise changes in ion channel expression in GEPD slo knock-in flies through RNAseq, and using this data, perform a modifier screen to determine which alterations are compensatory or pathogenic. Genetic suppressors identified via this strategy will represent promising targets for future therapeutic interventions.

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

How do middle ear stem cells and the immune system interact in the pathogenesis of chronic otitis media? 30 Sep 2017

Chronic middle ear inflammation (otitis media) poses a significant global burden of disease in adults and children leading to permanent deafness. The middle ear mucosa maintains a well-ventilated middle ear but undergoes abnormal remodelling in disease. Similar to the adult upper airway, basal cells are hypothesised to be stem cells actively maintaining middle ear mucosa. Pathological remodelling via abnormal repair pathways may underlie chronic otitis media and studying these could help understand and treat the disease. Aim: To identify and characterise the stem cell population of the middle ear in health and how maintenance of middle ear mucosa is disrupted by the immune system leading to chronic inflammatory disease. Methods: Murine and human biopsies will be grown and characterised in vitro, in 3T3 co-culture, air-liquid interface and 3D spheroid models to study differentiation and proliferation mechanisms in health and confirm markers of stem cell and cell fate. These markers will be used to perform lineage tracing in mice in healthy mice and in crosses with Junbo mouse model of otitis media. Finally, the role of the immune system, specifically the aryl hydrocarbon receptor (AhR – responsible for detoxification of pollutants that are linked to otitis media) will be studied using AhR agonists/antagonists and Ahr deficient mice crossed with Junbo mice.

Amount: £309,724
Funder: The Wellcome Trust
Recipient: University College London

Genetic background effects in human iPSCs and iPSC-derived cell types 12 May 2017

Human induced pluripotent stem cells (iPSC) have emerged as a key model system to study the function of genetic variants, as they provide access to relevant cell types and developmental lineages through cellular differentiation. However, while it has been shown that the genetic background of the donor individual has an effect on molecular phenotypes measured from iPSCs, it is currently not known how much the genetic background influences studies that use iPSCs to model rare disease mutations, making interpretation of results challenging. In this project, I will use CRISPR-Cas9 technology to study specific rare disease mutations in different genetic backgrounds. Specifically, I will focus on loss-of-function mutations causing Kabuki syndrome, a disorder of the epigenetic machinery, and use patient-derived iPSCs together with engineered mutant and control lines to quantify the contribution of the genetic background on the transcriptome and epigenome of the iPSCs as well as neuronal precursor cells derived from them. This project will establish the value of using patient-derived iPSCs over generic iPSC lines with engineered mutations. This information is critical for the design of any subsequent studies in which iPSCs serve as the baseline, such as directed differentiation experiments and therapeutic targeting of the mutation.

Amount: £99,935
Funder: The Wellcome Trust
Recipient: University College London

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.

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

Enhancing emotion-regulation in adolescence: A developmental window of opportunity 08 Nov 2017

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.

Amount: £250,000
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

Investigation of protein CoAlation in the process of apoptosis 27 Apr 2017

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.

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

Investigating the sleep modulating effect of oxytocin in zebrafish models of autism. 27 Apr 2017

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 [3] and [6]), 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.

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

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.

Amount: £857,450
Funder: The Wellcome Trust
Recipient: University College London

4 year PhD in Neuroscience 30 Sep 2017

Not available

Amount: £2,850,000
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