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Current Filters

Award Year:
2017
Recipients:
University College London

Results

UCL Unit for Stigma Research: Advancing theory and practice in the stigma field 04 Dec 2017

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.

Amount: £29,633
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

International Brain Laboratory 30 Sep 2017

Understanding mechanisms of brain function is a scientific frontier with enormous potential benefits which is now within reach, thanks to recent exciting technical innovations. However, given the brain’s extraordinary complexity, effectively harnessing these tools is beyond the reach of single laboratories pursuing problems in isolation. This initiative - the International Brain Laboratory - will focus the efforts of 20 laboratories to understand the neural mechanisms supporting decision-making behavior in mice. As in real-world foraging contexts, mice will combine information from sensory stimuli with internal estimates of evolving reward availability. To understand how sensory signals are integrated across the brain and combined with an internal, dynamic understanding of reward structure, we will measure brain-wide neuronal activity using 2-photon imaging and high-yield electrophysiology with Neuropixels probes. Theorists and experimentalists will work closely together to interpret data, making use of standardized data processing pipelines and immediate cloud-based data sharing. This is a paradigm-shifting approach in terms of its large-scale collaborative structure and its aim to provide a mechanistic explanation of decision-making behavior across brain structures. Further, by harnessing strategies for sharing data and analyses to ensure tight collaboration and improved reproducibility, we aim to provide a new template for global neuroscience collaborations.

Amount: £1,998,000
Funder: The Wellcome Trust
Recipient: University College London

Effective public policy for improving sexual health of migrants/refugees 30 Sep 2017

Summary: Identifying and implementing appropriate and effective public policy responses for improving the sexual health of migrants and refugees Global challenges are complex, interwoven "wicked problems" whose solutions require systemic thinking, cross-disciplinary collaboration, and engagement with a range of stakeholder opinions and positions. In this proposal we will address the interlinked problems of inequalities, migration/refugees and global health. Using the tracer example of sexual health (sexually transmitted infections including HIV) we will explore rigorous evidence for interventions to address upstream determinants driving poor health outcomes for refugees/migrants from West Asia/Middle East North Africa (WA/MENA). Results from systematic reviews, realist reviews and mathematical modelling will be synthesised to identify effective interventions which can be translated into policy (in a range of sectors). These policy options will be assessed and refined to enhance their ‘palatability’ – i.e. their legitimacy, feasibility and acceptability with a range of key stakeholders in countries in the WA/MENA region as well as in pan-EU and national level (UK) health institutions.

Amount: £673,516
Funder: The Wellcome Trust
Recipient: University College London

MRF2 National Alliance for Museums, Health and Wellbeing 30 Sep 2017

This project seeks to take forward work begun by the National Alliance for Museums, Health and Wellbeing. Since its establishment in July 2015 the Alliance has engaged with an of audience of 96,000, recruited 400 members, led an All Party Parliamentary Roundtable on Museums and Wellbeing, delivered the first National Museums and Wellbeing Conference and Week, and developed a database of over 600 museum-wellbeing projects. The proposal draws together the shared expertise of a number of allied organisations with interests in wellbeing. By working in partnership we will: share expertise and best practice across our diverse audiences; provide training to help develop the regional workforce; create online virtual training resources for building resilience in museums; provide leadership and advocacy at the highest levels of health and social care policy making; and develop an umbrella organisation across arts and culture to ensure future sustainability and legacy. The Alliance is a consortium led by UCL Museums, National Museums Liverpool, British Museum, Thackray Medical Museum, UK Medical Collections Group, Tyne & Wear Archives & Museums, Manchester Museums and Galleries, University of Leicester Research Centre for Museums and Galleries, Museums Association and National Alliance for Arts, Health & Wellbeing.

Amount: £15,000
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: £856,820
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

Roles of enhancer SINEs during mouse cortical development 31 Jan 2017

Mammalian brain development relies on the sequential generation of neurons that form the cortical and subcortical structures. Spatiotemporal control of cell behaviours and sequential production of neurons expressing layer-specific genes is achieved through tight control of transcription. The Riccio laboratory recently identified a subset of Short Interspersed Elements (SINEs) that control the expression of activity-regulated genes in cortical neurons. We discovered that these specific SINEs function as enhancers, and are transcribed from their internal RNA Polymerase III promoters to produce enhancer RNAs (eRNA). Importantly, SINE eRNA is necessary for enhancing the expression of RNAPII-dependent genes proximal to enhancer SINEs in the genome. It has been reported that specific SINEs can recapitulate expression patterns of neuronal genes and, through evolution, may have gained new functions as developmentally regulated enhancers. In this project I will select candidates from the enhancer SINEs previously identified by the Riccio laboratory and characterise their role in cortical development. The aims of my project are the following: To characterize eSINEs that regulate neural genes during cortical development, in vitro To analyse the role of selected eSINEs in cortical development using in utero electroporation Generation and analysis of a transgenic mouse lacking a selected eSINE

Amount: £70,617
Funder: The Wellcome Trust
Recipient: University College London

Local control of ventral subicular circuitry and its alteration by social isolation 31 Jan 2017

The overall aim of this project is to use viral tracing, electrophysiology and optogenetics to investigate the local circuitry of the ventral subiculum (vS), and how this circuit is altered by social isolation stress – a common route to affective disorders such as depression and anxiety. I will first investigate the anatomical distribution of neurons in vS that project to the prefrontal cortex or the NAc. These have been shown to be distinct parallel populations with unique circuit functions, but very little is known about their detailed local circuit organisation. Next I will use optogenetics, electrophysiology and viral tracing to determine the functional connectivity of the local circuit that defines the differential activity of these projections. Despite strong hypotheses that local control is key in this circuit, how this is acheived mechanistically remains unknown. Finally, I will determine how this detailed projection-specific circuitry is altered by social isolation - a manipulation that drammatically alters vS circuitry - and aim to provide more specific targets for in vivo manipulations aimed at reversing isolation-induced behavioural deficits. Overall, these experiments will provide for the first time mechanistic insight into the function and organisation of vS circuitry, from individual synaptic connections, to circuit function.

Amount: £30,524
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

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

Optimization of embryonic ESC-derived motor neuron grafts for restoration of lost muscle function 31 Jan 2017

Damage to motor neurons due to traumatic injury or degenerative conditions typically results in permanent muscle denervation and paralysis. We recently described1 a novel strategy to artificially restore functional control of paralyzed muscles, which employs embryonic stem cell-derived motor neurons (ESC-MNs), modified to express channelrhodopsin-2 and glial derived neurotrophic factor, to confer optogenetic control of neural activity and promote long-term survival, respectively. These ESC-MNs, contained within embryoid bodies (EBs), were engrafted into injured peripheral nerves of mice, resulting in reinnervation of paralyzed muscles and optical control of their function. Unfortunately, EBs contain pluripotent cells with an inherent potential to form teratomas, limiting their clinical utility. However, purified ESC-MN grafts have a limited to capacity to functionally reinnervate muscle targets because other cell types within EBs, particularly excitatory interneurons, appear necessary for successful reinnervation of target muscles by engrafted ESC-MNs. The aims of this project are to i) optimize the ESC-MN graft identity, by investigating the effect of interneurons on motor neuron maturation and muscle innervation; ii) to use the optimized grafts to reinnervate opposable flexor and extensor muscles, to demonstrate the therapeutic utility of this approach in the restoration of complex functions, such as hand grasping.

Amount: £16,673
Funder: The Wellcome Trust
Recipient: University College London

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), [1] 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.

Amount: £253,846
Funder: The Wellcome Trust
Recipient: University College London

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.

Amount: £50,239
Funder: The Wellcome Trust
Recipient: University College London

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.

Amount: £99,580
Funder: The Wellcome Trust
Recipient: University College London

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

Amount: £283,711
Funder: The Wellcome Trust
Recipient: University College London

Jeevan Shakti Mela - Funfair for lifeforce 28 Nov 2017

Type 2 Diabetes mellitus (T2DM) is often not well understood among marginalized populations, but its prevalence is increasing, particularly in low-income countries. We will address this challenge in rural plains Nepal, enabling female Maithil artists from the Janakpur Women’s Development Centre (JWDC) to engage with communities about T2DM through research, drama, and a funfair. First, a research skills workshop will bring JWDC artists and researchers together to plan and implement discussions with community members, people with diabetes, healthworkers, and pharmacists about local understandings and effects of T2DM. Building on these discussions, JWDC and independent artists will work together during three workshops to produce traditional Maithil paintings, props, interactive displays, and games for a funfair. The fair will run for 2 days in a large public park, with one ‘women and children only’ day to enable culturally acceptable participation. JWDC artists will develop and perform a drama at the fair and in 15 marginalised communities. A local and a national advisory committee will advise on content, quality, and reach of our activities at quarterly meetings. Through this engagement process, we hope to increase knowledge, understanding, and motivation to prevent diabetes among both JWDC artists and community members.

Amount: £75,000
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

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