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Recipients:
University College London

Results

Patient and public involvement in priority setting: should we listen to the will of the people? 13 Jan 2016

Decision-makers tasked with allocating resources within health systems often face huge pressure about funding decisions from patients and the public, often described as lobbying. One question that we may want to settle is how far particular priority setting decisions are influenced by lobbying and lobbyists. However, we might also ask another, ethical question: namely, to what extent should priority setters respond to political pressure when making decisions about the allocation of health care resources? In this project, I aim to provide a detailed philosophical analysis of how far decision-makers ought to respond to attempts by patient and public interest groups to influence priority setting decisions through lobbying and other forms of political pressure. The project will use an ‘empirical ethics’ approach, combining both philosophical analysis and qualitative research. Overall, the research is intended to achieve two primary goals: 1) To give a robust ethical analysis of priority-setters moral obligations to respond to, or act upon, lobbying and other kinds of political pressure by patients and the public when making decisions about how to allocate health care resources. 2) To give concrete practical advice to such decision-makers on how they ought to respond to lobbying in the future.

Amount: £149,624
Funder: The Wellcome Trust
Recipient: University College London

Understanding and predicting prognosis for adults with depression 02 Mar 2016

Depression is the most burdensome disease world-wide in terms of years of life lost to disability. Approximately 90% of depressed patients receiving psychological therapies in the UK are treated in Improving Access to Psychological Therapies (IAPT) services. Treatment outcomes vary between and within IAPT services, with between 24-71% of patients recovering after treatment, a large proportion improve without fully recovering, but a sizeable number do not improve at all or deteriorate while receiving treatment. This project aims to develop an algorithm that can predict prognosis for patients referred to IAPT services with depression. This is important because we are unable to determine what outcome a depressed patient referred to any given IAPT service will have, or account for the variability in outcomes between IAPT services. Predictions of outcome can inform decisions on whether or not a patient should start therapy, particularly for those most likely to not improve or deteriorate during treatment; help commissioners plan for the costs of treatment therefore saving the health service money, and compare between services while accounting for area-level differences and differences in the characteristics of referred patients; and allow services to focus resources on those likely to improve with treatment, potentially improving outcomes.

Amount: £228,328
Funder: The Wellcome Trust
Recipient: University College London

Social disengagement as a marker of cognitive decline 26 Nov 2015

Social disengagement is a criterion for dementia diagnosis but its timing is unknown. I aim to examine if social disengagement is an early behavioural marker for subsequent cognitive decline. Objectives 1) Test my hypothesis that social disengagement predicts subsequent cognitive decline. 2) Determine whether individuals whose social engagement decreases over 10 years are at higher risk of subsequent cognitive decline over 10 years than those with stable but low social engagement. 3) Explore the role of possible effect modifiers. Method Prospective cohort study, using participants from the Whitehall II cohort, and validating results with the Longitudinal Aging Study Amsterdam. These cohorts collected repeated measures of social and cognitive function. I will test my primary hypothesis using growth mixture modelling to categorise the cohorts’ trajectories of social change into homogeneous subpopulations, and then compare the rate of subsequent cognitive change in these different groups, using multilevel linear models. I will incorporate possible confounders. Key goals This research will elucidate the longitudinal association between social networks and cognitive function, clarifying the causal direction. This may provide new avenues for dementia research by detecting early markers or modifiable risk factors for cognitive decline, revealing new targets for aetiological and interventional research.

Amount: £191,266
Funder: The Wellcome Trust
Recipient: University College London

Single cell decision making in development and dedifferentiation 05 Jul 2016

Our goal is to understand how cells make stochastic cell fate decisions in development and dedifferentiation. Understanding how individual cells make decisions has until recently been intractable, because gene expression has been measured from population averages. These averages mask the dynamics and differences between cells that define development or dedifferentiation in complex cell populations. Recently, we have pioneered approaches to visualize the transcription of individual genes in single, living cells. This means we can continually monitor the expression of cell fate regulators in single cells as they commit to fate decisions. We will now combine our imaging methods with molecular genetics, to test the hypothesis that stochastic cell fate choices in development are derived from heterogeneity in the expression of cell fate regulators. To determine how cells overcome the rate-limiting steps in dedifferentiation, we will use our technologies to dissect the gene expression dynamics required for successful reversal of the differentiated state. Overall our work will define the fundamental characteristics of the gene expression underlying stochastic fate choices in development, and provide new directions for developing safe, effective regenerative medicine.

Amount: £1,565,642
Funder: The Wellcome Trust
Recipient: University College London

Psychophysics of predictive motor control: a novel model of post-stroke fatigue 01 Jun 2016

Fatigue in neurological conditions, unlike exercise induced fatigue, is chronic, irreversible and does not arise from altered sensory afferent input from peripheral musculature. A distinctive feature of such fatigue is requirement of high effort for everyday activity. Normally, everyday activity feels relatively effortless. This is due to re-afferent sensory feedback from voluntary movement being attenuated under normal circumstances (sensory attenuation). I propose that neurological perceptual fatigue is a result of poor attenuation of re-afferent sensory feedback making even the simplest of movements feel effortful. Using a combination of behavioural and electroencephalography techniques, in a series of systematic experiments, I will study the interaction between self-reported fatigue, effort, behavioural and neural correlates of sensory attenuation. Furthermore, using brain stimulation techniques I will modulate sensory attenuation to determine the direction of causality between fatigue and neural processing. I will study chronic stroke survivors where post-stroke fatigue is a major problem. Fatigue is commonly seen as a neuropsychiatric symptom in neurological conditions and what I propose is a significant shift away from fatigue as a psychiatric problem and towards neurological fatigue being a sensorimotor disorder. The proposed project is also likely to identify a potential therapeutic target to develop interventions for neurological fatigue.

Amount: £905,754
Funder: The Wellcome Trust
Recipient: University College London

Resolving the functions of uncharacterised signalling proteins using zebrafish 19 Apr 2016

Signalling pathways orchestrate almost all aspects of development. The Schier lab has recently used ribosome profiling to identify numerous previously uncharacterised proteins that are expressed during early embryogenesis in zebrafish and might function as signalling molecules. One of the novel signalling proteins, previously annotated as a non-coding RNA, is Toddler (also called Apela or Elabela). Toddler signals via the APJ/Apelin receptor and promotes cell movement during gastrulation. The cellular and molecular roles of Toddler signalling are not known. My first aim as a Sir Henry Wellcome postdoctoral fellow will be to identify proteins that are regulated by Toddler signalling and reveal the cellular mechanisms that mediate the motogenic function of Toddler. My second aim is to employ a similar ribosome profiling approach to discover uncharacterised signalling molecules involved in the development of the nervous system. I will use genome engineering and take advantage of the complementary experience and expertise of the Schier and Wilson labs in behavioural and neuroanatomical studies to identify and analyse these signals. Their cellular and molecular functions will then be investigated. This project has the potential to discover signals with essential roles in neuronal migration, specification of neuronal identity and diversity, circuit formation and function.

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

Salt, Diet & Hypertension: An integrative in vivo physiological investigation of WNK pathway controlled renal electrolyte and blood pressure homeostasis. 11 Nov 2015

This project is designed to directly address a technique/technology gap that has prevented us from answering key biomedical questions in WNK controlled cardio-renal physiology. By modular combination of existing techniques/technologies the project puts forth a novel strategy to address the lack of direct, tubular segment-specific measurements of the renal physiology in vivo that may be integrated with other primary data. By the end of the project several outstanding biomedical questions in field of WNK biology and electrolyte homeostasis will have been directly addressed for the first time, and the first integrated map of distal convoluted tubular functional will have been produced. Key goals: 1) Develop an in vivo technique to simultaneously quantify renal tubule ion transport and intracellular chloride and pH by combining live imaging of GFP-based biosensor transgenic mice and micropuncture/perfusion techniques. 2) Integrate tubular ion transport functional readouts with bio chemical and morphological data obtained from microdissected tubule segments and whole tissue 3D fluorescent imaging using the CLARITY technique. 3) Validate the current model (Figure 2) used to explain the relationship between blood potassium levels, intracellular chloride, WNK/SPAK/NCC activity and blood pressure; reconcile the model with the paradoxes presented by Gordon and Gitelman syndrome.

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

Multisensory Integration in Time and Space. 11 Nov 2015

Although the majority of neuroscience research focuses on isolated sensory cues, in natural environments, the brain is invariably faced with a vast array of sensory stimuli. Animals must continually evaluate which of these multimodal cues should be associated with a single physical object, and which are separate. To this end, animals, including humans, take advantage of two types of correlation: spatial and temporal. Psychophysical studies of this phenomena are abundant, but neural recordings re main minimal and have been limited to specific brain areas like the superior colliculus and parietal cortex. In addition, past work has been focused on spatial correlations between multisensory cues, largely ignoring the effects of temporal correlations. I propose to characterize both the spatial and the temporal aspects of multisensory integration by exploiting advanced behavioral and recording techniques in the mouse cortex. I will 1) train mice to perform novel behavioral tasks which neces sitate multisensory integration, 2) identify cortical regions responding to audiovisual correlations in space and time using widefield imaging and two-photon microscopy during passive viewing, and 3) identify the neural correlates of multisensory integration using optogenetic perturbations and two-photon imaging during behavioral tasks.

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

Loss of GABAergic cells and night-time hyperactivity in zebrafish mutants of autism risk genes 01 Apr 2016

Night-time hyperactivity makes up part of the unique behavioural profile of autism spectrum disorder (ASDs). Recent studies on zebrafish revealed that loss-of-function mutations in autism risk genes (e.g. CNTNAP2) lead to a reduction in GABAergic neurons in the hypothalamus. GABAergic cells are sleep promoting and play an important role in the regulation of sleep-wake cycle. There are different subtypes of GABAergic cells, such as galanin-positive and MCH-positive neurons. In this project, we are going to investigate what subtypes of GABAergic cells are lost in autism mutants, using in situ hybridisation and basic microscopy. Significant difference in the amount of cells present in the wild-type and mutant will be expected.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University College London

Investigating the development of visual object perception from noisy images 01 Apr 2016

As we perceive the world, our brain continuously makes educated guesses about what we will see next. These inferences allow us to distinguish objects in our field of vision without having to examine every detail. This is known as the Bayesian model of visual perception. Recent evidence suggests that object recognition tasks for which such inferences are likely to be crucial may develop well into adolescence. There is anecdotal evidence that children find tasks such as identifying objects in poor lighting conditions or when borders are unclear (Bova, 2007) very difficult, even when they know exactly what the object they are looking for looks like (Yoon, 2007). This suggests that the robust object perception described in Bayesian models of the adult system takes surprisingly long to develop. This piece of research will test this hypothesis by (a) measuring children’s ability to recognize objects in a distorted ("noisy") image, and (b) testing how expectations about the objects (e.g. what it will look like) can improve perception. This aims to further our understanding of how the brain learns to use existing knowledge to interpret new sensory information, and make better inferences about the world.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University College London

Investigating the neural odometer function of entorhinal grid cells in rats navigating a multi-planar environment. 01 Apr 2016

It has been proposed that the grid cell system in the medial entorhinal cortex acts as a ‘neural odometer’, encoding both distance travelled and an animal's position in space. These features may be necessary for spatial computations such as path integration, but the relationship of grid cell firing patterns to behaviour remains speculative. In not-yet-published work, it has been shown that for a rat climbing a wall with its body plane aligned vertically the grid fields are expanded, as if the cells underestimate distance travelled. If grid cells support spatial computations then rats should also underestimate distances in this plane. To test this hypothesis rats will learn a distance match-to-sample task leading to triangle completion while both sample and choice phases are in the same plane (both horizontal or both vertical). In probe trials, the sample will be horizontal but the choice vertical. Distance underestimation in the probe trials (walking too far on the vertical wall to achieve a match to the horizontal sample) will link grid cells to behaviour, while the basic distance-matching task will serve as a springboard for neurobiological studies investigating the role of grid cells in odometry generally.

Amount: £2,000
Funder: The Wellcome Trust
Recipient: University College London

AMARI: African Mental Health Research Initiative 05 May 2015

Mental, neurological and substance use (MNS) disorders are a leading, but neglected, cause of morbidity and mortality in sub-Saharan Africa [1]. MNS disorders account for >25% of all years lived with disability globally, more than cardiac disease or cancer [2]. The treatment gap is vast, only 10% of people with MNS disorders in low-income countries access evidence-based treatments, compared to 33% in high-income countries [3]. Reasons for this include low awareness ofthe burden of MNS disorders and limited evidence to support development, adaptation and implementation of effective and feasible treatments. While pockets of mental health research excellence exist in Africa, MNS research capacity is generally limited, particularly in mental health intervention, service and system research. Mental health research excellence is currently undermined by restricted opportunities for training and mentorship, unclear career pathways, lack of integration in general medical settings, limited multi-disciplinary collaboration and the lack of a critical mass of MNS researchers and leaders. The overall goals of the African Mental Health Research Initiative (AMARI) areto build an African-led network of MNS researchers in Ethiopia, Malawi, South Africa and Zimbabwe, equipped to lead high quality mental health research programmes that meet the needs of their countries, and to establish a sustainable career pipeline for these researchers with the emphasis on integrating MNS research into existing programmes such as HIV/AIDS, maternal and child health. The objectives are to: 1. Select and train MNS research fellows from a range of disciplines at masters (n=25), PhD (n=20) and post-doctoral (n=6) levels in research excellence; 2. Build leadership skills of 26 fellows through adaptation of KCL Career Development Series on Leadership, Management and Mentoring; 3. Design and test an advocacy and systems change strategy for each country, aimed at building sustainable career pathways in MNS academia; 4. Develop a web-based support platform for training, supervision and networking. In year 1 we will undertake preparatory work to inform course development, thedesign of the advocacy and systems change strategy and gather baseline data for each country, for evaluation purposes, conducting qualitative and quantitative interviews with local policymakers and service users to identify needs and priorities through a theory of change map. We willtrain local supervisors, run pre-application workshops for potential applicants and assess existing training materials. . In years 2-5, fellows will begin higher degrees and courses as relevant. Trainingwill be mostly in Africa and using a) joint supervision by local and external supervisors with multidisciplinary expertise, b) taught modules in advanced MNS research methods, writing, and engagement with policy makers, and c) undertaking high priority MNS research. The underlying ethos of AMARI will be to ensure LMIC partner capacity is strengthened progressively towards self-sufficiency to ensure sustainability longer term. AMARI will be led by University of Zimbabwe College of Health Sciences (UZ-CHS). All consortium institutions will provide course facilitators and supervisors, with the Centrefor Global Mental Health (CGMH), University of Cape Town (UCT) and University College London (UCL) providing external supervision, research experts and materials for adaptation.

Amount: £49,068
Funder: The Wellcome Trust
Recipient: University College London

Non Invasive Prenatal Testing: A Comparative International Conference. 20 Jul 2015

This 3-day workshop will bring together 23 multi-disciplinary international researchers and health care professionals to explore the ethical, legal, and social implications of the global expansion of non-invasive prenatal testing (NIPT) with an emphasis on including non-Western and low and middle income countries (LMIC). NIPT is a relatively new prenatal screening technology that became available commercially in China in 2010[1], the US in 2011[2], and Europe in 2012[3]. It is now available vari ably across the globe. NIPT analyzes cell free DNA circulating in maternal blood to provide information about the risk of selected conditions (such as Down syndrome) earlier in pregnancy and without the procedural risk to the fetus of standard invasive methods[4]. NIPT is rapidly diffusing to LMIC and non-Western nations including India, South America, the Middle East[5], and some African nations[6]. Very little is known about the implementation of NIPT internationally or its ethical implication s in varied national and cultural contexts--a critical gap this conference addresses. Conference papers will form the basis of a special journal issue reflecting key findings. The workshop will be hosted by the Brocher Foundation (Geneva). This application requests supplemental travel funds specifically for researchers from non-Western and LMIC countries.

Amount: £10,000
Funder: The Wellcome Trust
Recipient: University College London

Development of TIPS microspheres for the treatment of fistulas 15 Dec 2014

Perianal fistulas are abnormal channels formed between the anal canal and the skin surface. Existing treatments to close these channels typically involve medical and surgical approaches, however both have limitations. Medical agents are usually delivered systematically, but this may predispose the patient to severe infection and autoimmune reactions. Surgery using existing anal fistula plugs is successful in the treatment of simple fistulas but is associated with a high failure rate in more complex fistulas and in patients with Crohn’s disease. Dr Richard Day from University College London has received a Translation Award to develop a potential solution to this problem. He and his team have developed microspheres that, when packed into a fistula, provide a ’scaffold’ that cells can grow between and into. As the microspheres dissolve, they are replaced by new tissue to heal the fistula. With this award, Dr Day and his team aim to demonstrate that the microspheres are safe when implanted into perianal fistulas in humans.

Amount: £91,754
Funder: The Wellcome Trust
Recipient: University College London

Soft Robotic Total Larynx Replacement 27 Jan 2015

The technology to be developed combines novel soft robotics with proven biocompatible materials and electromyography to produce a synthetic total larynx replacement. T radWonal robotic approaches that utilise rigid material are not sufted for long term integration in the larynx due to insufficient replication of the natural musculature and physiology and the requirement for multi-component designs that increase infection risks. By exploiting advances in soft robotics, which utilises flexible and elastic intelligent materials to morph compliant structures into complex shapes, we bypass the difficultiesencountered with traditional, hard, robotics. This enables the manufacture of a monolithic synthetic larynx, made biocompatible through combination with a clinically proven airway implantable synthetic polymer. The device is controlled by electromyography of the strap muscles and muscles of the floor of the mouth, which can be preserved in laryngectomy, to infer when the patient is speaking or swallowing. The implanted device will robustly replicate the core functionality of the larynx (aspiration prevention, respiration and phonation) with a failsafe modality.

Amount: £1,395,353
Funder: The Wellcome Trust
Recipient: University College London

FunVar: Impacts of Genetic Variations on Protein Functions and Functional Pathways. 25 Jun 2014

We will maintain and extend our integrated resources by developing new computational platforms. FunVar will analyse the impacts of genetic variants on the structures/functions of proteins and the networks in which they participate. DISASTR will exploit FunVar to provide web-based reports of impacts for all known, human, disease-associated variants. This will require development and further integration of our resources CATH-Gene3D (Orengo group), a unique, internationally renowned domain stru cture classification, with the functional resources of the Thornton group. CATH-Gene3D classifies ~30 million protein sequences into evolutionary superfamilies and provides information on functions (eg GO). It also describes biological roles by reporting protein interactions/networks. Functional resources in the Thornton group provide complementary data eg protein-ligand interactions (PDBsum) and catalytic residues (CSA). We will provide a unique perspective by focusing on domain structu re and accurately considering the functional role of the domain in its biological context eg complexes/networks. Our resources are unique in classifying domains into functional families. DISASTR will be a new and unique catalogue reporting structural/functional impacts for publicly available genetic variations linked to classified diseases. We will also establish a FunVar webserver for clinicians/biomedical researchers to learn the impacts of novel variants.

Amount: £536,722
Funder: The Wellcome Trust
Recipient: University College London

Neuronal integration in sensory cortex: New paths to discovery. 04 Apr 2014

The cortex is known to process images and sounds through the activity of neurons in visual and auditory areas. However, little is known about how cortical populations integrate multiple sensory streams and modalities into coherent pattern, and how sensory-driven activity interacts with non-sensory, endogenous patterns of activity. These patterns may provide the context needed to interpret sensory signals and act upon them. We seek a unified view of how the cortex integrates multiple external and endogenous signals into the activity of neuronal populations. To this end, we will address a series of related questions within a common experimental framework: (1) What is the structure of population activity in sensory areas of the awake cortex? (2) What are the rules of interaction of multiple signals in awake cortex? (3) How does the structure of population responses change with cortical state? (4) How does cortical population activity relate to sensory-driven behavior? (5) What mechanisms control brain state and the structure of population activity? By answering these questions we seek to uncover fundamental laws that predict the population activity from sensory input and internal state, and that predict perceptual choice from population activity, and to provide insight into the underlying circuits and mechanisms.

Amount: £160,000
Funder: The Wellcome Trust
Recipient: University College London

Institutional Strategic Support Fund 2013/14 14 Oct 2013

We were successful in renewing our WTISSF, which provides £3million over the next two years and will cover five key areas: Investment in excellent researchers Investment in infrastructure Translational research Cross and interdisciplinary research Public engagement. The remit of the renewal is more focussed than it was previously. It now concentrates on supporting activities that align with the strategic priorities of the UCL School of Life and Medical Sciences (SLMS) and the four faculties. The next call will be seeking applications in the following three areas, with approximately £800,000 of WTISSF funding available: 1) Neuroscience - funding can be requested to support the following activities: Planned staff recruitment; contribution to the recruitment of senior staff, or exceptionally bridging funds for key personnel. Please note that for bridging funds it is essential to detail the added value of the bridging funds and how the post funded will be supported in the future. Planned equipment purchase of specific items of equipment, or a contribution to the cost. Collaborative interdisciplinary projects and networking activities; funding to support new collaborative research projects or networking activities. 2) Informatics - funding can be requested to support the following activity: Planned staff recruitment; to develop capacity in people (researchers or technical staff) with expertise in computational biology, health informatics, large datasets or developing new analytical techniques. 3) Imaging - funding can be requested to take advantage of our capital investment in imaging to develop these technologies: Pump-priming research projects. Planned recruitment of technical support staff.

Amount: £1,500,000
Funder: The Wellcome Trust
Recipient: University College London

Anaplastic lymphoma kinase-targeted immunotherapy strategies as treatment for neuroblastoma 21 Nov 2013

Chimeric antigen receptors (CARs) consist of the antigen recognizing domain of an antibody linked to intracellular portions of T-cell signalling receptors. Adoptive immunotherapy with T-cells engineered to express CARs has shown promise in a phase I study in neuroblastoma and recently has led to unprecedented responses in patients with chemotherapy resistant leukaemias. Our CAR strategies in neuroblastoma to date have focussed on disialoganglioside GD2. We aim to broaden this approach to anapl astic lymphoma kinase (ALK), a tyrosine kinase present on the majority of neuroblastomas while largely absent from normal tissue. Aim of this fellowship is to develop an ALK-targeting CAR strategy against neuroblastoma. I will generate ALK-binders using a hybrid vaccination/phage display strategy. With these I will perform extensive target validation of ALK. I will identify a binder which results in the optimal CAR recognizing ALK on neuroblastoma. Next, I will explore combining this anti-ALK C AR with small molecule ALK-inhibitors as these may increase ALK surface expression. Further, I will explore restricting CAR-activity to cells expressing both GD2 and ALK; as presence of these antigens in normal tissue appears distinct this may avoid on-target off-tumour toxicity. I intend to lead this work onto a phase I study of ALK-based CAR-therapy.

Amount: £796,544
Funder: The Wellcome Trust
Recipient: University College London

Exploring the Group Mind with Mass Participation Experiments. 08 Jul 2014

Our goal is to provoke and engage the audience with a simple, compelling question: What is more fundamental to being human: the I of an individual person, or the we of a group, family or society? Scientifically, there are two ways to understand human behaviour. On the one hand, psychological models focus on the individuals thoughts and beliefs. On the other hand, sociological and biological models often understand human collective behaviour in the same way as they model insects and herds. Which of these approaches gives a better insight into how we vote in elections, riot on the streets, experience a concert, or support a football team? In our public engagement events, audience members will explore these issues by taking part in unique mass participation experiments. By downloading a simple application to their phones, they will be able to connect to a screen at the front of the theatre, museum or festival space. Together they will play video games, make music, resolve disagreements and take difficult decisions. Will people perform better when they compete against each other as individuals, or when they cooperate together as a group? How does it change our feelings about ourselves and each other to act with or against the groups interests? At the end of each event, the audience members will have a new appreciation of the science behind collective behaviour, and understand the conditions under which we act better as individuals, and the times we are stronger as a group.

Amount: £29,600
Funder: The Wellcome Trust
Recipient: University College London