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Results

Regulation of microglial phagocytosis 30 Sep 2018

Microglia are the brain's immune cells. They constantly survey the brain to search for invading micro-organisms, unwanted molecules (such as amyloid plaques in Alzheimer's disease) or dying cells, but also play a key role in sculpting the circuitry of the brain by removing unnecessary cells and synapses during development. The mechanisms by which microglia constantly move their processes to survey the brain, and then remove invading micro-organisms, plaques, cells or synapses, are poorly understood. I will use 2-photon and confocal imaging techniques to investigate these events, taking advantage of recent discoveries from the Attwell lab which have revealed the importance of microglial potassium channels and purinergic receptors in controlling these events.

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

Characterising the neural mechanisms of human memory at high resolution 10 Apr 2018

Our past experiences are captured in autobiographical memories that serve to sustain our sense of self, enable independent living and prolong survival. Despite their clear importance and the devastation wreaked when this capacity is compromised, the neural implementation of autobiographical memories has eluded detailed scrutiny. My goal is to understand precisely how autobiographical memories are built, how they are re-constructed during recollection and how these memory representations change over time. My aim is to identify the mechanisms involved in these processes and thereby establish a theoretically enriched account of their breakdown in pathology. This endeavour will be enabled by cutting-edge, multi-modal technology that includes a new wearable MEG system and ultra-high-resolution MRI. The ventromedial prefrontal cortex and hippocampus are heavily implicated in autobiographical memory. I will test a novel hierarchical model that specifies their distinct roles and how they interact to produce the seamless encoding and recollection of our lived experiences. Overall, this new extension of my work will expose autobiographical memories as never before, revealing the millisecond temporal dynamics, and the laminar-specific and hippocampal subfield processing that supports their evolution from the point of inception, through initial sleep cycles and then over longer timescales.

Amount: £2,359,757
Funder: The Wellcome Trust
Recipient: University College London

Gene Editing using CRISPR/Cas9 for Gene Correction in Recessive Dystrophic Epidermolysis Bullosa (RDEB) 31 May 2018

Conventional gene therapy approaches rely on the addition of a corrected gene copy via viral vector transduction. Such strategies are currently being applied to recessive dystrophic epidermolysis bullosa (RDEB) where there is defective collagen type VII protein. However, use of constitutive exogenous promoters in viral vectors results in sustained gene expression that is not subject to the normal regulatory mechanisms of C7 expression. Integrating properties of vectors also pose risk for insertional mutagenic-derived events and efficiency of gene transfer has been challenging given the large size of COL7A1 cDNA. Whereas, gene-editing tools can be designed and engineered to target and repair specific defined regions of DNA, thereby alleviating genomic toxicity and maintaining endogenous gene expression control. Existence of well-known mutation hotspots within COL7A1 allows CRISPR reagents to be designed that would target the mutations found in the UK population with RDEB. Investigations outlined in this proposal aim to identify the most effective CRISPR reagent for a chosen mutation hotspot within COL7A1 gene. In skin, keratinocytes predominantly produce collagen type VII. Therefore, this project will evaluate feasibility of gene editing approaches using CRISPR/Cas9 system in HACAT keratinocytes cell line, and help address critical aspects of CRISPR/Cas9 efficiency at a chosen loci.

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

Politics, Philosophy and Economics of Health 30 Jun 2018

This project will examine benefits sharing for the provision of genetic information in the creation of medical treatments for infectious diseases. Networks to enable the international sharing of genetic material are a cornerstone of pandemic preparedness initiatives. Countries with the highest disease burdens share their isolated virus strains, that are utilised by pharmaceutical companies to create patented therapies, typically inaccessible to the citizens of the country from which they originated. The inequity of such a system is clear. In response to Indonesia’s 2006 protest, the Pandemic Influenza Preparedness Framework (PIP) was developed to facilitate benefits sharing. Uniquely, this framework set a standard of practice for governments, academics, and the private sector, and enabled it to be enforced through the use of civil contractual legislation. However, recent scientific and technological advancements, such as gene sequencing data (GSD), may serve to diminish the framework’s capacity to promote global health justice. Through an evaluation of the effectiveness and equity of current policy, this research attempts to highlight areas of tensions that arise in light of recent innovation. If left unaddressed, these new gaps could impede the goal of fairness that these policies set out to achieve, directly impacting the health of individuals globally.

Amount: £27,140
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

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

Using visual dysfunction to understand dementia in Parkinson’s disease 06 Dec 2016

Dementia affects half of patients with Parkinson’s disease (PD) but there are no robust measures to predict who is at highest risk. Visual hallucinations are highly distressing to patients and carers but are poorly understood. This Fellowship will use visuo-perceptual dysfunction to predict dementia and understand hallucinations in PD. I have developed a novel test using skewed images to detect visuo-perceptual deficits in Parkinson’s patients. I have also developed a web-based platform to enable this and other visual tests to be accessed by large numbers of patients with PD. In this proposal I will use visual perceptual tests combined with neuroimaging over time to determine the sequence of visuo-perceptual deficits in PD. I will relate these to changes in hallucinations. I will use my web-based platform to identify clinical and genetic associations with visual deficits and determine their role in predicting dementia in PD. Goals 1. Characterise changes in visuo-perception as PD progresses and correlate deficits with brain atrophy. 2. Relate MRI structural connectivity changes with disease progression. 3. Examine clinical and genetic associations of visual dysfunction in PD. 4. Test whether transcranial stimulation can improve visuo-perceptual function in PD. 5. Determine how visual hallucinations become distressing as PD advances.

Amount: £1,223,282
Funder: The Wellcome Trust
Recipient: University College London

Analysis of cytomegalovirus pathogenesis in a human challenge system 30 Nov 2016

Our research has made major contributions to understanding the natural history and pathogenesis of human cytomegalovirus (HCMV) in allograft recipients. Critically, we have demonstrated that biomarkers can be applied to stratify patients most at risk of HCMV disease and thus inform clinical practice to reduce HCMV end-organ disease. This clinical approach of administration of antivirals to individuals with elevated viraemia above designated levels provides a unique opportunity to gain fundamental insight into disease processes in a human challenge model of HCMV infection. A multi-disciplinary consortium has been recruited to apply next generation DNA sequencing, molecular virology and functional immunological assays to identify virus and host cell determinants of disease susceptibility. Whole genome sequencing of virus in organ donors (live and cadaveric) and recipients will be used to track the source, replication kinetics and evolution of HCMV strains in seronegative and seropositive recipients. We will then define in vitro humoral, cell-mediated immunity and natural killer responses against HCMV that correlate with protective immunity against primary infection, reinfection and reactivation in these patient groups. This approach has the potential to provide unique insights into the natural history and pathogenesis of HCMV and identify innovative therapeutic approaches against it.

Amount: £2,669,767
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

Advancing Psychiatric Mapping Translated into Innovations for Care: PsyMaptic-A 05 Dec 2016

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.

Amount: £204,479
Funder: The Wellcome Trust
Recipient: University College London

Co-evolution of tumour mutational and CD4 T-cell differentiation landscapes 30 Sep 2018

Lung cancer is the second most commonly diagnosed cancer in the UK and the greatest cause of cancer-related death. A type of this disease called non-small cell lung cancer (NSCLC) accounts for the majority (85%) of cases. T-lymphocyte cells (T-cells) of the immune system patrol the body and can recognise and destroy cancer cells by recognising mutated proteins (neoantigens) on them. Despite this, the majority of patients with advanced lung cancer die of the disease, indicating the ineffective function of the immune system. In particular, little is known about the role of a particular group of immune cells called T-helper cells that are thought to be important. In chronic infections where T-cells are constantly exposed to their targets, they become less responsive as younger cells are driven to turn into later ones more rapidly. As younger cells are lost, the body's ability to fight the infection reduces. In cancer, it is possible that mutations drive a similar problem. Using lung cancer specimens from patients on a clinical trial and animal models of cancer, we propose to study the question of whether and how mutations can paralyse the ability of T-helper cells to fight the disease.

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

UCL/WT Translational Partnership 2018 - Widening Participation and Enhancing Translational Culture 30 Sep 2018

The biomedical translational strategy of UCL and its partner hospitals is based upon harnessing the wealth of talent and ideas across disciplines to make a difference to patients and their families. The WT Translational Partnership Award supports the pursuit of excellence in the universities tripartite mission "Research, Education and Innovation" and will enhance the knowledge, culture and support available for translation: • Provide funding to develop pilot data enabling progression of projects to our internal Therapeutic Acceleration Fund. Aimed at encouraging Early Career Scientists to take the first step along the translational pathway (RESEARCH) • Enable a greater understanding of translation amongst early career researchers through a mixture of on-line training material and workshops (EDUCATION) • Supporting our Therapeutic Innovation Networks (TINs) in small molecule, biologics, cell, gene & regenerative medicine, devices, diagnostics and repurposing. These "early discovery therapeutic accelerators" will identify and address barriers encountered, share knowledge/best practice and use Industry expertise to progress specific projects (INNOVATION)

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

Investigating prevention of cervical cancer, disease burden, and opportunities for improvement in inclusion health women (IHW) 30 Sep 2018

Cervical cancer is preventable due to screening and vaccination against human papillomavirus (HPV), the main cause of cervical cancer. However, there were 3,224 new cases and 890 deaths in the UK in 2014. By 2035, this is predicted to rise by 43% due to screening non-attendance. Living in a deprived area increases cervical cancer rates and non-attendance at screening. Inclusion health addresses needs of groups frequently underserved by health services who have worse overall health than people in deprived areas. These include homeless people, migrants, substance misusers, prisoners, and sex workers. It is likely that they engage the least with cervical cancer prevention and have the greatest need for intervention. Unfortunately, they are rarely included in cervical cancer prevention research. This fellowship will fill this knowledge gap. I will measure disease levels, engagement in prevention, and find ways to improve outcomes in inclusion health women. This is needed to eliminate cervical cancer. I will achieve this in three ways: (1) a review of existing studies on inclusion health and cervical cancer (2) a study linking information on 1.6 million migrants to cervical screening and vaccination data and (3) a survey and HPV testing of inclusion health women attending outreach services.

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

Lancet Countdown: Tracking Progress on Health and Climate Change 30 Sep 2018

Please see the Executive Summary of the attached document for a summary of the proposal.

Amount: £5,528,492
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

Computer-based analysis of early fibrosing lung disease 06 Dec 2017

Fibrosing lung disease (FLD) is an idiopathic condition, affecting older patients (median age=65 years) and smokers, accounting for 0.9% of all UK deaths in 2012. Unfortunately, despite newly available treatment options, FLD is typically diagnosed at an advanced stage with patients already markedly functionally impaired. Patient decline is often rapid. A constraint with diagnosing disease at an early stage is that subtle minor CT abnormalities that may evolve into rapidly progressive disease, are hard to identify and yet to be characterised visually. Large population studies may identify those subtle CT features portending progressive disease. Such large-scale analysis of CT imaging would be best suited to advanced computer analytic tools. We therefore aim to develop sophisticated computer tools to evaluate CTs in 20,000 heavy-smoker patients undergoing repeated chest imaging, as part of a lung cancer screening study, to identify early and potentially progressive FLD on CT. GOALS 1.Characterise baseline CT patterns indicative of early FLD and progressive FLD. 2. Predict the trajectory of a patient’s fibrosis progression using computer quantitation of change in an individuals CT features. 3. Generate population-wide quantitative CT metrics (age, gender and race specific) as a reference range applicable to other worldwide lung cancer screening studies.

Amount: £1,034,494
Funder: The Wellcome Trust
Recipient: University College London

Pre-configured and learned properties of hippocampal circuits 10 Apr 2018

Despite recent advances in systems and computational neuroscience, very little is known about how the brain’s functional complexity arises during ontogenesis and which developmental mechanisms determine the emergence of complex behaviour. The proposed research aims to bridge this gap between developmental neurobiology and systems neuroscience by defining the relative roles of early embryonic events and post-natal learning in the development of spatial and non-spatial coding in the hippocampal formation. Our key goals are to: 1) establish whether the functional diversity in hippocampal place cells is defined by early embryonic divergence; 2) test whether ‘non-place’ coding in the hippocampus is intrinsic to the network (as place coding appears to be), or whether it requires late post-natal learning; 3) discover the relative contributions of experience-dependent and independent processes in creating the specific neural architecture (‘continuous attractor') underlying codes for direction and distance. We will deliver these goals using chronic in vivo recording of neural activity (high density electrophysiology and calcium imaging) in developing animals coupled with neuronal birth tagging, behavioural testing and functional inactivation of crucial targets, to discover which self-organised embryonic events and instructive signals are necessary to organise hippocampal circuits.

Amount: £1,097,310
Funder: The Wellcome Trust
Recipient: University College London

Lysosome turnover in health, aging and disease 17 Jul 2018

Lysosome dysfunction is implicated in lysosomal storage diseases, and multiple age-related neurodegenerative diseases, including Parkinson’s, Alzheimer’s and age-related macular disease. Lysosomes are signalling organelles central to maintaining cellular homeostasis. Nutrient sensing on the lysosome can lead to nuclear translocation of the transcription factor, TFEB, and lysosomal gene transcription. However, it remains unclear how newly synthesised lysosomal proteins are packaged into new lysosomes and how old/damaged lysosomes are cleared. We recently established models of lysosomal aging/dysfunction in retinal pigment epithelial cells, taking advantage of their huge degradative burden, and identified conditions that upregulate lysosome biogenesis/activity. We propose to identify the trafficking steps and molecular machinery underlying lysosome biogenesis and test the relative contributions of lysosome exocytosis and lysophagy (lysosome autophagy) to cellular clearance of aged/damaged lysosomes. Our ultimate goal is to exploit these mechanisms to promote damaged lysosome clearance or rejuvenation and/or promote lysosome biogenesis for the treatment of diseases where lysosome activity is compromised. Treatment efficacy in upregulating lysosome activity, whilst readily measurable in culture, is difficult to assess in vivo. We will establish a molecular signature of aged/damaged lysosomes in cultured RPE that can be used to identify damaged lysosomes in aged/diseased retinae.

Amount: £1,283,350
Funder: The Wellcome Trust
Recipient: University College London

Multi-spectral in vivo optical imaging system 05 Jul 2018

The use of bioluminescence reporting has revolutionized the imaging of small animals. Bioluminescence imaging (BLI) provides a robust technique, enabling researchers to gain essential insights into complex biological systems. BLI is used for the tracking of events in vivo, including the longitudinal monitoring of gene expression, tumour growth, enzyme activity, response to experimental drug therapies, and protein-protein interactions. The IVIS Spectrum is a state-of-the-art preclinical optical imaging system that allows for the sensitive detection of bioluminescence and fluorescence, providing a high-throughput platform for the functional whole-body molecular imaging across all organs in rodents. The equipment is simple to use, and the data obtained straightforward to analyse, making it ideal for multiple and non-expert users. The equipment has a vast range of applications across all biomedical disciplines, including the quantification of regenerative stem-cell and therapeutic immune-cell homing; monitoring bacterial infection; and following the development and treatment of tumours. Multispectral BLI can report on the location of multiple cells type or biological events. In vivo fluorescence imaging is capable of detecting targeted and activatable fluorescent probes and reporters against specific molecular processes, allowing in vivo assessment of angiogenesis, apoptosis and matrix remodelling. Cherenkov imaging of radioactive isotopes provides opportunities for radiotracer development.

Amount: £269,539
Funder: The Wellcome Trust
Recipient: University College London