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Recipients:
University College London

Results

A Two-day Conference on the Human Right to Health, Universal Health Coverage and Priority Setting. 27 Oct 2014

This grant would be used to fund a two-day conference exploring the various tensions between what the UN refers to as the progressive realisation of the human right to health, the international effort to secure universal health coverage and the inevitable need to set priorities between different treatments and services. The conference would bring together three research centres within UCL (the Institute of Global Health, the Institute of Global Governance and the Centre for Philosophy, Justi ce and Health) to hear new evidence from researchers, policy-makers and practitioners from both the UK and abroad. The conference would: i) explore existing policy drives towards HRH, universal health coverage and priority setting activities; ii) reflect upon conceptual and ethical tensions between such policies; and iii) assess the feasibility of solutions aimed at resolving this tension. The conference's main output would be a consensus statement, drawn up by Benedict Rumbold and circula ted to delegates before the meeting and discussed by attendees on Day Two of the conference itself, setting out the delegates thoughts on the next steps towards remedying the current conflict between HRH, the drive towards Universal Coverage and priority setting.

Amount: £4,760
Funder: The Wellcome Trust
Recipient: University College London

Functional neuromics of the cerebral cortex. 21 Jul 2015

Cortical circuits comprise multiple classes of neurons and glia, whose interactions govern perception, behaviour, and thought. We propose to combine several new techniques to probe this circuitry with unprecedented precision by identifying, monitoring, and controlling the participating cells. We will: 1. Provide a definitive taxonomy of cortical cell classes. By applying single-cell RNA sequencing to tens of thousands of neocortical and hippocampal cells, we will identify cell classes and su bclasses, together with marker genes that in combination identify them. 2. Understand the anatomical organization of these classes. By applying in situ transcriptomics to cortical tissue, we will understand the position of each class in the circuit, and determine the molecular identity of selected projection classes. 3. Understand how these classes participate in sensory processing and behaviour. We will record the activity of neurons and glia in the neocortex and hippocampus of behaving mice, then classify the recorded cells by retrospective in situ transcriptomics. 4. Identify causal interactions among cell classes in vivo. We will reveal the causal influence of molecularly identified cells on the network by stimulating them using 2-photon optogenetics, while recording population activity. These data will constrain mechanistic models of the underlying circuit.

Amount: £4,189,482
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

Biomedical Vacation Scholarship 22 Jun 2015

Not available

Amount: £19,750
Funder: The Wellcome Trust
Recipient: University College London

2 month costed extension 20 Jul 2015

Not available

Amount: £252,519
Funder: The Wellcome Trust
Recipient: University College London

Exploring the neurocomputational mechanisms of adaptive and pathological anxiety. 12 Jan 2015

At present the majority of people with anxiety fail to respond to their first treatment. Refining our understanding of the mechanisms underpinning anxiety, as well as the process by which adaptive anxiety becomes maladaptive is critical in order to improve diagnosis and treatment outcomes. To this end, the objective for this collaborative doctoral research project between UCL and the NIMH is to investigate the neurocomputational basis of adaptive and pathological anxiety. Specifically, what are the decision-making variables involved in adaptive and pathological anxiety and what are the underlying computations in the neural level?

Amount: £80,000
Funder: The Wellcome Trust
Recipient: University College London

Investigation into LRRK2 vesicular trafficking pathways to provide further insight into Parkinson's disease pathogenesis. 12 Jan 2015

How do Parkinson’s disease causing mutations in LRRK2 impact vesicular trafficking within the trans-golgi network (TGN)? In addition, what is the functional nature of LRRK2- arfaptin-2 and ARL6IP1 interactions within this pathway?

Amount: £80,000
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

Predicting language outcome and recovery after stroke (PLORAS) 04 Jun 2014

The main goal is to provide proof of principle for a clinically useful tool that will predict recovery of language abilities after stroke. There are three separate but interacting lines of research, to be conducted in parallel: (A) Using structural neuroimaging and behavioural assessments, we will identify lesion and non-lesion factors that are most likely, and least likely, to cause long term communication difficulties. The influence of the identified factors will be tracked over months and years following the stroke to understand how recovery unfolds over time. (B) Using functional neuroimaging and dynamic causal modelling, we will map the brain areas that are activated when the patient is speaking or comprehending speech. This will provide a mechanistic understanding of the language pathways that are able to support recovery after damage to the normal system. (C) We will develop an easy-to-use web-basedsystem that will provide patients, their carers and clinicians with the likely time course of recovery on the basis of probabilistic summaries ofother patients in our database who have corresponding brain damage according to the carefully constrained criteria developed in (A).

Amount: £156,004
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

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 neededto 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) Howdoes the structure of population responses change with cortical state? (4) Howdoes 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 thethe 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: £124,741
Funder: The Wellcome Trust
Recipient: University College London

Automatic anomaly detection for brain imaging triage and classification 24 Apr 2014

Modern brain imaging contains vastly more information than historical radiographs, yet its clinically informative output has remained the same: a radiologist’s verbal report. As the information content of imaging increases, a void has opened between what we expensively collect and what we actually use.This is both a lost opportunity, and an obstacle to the continued growth of brain imaging. Technology being developed by Dr Parashkev Nachev and colleagues at University College London seeks to close this gap by applying novel computer-assisted algorithms so as to exploit much more of the information in each scan than a verbal report contains. An automatic “anomaly map” for each scan, indexing the deviation from normality of each point, will assist radiological reporting, allow the application of computer systems that predict clinical outcomes from patterns of anomaly, and guide radiological triage and resource/performance management. The project aims to demonstrate the feasibility, robustness, clinical, and managerial value of the approach using a large collection of standard brain imaging, and to deliver a pilot system capable of translation into a full clinical product. Without changing any clinical pathways or adding new investigations, the system will improve radiological reporting and optimise radiological triage and management, while creating a scalable major new platform for computational imaging analysis.

Amount: £368,910
Funder: The Wellcome Trust
Recipient: University College London

Automatic anomaly detection for brain imaging triage and classification 15 Sep 2014

Modern brain imaging contains vastly more information than historical radiographs, yet its clinically informative output has remained the same: a radiologist’s verbal report. As the information content of imaging increases, a void has opened between what we expensively collect and what we actually use.This is both a lost opportunity, and an obstacle to the continued growth of brain imaging. Technology being developed by Dr Parashkev Nachev and colleagues at University College London seeks to close this gap by applying novel computer-assisted algorithms so as to exploit much more of the information in each scan than a verbal report contains. An automatic “anomaly map” for each scan, indexing the deviation from normality of each point, will assist radiological reporting, allow the application of computer systems that predict clinical outcomes from patterns of anomaly, and guide radiological triage and resource/performance management. The project aims to demonstrate the feasibility, robustness, clinical, and managerial value of the approach using a large collection of standard brain imaging, and to deliver a pilot system capable of translation into a full clinical product. Without changing any clinical pathways or adding new investigations, the system will improve radiological reporting and optimise radiological triage and management, while creating a scalable major new platform for computational imaging analysis.

Amount: £4,000
Funder: The Wellcome Trust
Recipient: University College London

Albumin to prevent infection in Acute-on-Chronic Liver Failure (ATTIRE) 28 Nov 2013

Liver disease is the 5th commonest cause of death in the UK and the only one of the top 10 currently rising. Approximately 110,000 patients with symptoms of advanced cirrhosis, (commonly related to alcohol excess) e.g. jaundice, confusion and bleeding from the stomach, were admitted to UK hospitals in 2011-12. The most common cause of death in these patients is infection. These patients have a weakened immune system making them highly vulnerable to infection and no effective strategy exists to improve this. A research group headed by Dr Alastair O'Brien at University College London discovered that the cause of this vulnerability is an increase in blood levels of a lipid hormone called Prostaglandin E2 (PGE2) which reduces white blood cell function, the cells that fight infection. They have discovered that their immune systems can be boosted for at least 24 hours by infusing albumin into a vein which reduces PGE/s effects. This safe process is currently given when patients need extra fluid e.g. those with kidney damage. They propose this new exciting use for albumin to be given daily to improve cirrhosis patients' immune systems and therefore prevent infection. They hope that this will save lives and reduce health-care costs and propose to investigate this in a large scale clinical trial.

Amount: £501,781
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

Functional characterisation of the role of PPP2R3B in malignant melanoma. 14 May 2014

The Fellow will be based at the UCL Institute of Child Health, and the CRUK London Research Institute. The key finding underpinning this project is the association of a novel germline copy number change of the gene PPP2R3B and melanocytic neoplasia. Key goals: 1. Full characterisation of the human germline genotype-melanoma disease phenotype associations of PPP2R3B copy number abnormalities, using two accurately-phenotyped cohorts 2. Elucidation of the molecular mechanism of oncogenesis induc ed by PPP2R3B copy number change in vitro. shRNA knock-down and over-expression of PPP2R3B in melanoma cell lines using lentiviral vector-mediated transfection will be compared to mock-transfected controls. Functional assays will include RT-PCR and immunoblotting for downstream targets of the MAPK, p53 and PI3K/Akt pathways, cell viability/apoptosis assays and cell cycle stage assays. Identification of potential therapeutic candidates from a targeted siRNA screen and testing of the FDA-approv ed PP2A activator FTY720. 3. Modelling of PPP2R3B copy number changes in animal models to document in vivo effects. Both murine and zebrafish knock-down and transgenic overexpression models will be made, with assessment of MM development and MAPK pathway functional analysis. Promising therapeutic candidates from the cellular model screens will be tested in the animal models.

Amount: £827,424
Funder: The Wellcome Trust
Recipient: University College London

Investigating the immune response to somatic corneal stem cell allografts 21 Nov 2013

This project will examine the interaction between tissue specific stem cells and the immune system using the eye as a model. This is a critical aspect of cellular therapy about which little is known. Two populations of corneal stem cells will be used, LESC and CSSC. The specific objectives are: 1. To determine the immunological characteristics of LESC and CSSC in terms of their ability to activate or suppress T cell mediated immune responses. This will be achieved by detailed phenotypic anal yses of the stem cell populations together with in vitro functional immunological assays. 2. To create a mouse model of LSCD in which LESC and CSSC allograft rejection can be studied. 3. To demonstrate the mechanisms of allograft rejection following LESC and CSSC transplantation in the mouse model. 4. To investigate whether the immunomodulatory properties of CSSC can confer improved cell survival onto LESC allografts when both cell types are co-transplanted. 5. To determine whether co-trans plantation of LESC and CSSC from different allogeneic donors is a viable therapeutic option or whether co-transplantation requires a common allogeneic donor for both cell types. The findings will guide immunosuppressive regimes and strategies in corneal cell therapy.

Amount: £828,795
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

Medicine Corner extension. 14 Jul 2014

Background: More than half of Mumbai's people live in vibrant localities described by the loaded word slum. A previous Wellcome Trust Award supported Dekha Undekha (Seen and Unseen), a project in which mentor artists and local participants worked together to create a multimedia installation. Held in Dharavi, the city's most well-known informal settlement, Ghari/Ghar pe/At homewas an exhibition about health framed within a virtual home. Big idea: A 33-month programme, the Dharavi Biennale builds on this success. We want to give emerging local artists the opportunity to consolidate their conceptual, practical and leadership skills, bring in new participants, engage more deeplywith health issues, and emphasize sustainability. A series of standalone activities (Artboxes) within the whole will involve about 200 participants. The overarching theme will be recycling: artworks will use recycled materials and will address the health effects of recycled behaviours. Plan: In Year 1, we will build skills and consensus and conduct specific art workshops. In Year2, we will plan and then mount the Dharavi Biennale, an event that brings together multimedia work in an exhibition, performances, screenings and site-specific installations. We estimate a direct audience of 3000. In Year 3, we will emphasize participant autonomy and sustainability. Subgrants over the project cycle will support emerging artists in developing their own activities.

Amount: £5,952
Funder: The Wellcome Trust
Recipient: University College London