- Total grants
- Total funders
- Total recipients
- Earliest award date
- 11 Jan 2016
- Latest award date
- 06 Dec 2016
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
My request for enhancement funding arises from the component of my existing award focused on developing T cell immunotherapy of hepatitis B and hepatocellular carcinoma using patient samples. We recently made important contributions to the testing of genetically redirected T cells for a first-in-man treatment of HBV-related hepatocellular carcinoma1. We are also collaborating with academic and pharmaceutical partners to develop immunotherapeutic vaccines aiming to boost antiviral T cells for hepatitis B control. However, these approaches remain limited by the profound exhaustion and other immune constraints imposed on T cells by high-level antigenic stimulation in the tolerogenic liver. Front-line candidates to revive T cells are checkpoint inhibitors such as PD-1 blockade. However, we have found that genetic knockdown of PD-1 can initiate detrimental effects in virus-specific T cells (Fig.1). The emerging concept that PD- 1 may actually be required to support long-term maintenance of T cells in the setting of persistent antigenic stimulation is underscored by recent work in murine models2, 3 and by our finding that liver-resident PD-1+T cells can remain highly functional (Pallett, in preparation). These discoveries underscore the need to investigate more fundamental drivers and mediators of T cell failure as alternatives or additions to checkpoint inhibition.
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.
CDK1 and APC/C are two key regulatory enzymes controlling the cell division, growth, differentiation and death, through phosphorylation and ubiquitylation, respectively. Although it has long been apparent that phosphorylation modifies APC/C function, the challenges posed by the need for functional assays to study this control puts the elucidation of the molecular basis of phosphorylation control beyond our grasp. We have recently overcome these limitations with a pipeline that uses reconstituted recombinant APC/C in Xenopus cell free extracts to show how CDK1 activates the APC/C through coordinated phosphorylation of Apc3 and Apc1. We will now extend this pipeline with targeted assays that will determine how phosphatases regulate these phosphorylation events. Because we have found that the disordered loop domains of APC/C subunits are targets for both post-translational modifications (PTMs) and interacting partners, including protein phosphatases, we will study how the loop domain controls the APC/C. Cell cycle specific and stress-dependent PTMs and binding proteins will be identified and we will determine their impact upon APC/C-dependent ubiquitylation. This approach of combining high throughput reconstitution mutated apo-APC/C in extracts from which any component of interest can be depleted offers a unique opportunity to gain an unprecedented insight into APC/C function and control.
At the interface between blood and tissues, vascular endothelial cells (ECs) provide signalling hubs for vascular adaptation to physiological needs. Quiescent ECs form a non-thrombotic surface that facilitates the exchange of gases, molecules and cells between blood and tissues, but they respond to hypoxia-induced signals with vascular expansion and regulate leukocyte extravasation in response to injury. Our unpublished observations indicate that the cell surface receptor neuropilin 1 (NRP1) relays signals from the extracellular environment to the endothelial nucleus to enable such context-dependent responses. Thus, we hypothesise that NRP1 integrates growth factor and extracellular matrix signalling with gene transcription programmes to balance EC behaviours that enable vascular growth and to prevent the senescent and proinflammatory endothelial phenotype common to many chronic diseases. To determine how vascular growth and homeostasis depend on NRP1-mediated pathways, we will investigate novel mechanisms by which NRP1 conveys signals for tissue vascularisation, protects ECs from premature senescence and regulates gene transcription for vascular growth and homeostasis. The knowledge gained will significantly advance our understanding of how extracellular signals are integrated with gene regulation to control EC behaviour, and will likely uncover pathways for therapeutic intervention in diseases with vascular dysfunction.
Behavior arises from the coordinated function of vast numbers of neurons across the brain. However, we lack answers to fundamental questions concerning this coordinated function. How is the activity of multiple brain areas globally structured? How does this global structure relate to the firing of local neuronal populations? And what is the role of this coordination in producing animal behavior? Until recently, these questions were barely answerable: one could only record from tens or hundreds of neurons, and during single behaviors. They are now answerable, thanks to new, powerful techniques available in the brain of the mouse: optical recordings of over 10,000 neurons simultaneously, optical and ultrasound measures of mesoscopic activity in multiple brain regions, next-generation electrode arrays that record thousands of neurons across multiple areas, and temporally targeted optogenetic manipulations. We will combine these techniques to understand how brain-wide neuronal populations operate in the mouse brain during different behavioral conditions: rest, passive sensory stimulation, locomotion, sensory discrimination, and goal-directed navigation. These data will provide an unprecedented view on the neuronal-level organization of populations across the brain during behavior.
The mechanisms of photoreceptor cell death 30 Nov 2016
Problems of protein homeostasis (proteostasis) that lead to protein misfolding, improper traffic and aggregation are associated with many forms of neurodegeneration. The neurodegeneration retinitis pigmentosa (RP) offers an excellent paradigm to study why proteostasis is critical for neuronal function and survival. Rhodopsin mutations cause dominant RP and disturb proteostasis, yet the underlying disease mechanisms and effective therapies remain elusive. I will exploit recent advances in gene editing technology and stem cell biology to produce new animal and patient derived models of the most common rhodopsin mutations in the UK. I will use these to address my key goals, i) to define any common disease mechanisms between the different classes of mutation, and ii) identify new therapeutic approaches for rhodopsin RP. I will use a combination of genetic and chemical manipulation of the major cell stress and degradation pathways, and identify the partner proteins of rhodopsin mutants using unbiased proteomic analyses. These complementary studies will be based on a series of interlinked hypotheses to determine how rhodopsin mutations disturb protein homeostasis and if this can be restored. The findings will have broader implications not only for other forms of retinal degeneration, but also neurodegenerative disease where proteostasis is disturbed.
The CTLA-4 pathway is a key immune regulator whose absence or mutation leads to profound autoimmunity. CTLA-4 and its relative CD28 have opposing inhibitory and stimulatory functions respectively and interact with two ligands CD80 and CD86. Despite the key role of this pathway in immune regulation and high profile therapies in tumour immunology, our understanding of how CTLA-4 functionally interacts with its two natural ligands is remarkably incomplete. The aim of this proposal is to generate a robust molecular, cellular and functional framework for CTLA-4 biology which can be used to understand the impact of disease mutations, which are being identified as a result of next generation sequencing programmes, and generate knowledge which can underpin new approaches to manipulation of this key immune axis. We will address three key aims: 1). What is the cellular machinery used by CTLA-4 to capture and transfer ligands between cells? 2). How do CTLA-4 interactions with its natural ligands influence its function? 3). How do clinically identified mutations inform our understanding of the CTLA-4 pathway?
The CUSSH programme will deliver strategically vital global research on the complex systemic connections between urban development and health. Based on transdisciplinary methods, it will develop critical evidence on how to achieve the far-reaching transformation of cities needed to address vital environmental imperatives for population and planetary health in the 21st century. Its core components include: a systematic review of evidence on potential solutions; the development and application of methods for tracking the progress of cities to towards sustainability and health goals; the development and application of models to assess the impact on population health, health inequalities, socio-economic development and environmental parameters of alternative urban development strategies to support policy decisions; iterative in-depth engagements with stakeholders in partner cities in low-, middle- and high-income settings, based on participatory methods, to test and deliver the implementation of the transformative changes needed to meet local and global health and sustainability objectives. Through these steps, the project will provide transferable evidence on how to accelerate actions essential to achieving population-level changes in such areas as energy provision, transport infrastructure, green infrastructure, water and sanitation, and housing. Associated public engagement and training, based on principles of co-generation of research, will be embedded throughout.
My aim is to develop a theoretical model of language processing that explains inter-patient variability in outcome after stroke. My hypotheses are that the same language task (e.g. describing a picture) can be sustained by different sets of brain regions (and neuronal pathways) and that inter-subject variability in neuronal pathways for the same language task reflect an individual’s inherent potential and prior experience. My investigations will (1) use functional neuroimaging to characterize inter-subject variability in neuronal pathways in a range of language tasks; (2) cluster healthy individuals and stroke patients into different groups according to the neural systems used for the same task; and (3) compare the identified groups on a multitude of demographic, behavioural and structural imaging measures. The results will identify the factors that distinguish which neuronal pathways a subject typically uses and which neural pathways are available to support recovery. The work will provide: (i) greater understanding of the neuronal pathways sustaining recovery; (ii) improved accuracy and precision in our prognoses for whether and when patients with aphasia will recover after stroke, and (iii) a new patient stratification system that can be used to design effective, individualised therapeutic interventions.
Challenges to the 'Mental Deficiency System': The National Association for Mental Health's role in Legislative Change and the Development of Community Care 1946-1967 15 Nov 2016
From its formation in 1946 the National Association for Mental Health (NAMH) was a key stakeholder in ‘mental deficiency’ services. It provided professional training, experimental hostels, and advice to the government and public. An examination of its activities is crucial to understanding post-war developments in services. However, academic commentaries commonly give NAMH little role. Instead they focus on three other stakeholders (Welshman and Walmsley 2006): The National Council for Civil Liberties (NCCL) attacked the workings of the Mental Deficiency Acts, psychologists showed patient’s abilities were higher than claimed, and the National Association for Parents of Backward Children (NAPBC – now Mencap) gradually influenced policy and practice. The recent opening of the MIND archive offers the first opportunity to develop a rigorous account of NAMH’s role, including its significant relationships with all of these groups. NAMH had a close relationship with NAPBC from its formation. Leading psychologists who critiqued mental deficiency services worked with NAMH. And all these groups engaged closely with NCCL’s campaigning. These groups were involved in two particular areas: legislative change and developing community care. This project’s key objective is to understand NAMH’s role in these areas in the context of its relationship to these other important stakeholders.
Minoritized Youth, addresses fundamental equity issues in informal STEM learning (SL+ priority D, Equity, diversity and access to informal learning settings). The major goal of our Partnership is for practitioners and researchers, working with minoritized youth, to develop new understandings of how and under what conditions minoritized youth participate in Informal STEM Learning (ISL) over time and across settings, and how they may connect these experiences towards pathways into STEM. We will: 1) Develop new understandings of ISL pathways that are equitable and transformative for minoritized youth; 2) Co-develop high leverage practices and tools that support these equitable and transformative ISL pathways (and the agency youth need to path-make); and 3) Strengthen and increase professional capacity to broaden participation among youth from minoritized communities in STEM through ISL. Our work is grounded in longitudinal youth participatory ethnographies, surveys, and design-based implementation research methodologies. Our major goal responds to three challenges at the intersections of ISL research and practice in the US/UK: 1) lack of shared understanding of how minoritized youth perceive and experience ISL opportunities across the US/UK, and the practices and tools needed to support empowered movement through ISL; 2) limited shared understanding and evidence of core high-leverage practices that support minoritized youth in progressing within and across ISL, and 3) limited understanding of how ISL might be equitable and transformative for minoritized youth seeking to develop their own pathways into STEM. We focus on minoritized youth, ages 11-14, for whom there are wide and persistent gaps in representation in STEM, and for whom STEM careers and pursuits remain elusive. The project will be carried out by RPPs in 4 cities: London & Bristol, UK and Lansing, MI & Portland, OR, US, involving university researchers (Kings College, University College London, Michigan State University, Oregon State University) practitioners in science museums (@Bristol Science Centre, Brent Lodge Park Animal Centre, Impressions 5, OMSI) and community-based centers (STEMettes, Knowle West Media Centre, Boys & Girls Clubs of Lansing, and Girls, Inc.).
Imaging and activation of glymphatic clearance: a novel strategy for Alzheimer’s Disease 26 Oct 2016
There is a critical need for early and accurate biomarkers of the pre-symptomatic phase of Alzheimer's disease (AD), to maximise the efficacy of emerging therapies. Recent evidence implicates cerebral glymphatic exchange as a key mechanism in early AD pathogenesis [Figure 1] [1-4]. I will develop the first non-invasive method for the quantitative assessment of glymphatic clearance, using MRI. These novel methods will be carefully validated by comparison with the invasive measures , that I have previously established, in normal, aged and AQP4 null mice. I will apply these novel techniques longitudinally to mouse models of ageing and AD (amyloid and tau) to investigate impairment of glymphatic clearance relative to more established markers of AD pathogenesis such as structural imaging, perfusion and histological assessment of plaque/tangle burden. As such, these data will be the first to elucidate the chronology of abnormal glymphatic clearance in AD pathogenesis. Finally, I will combine these methods with targeted optogenetics to assess the interaction of vessel tone and vasomotion to rates of glymphatic clearance in order to characterise the underlying mechanisms that drive CSF-ISF exchange.
Cellular and network mechanisms of hippocampal -prefrontal coordination during memory consolidation 09 Nov 2016
Consolidation of newly acquired memories takes place during sleep and involves the interaction of hippocampus and prefrontal cortex. The cellular mechanisms and synaptic pathways underlying this process are not fully understood but it has been hypothesized that synchronous hippocampal ripples and prefrontal cortex spindles mediate it. The present project proposes a multimodal approach to investigate these mechanisms in rodents. The first goal will be to dissect the fine-scale dynamics of memory reactivation in hippocampus and cortex during sleep after learning of a spatial memory task. This aim will be achieved with simultaneous large-scale recordings in both structures and advanced analysis of population activity. The second goal will be to unveil which anatomical regions and synaptic pathways are mediating this inter-regional synchronization. Simultaneous electrophysiological and functional magnetic resonance recordings will be performed in sleeping rats before and after the task and wide-brain activity will be assessed at times of high hippocampal-prefrontal synchrony. The last goal will be to causally verify the participation in inter-areal coordination and memory consolidation of the key synaptic pathway(s) pointed out in the previous stage. To achieve this, closed-loop optogenetic silencing of specific cellular populations would be performed at times of hippocampal-prefrontal synchrony during sleep memory consolidation.
Molecular Control of Adhesion-Free Migration 09 Nov 2016
Many cells have the capacity of directed motion, which is essential for several physiological and pathological processes, including development, immune-response, and metastasis. During canonical, focal adhesion-based migration, actin dynamics are converted to traction force through integrin-based anchors to the substrate. However, integrins are dispensable for in vivo and 3D-confined migration of various cell types. Recently, an alternative migration mode was discovered, during which propulsion forces are generated through non-specific friction between the cell cortex and its substrate. However, nothing is known about the molecular mechanism underlying friction-driven migration. I will elucidate this process, first by performing a candidate-based screen and state-of-the-art microfabrication assays to identify the molecules responsible for generating friction. Next, I will create knock-out zebrafish lines to determine the in vivo relevance of friction-driven migration. Finally, I will study how cells transition between adhesive and adhesion-free migration, which is crucial e.g. during cancer progression. To identify the key processes underlying these transitions, I will perform live cell microscopy of friction-generating and adhesion molecules and integrate my findings into a mathematical model of cell migration. Ultimately, this project will shed light on a newly uncovered migration mode that is likely of fundamental importance for in vivo cell motility.
The cerebellum is a core structure in sensorimotor integration, receiving converging sensory and motor input and sending output to premotor regions. It thus sits at an ideal place to determine mechanisms by which the brain transforms sensorimotor information into a code that controls behaviour. However, our understanding of how the cerebellar cortex encodes sensory inputs in the context of motor activity is far from established because most studies of sensory processing have been performed under anaesthesia when sensors are immobile. This proposed research aims to elucidate fundamental computations (i.e. neural codes) and underlying mechanisms (i.e. circuitry implementation) that govern information processing in cerebellar circuits during active sensing, both at the cellular and systems neuroscience level. What sensory and motor variables are represented in cerebellar circuits during active sensing? How sensory-motor signals are transformed within the cerebellar cortex? What neuronal mechanisms underlie sensorimotor integration in the cerebellum? I will take advantage of a well-defined sensorimotor model, the mouse whisker system, to tackle these key questions. By studying the neural basis of active sensing in the cerebellum, I hope to build an integrated model of the circuitry that incorporates a greater understanding of neuronal computations and mechanisms during behaviour.
The ultimate goal of modern neuroscience is to understand how brain activity generates behaviour. Thus far, mainly because of technical limitations, neuroscientists have been primarily focusing their research on how the activity of single neurons or small populations of neurons encodes the representation of either sensory stimuli or motor programs. However, given the current technological advancements allowing neural recording and manipulations across brain areas, it is now impelling to start tackling this crucial biological question: how do sensory representations trigger the selection and execution of appropriate motor programs? In my proposed project I aim to provide a mechanistic, cellular-level description of how larval zebrafish execute prey hunting routines in response to defined visual stimuli. Using a wide range of cutting-edge techniques, including simultaneous behavioural monitoring while performing calcium imaging/optogenetics, I will dissect the activity dynamics and circuit mechanisms of a key neural network hub in the anterior-ventral optic tectum capable of triggering the characteristic motor output of hunting behaviour. Crucially, I will reveal how this network hub is recruited by sensory neurons and how, in turn, this hub coordinates the activity of premotor neurons in multiple brain areas, therefore shedding new light on how the brain generates actions from perceptions.
Decades of research in collective decision-making show that the reliability of joint decisions is far from guaranteed raising the obvious question: why is collective decision making so popular in human interactions? I suggest an alternative to the quest for collective accuracy. I hypothesise that collective decisions are adaptive because (1) joint (vs. individual) decisions decrease the sense of responsibility for mistakes both at behavioural and neuronal level ; (2) individuals seek to diminish the chances of punishments through engaging in collective decisions; and (3) individuals are assigned more responsibility and punished more severely than groups. I predict that shared responsibility and punishment avoidance in group decisions modulate the same cognitive/neuronal mechanisms that underlie the sense of agency and norm-enforcement in individual behaviour. By empirically testing these predictions behaviourally and neurally (using Magnetoencephalography and Transcranial Magnetic Stimulation), I will characterize the function of collective decisions, and help clarify the utility of cooperation.
Wellcome Centre for Human Neuroimaging 30 Oct 2016
Our vision is to deliver clinically-transformative applications of neuroimaging that provide computationally-derived biomarkers for personalised prognosis and treatment planning. We investigate how the human brain functions in health and disease and how this knowledge can inform prognoses in patients with neurological and psychiatric disorders. By integrating cutting-edge neuroimaging technologies with neuronal and behavioural modelling, we seek to establish non-invasive quantitative measures of neuronal function that can be used to identify pathophysiology, deliver personalised prognoses, and develop or assess therapeutic interventions. Our strategy combines two key elements that are unique to our location, staff and facilities. First, we bring together internationally-renowned expertise in neuroimaging, biophysical modelling, cognitive, computational, mathematical and clinical neuroscience. Second, we create an environment that fosters interactions between those asking key neurobiological questions and those developing methods and theories that make these questions tractable. Our clinical focus reflects a long-standing commitment to developing neuroimaging methods that provide mechanistic explanations of how the human brain supports sensory, motor and cognitive functions in health, how these mechanisms are affected by disease, and how they respond to therapeutic interventions. We are in a unique position to conduct this work given our our location opposite the National Hospital for Neurology and Neurosurgery.
Image-guided Intervention (IGI) has enabled greater surgical precision resulting in reduced tissue trauma, co-morbidity, complications, and hospitalisation time. However, significant limitations arise from the challenging use of IGI systems, and their predominant reliance on preoperative anatomical images. Disrupting existing IGI, we will deliver pathologically, anatomically, and physiologically optimal surgery by combining diagnostic-quality imaging/sensing with ergonomic smart instruments. The Wellcome Trust Centre for Surgical and Interventional Sciences (WTC-SIS) will launch a new phase in which anatomical cues, which have driven interventional therapies for centuries, are augmented by physiological and pathological insight. Three fundamental research themes will link the WTC-SIS interdisciplinary groups: Physiological navigation, focusing on fusing anatomical, physiological and pathological information for real-time guidance/monitoring. Clinician experience, focusing on optimising the clinical team cognitive/ergonomic workload. Precision instrumentation, focusing on designing interventional devices that both sense physiological/pathological information and interact with tissue. WTC-SIS will serve as a hub-and-spoke translational catalyst for indication-specific externally-funded projects across surgical domains. A single unified Centre (hub) will provide all relevant skills and know-how, from scientific expertise to good manufacturing principles. This will drive rapid translation in our clinical satellites (spokes) and industry engagement through the development of a Health Technology Assessment programme.
Our aim is to reduce the huge burden of HIV and TB in KwaZulu-Natal as a precursor to the eradication of these diseases. This will be facilitated by merging the population based research excellence of the Wellcome Trust (WT)-funded Africa Centre (AC), with the cutting edge laboratory science and experimental medicine approaches of the Howard Hughes Medical Institute (HHMI)- funded KwaZulu-Natal Institute for Research in TB and HIV (K-RITH) to create an exciting, interdisciplinary South African based research initiative. Our 5-year vision is to use basic science, systems biology, health systems and social science research to undertake fundamental discoveries into the susceptibility, transmission and cure of HIV and TB. Our specific questions are: 1. How can new HIV infections best be eliminated? 2. How can TB transmission be interrupted and how can drug-resistance be contained? 3. How can the health of pregnant women with HIV and their offspring be improved? 4. How can we improve the health-system delivery and population-level impact of HIV treatment and other chronic disease care? 5. How is health and wellbeing affected by migration, economic and other inequalities