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Award Year:
2015
Recipients:
University College London

Results

High altitude adaptation and pregnancy outcome study (HAPS): investigating the influence of hypoxia on birth weight 18 Sep 2015

A baby unable to grow to its full potential in the womb (intrauterine growth restriction, IUGR) results in low birth weight (LBW). Failure to adapt to a low-oxygen environment may impede placental growth and consequently, result in a LBW baby. LBW is especially common amongst newcomers to high altitude (HA) environments, however, populations with long HA residency are relatively protected, potentially through evolutionary selection of advantageous hypoxia related gene variants. Identification of such variants would implicate pathways involved in causing, or protecting from, IUGR. Researchers from the UK and India will collaborate to investigate this. We will recruit 300 pregnant women from a hospital situated at HA in Leh, India. Gene variants in the baby (the discovery cohort), associated with its birth weight, will be identified. We will then seek evidence of how these gene variants might affect growth: placental size and umbilical blood flow will be measured during pregnancy using ultrasound, and metabolic markers from the cord blood of newborn will be studied to see they are associated with significant gene variants. This work will inform further replication studies at HA and aid investigation of factors that play a role in causing IUGR/LBW at low altitude.

Amount: £90,255
Funder: The Wellcome Trust
Recipient: University College London

Profiling dementias using complex sound: from symptoms to brain networks 01 Apr 2015

What is the nature and brain basis of disordered complex sound processing in the commondementias, and can behavioural and brain correlates of cortical auditory processing be used todefine specific profiles of brain dysfunction with diagnostic and predictive value in these diseases?

Amount: £237,071
Funder: The Wellcome Trust
Recipient: University College London

How to promote positive physical activity behaviour in parents and their preschool-aged children: using cohort data to inform interventions. 13 Apr 2015

Physical activity is beneficial for adults and children alike, yet activity levels decrease throughout childhood into adulthood. Parents of preschool-aged children are at particularly high risk of insufficient activity, and their activity levels are associated with those of their young children. Low activity levels may therefore be detrimental to parents' and their child's health. Understanding what influences physical activity in these groups is important to determine who and what influences ch ange in activity, and when, to develop successful interventions to promote higher activity levels in preschoolers and their parents. This fellowship aims to establish determinants of change in activity in parents and their young children. First I will synthesize evidence of determinants and mechanisms of change from existing family-based interventions (phase 1). This will inform subsequent analyses of objectively measured physical activity data from UK and US cohort studies which aims to de termine: what individual, social and environmental factors are associated with change in activity in mothers (phase 2) and preschool-aged children (phase 3), and how maternal-child physical activity is associated over time (phase 4). This will provide important new information to aid development of population health interventions to positively impact the activity levels and subsequent health of families.

Amount: £250,000
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

A reappraisal of peripheral pain pathways 08 Dec 2015

Action potential propagation velocity provided a useful system for categorising peripheral nerves for 75 years. Now, genetic definition of sensory neuron subsets is providing a more precise functional distinction; individual sensory neurons and their target dorsal horn neurons can be activated, silenced or killed genetically and defined in terms of their transcriptomes, and linked to behavioural changes. In addition, physiological stimuli can be used to drive activity dependent reporters allowing further definition of neuronal subtypes. In this proposal, we show how the exploitation of these methods will inform our knowledge of peripheral pain pathways, the key element in almost all chronic pain syndromes, and identify cell types and molecular targets that are critical for distinct types of pain sensation. Our work will encompass human and animal genetics and should provide clinically significant information.

Amount: £3,631,275
Funder: The Wellcome Trust
Recipient: University College London

Mechanisms of glia-derived neurogenesis 05 Oct 2015

Classic forward genetic screens in C.elegans have revealed many evolutionarily conserved genes required to generate individual terminal neuron types. However, little attention has been paid to the molecular and cellular mechanisms that act early during embryogenesis to specify neuronal lineages. The overall goal of this research is to characterise these events. Surprisingly, one third of bilateral pairs of neurons in C. elegans derive from asymmetric lineage origins. I have identified a prone ural gene, hlh-14/achaete-scute that acts, along with other unknown factors to impose bilaterally symmetric neuronal differentiation on a pair of neuroblasts from asymmetric lineage origins. The first key goal of this project is to identify using reverse genetics, promoter analysis and laser ablation studies the cis-regulatory mechanisms and trans-acting factors that regulate early hlh-14 expression in C. elegans. The second key goal of this project, through a forward genetic screen, lineage ana lysis and second-generation sequencing based transcriptome analysis is to isolate novel factors that act to specify neuronal lineages and impose bilateral symmetry on the nervous system. This work will have broad implications for neural development in higher vertebrates and provide novel insights relevant to the prevention of human neurological disease.

Amount: £95,036
Funder: The Wellcome Trust
Recipient: University College London

Characterisation of cell types obtained from mixed cell cultures of the human olfactory mucosa, for the application of central nerve repair 23 Nov 2015

Spinal cord and root injuries are commonly due to road traffic accidents and can result in permanent paralysis with major physical, psychological and economic impacts. Although surgical repair of spinal root and cord injuries can restore some movement, patients seldom report good functional outcome. Olfactory ensheathing cells (OECs) are a promising cell candidate for nerve repair and can be obtained from the olfactory mucosa of the nose, where they normally induce repair of damaged olfactory nerve fibres for the sense of smell. They can be obtained by a simple biopsy of the olfactory mucosa using an endoscope. Through funding from the Health Innovation Challenge Fund, Mr David Choi and colleagues at UCL aim to better understand the cell quality attributes and final product formulation to ensure a robust, well-characterised cell product that is effective in laboratory assay systems and satisfies regulatory requirements. With this information the team can then proceed with production of cells for transplantation and plan to start a phase 1 clinical trial involving transplanting a patient's own OECs during the surgical repair of brachial plexus avulsion, within three years. Positive results would impact not only patients with brachial plexus injuries, but also patients with spinal cord injury or stroke.

Amount: £1,163,250
Funder: The Wellcome Trust
Recipient: University College London

Tuning spinal motoneurons for movement. 02 Dec 2015

My overall aim is to understand how neural circuits are organised in order to control motor behaviour. Furthermore, I aim to understand dysfunction of these circuits in disease or injury in order to form the foundation for strategies to improve motor function. My research programme includes neural circuit studies in mice and in humans. Here, I will focus on one key question: how are spinal motoneurons tuned in order to produce trains of action potentials of appropriate frequencies so as to achieve the muscle contraction required for a particular motor task? This application is based on the hypothesis that motoneurons learn these firing frequencies during development, and adjust their expression of potassium channels located at sites post-synaptic to C-boutons, large cholinergic terminals forming neuromodulatory synapses on motoneuronal somata. We will address three specific aims: Aim 1: to characterise the development of SK channels, motoneuron excitability, and C-boutons Aim 2: to determine the role of Kv2.1 channels in motoneuron excitability and and C-bouton physiology Aim 3: to establish whether homeostatic mechanisms determine motoneuron.

Amount: £2,512,185
Funder: The Wellcome Trust
Recipient: University College London

Avoiding on-target off-tumour toxicity in cancer immunotherapy. 19 Nov 2015

Chimeric antigen receptors link MHC-unrestricted antigen specificity with T-cell signalling, facilitating potent and regulatable antigen-specific cancer recognition and killing. Clinical trials of CAR gene modified T-cells show unprecedented clinical responses, with the major limitation of on-target off-tumour toxicity due to expression of most cancer antigens on some normal tissues. In my Wellcome clinical training fellowship I identified a novel method of avoiding such toxicity by designing CA Rs for use in gdT-cells. These gdT-CAR cells combine innate killing limited to sites of cancer or injury with CARs providing co-stimulation to overcome the immunoinhibitory tumour microenvironment. I demonstrated proof of concept using two model antigens, GD2 and CD33, applicable to solid cancers (e.g. neuroblastoma) and myeloid leukaemias (e.g. AML) respectively. In my fellowship I will develop this by: 1) Identifying mechanism and relative efficacy of different co-stimulatory CAR endodomains in gdT cells 2) Investigate selectivity of co-stimulatory CARs in gdT against acute myeloid leukaemia compared with healthy blood cells bearing the same tissue antigen. 3) Investigate the use of mass cytometry for high-dimensional signalling analysis to inform CAR design. Efficacy, toxicity and mechanism will be assessed in a staged manner using cell lines and primary tissue.

Amount: £275,672
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

Topical delivery of Ranibizumab for non-invasive treatment of retinal disease 16 Apr 2015

Age-related macular degeneration (AMD) is a major cause of blindness, affecting 30- 50 million people worldwide, with a rising incidence due to the rapidly increasing aging population. Current treatments, of which Ranibizumab is the most frequently prescribed, involve monthly injections into the eye to block a protein known as VEGF (vascular endothelial growth factor), responsible for new blood vessel formation. However, at £85 million/year in the UK, injections carry a high burden to the health system, requiring specialist-clinic administration. There is a clear, unmet need for anti-VEGF treatments therefore to be non-invasive, easy to administer and less expensive. Professor M Francesca Cordeiro and her team at UCL have developed a formulation that can be used to replace monthly hospital-administered intraocular anti-VEGF injections with daily self-administered eye-drops. This project aims to optimize the formulation for Ranibizumab, develop its manufacturing process, and assess its safety and tolerability to enable it to be tested in First-in-Man clinical trials. If successful, the Ranibizumab eye-drop will lead to widespread treatment programmes - potentially reducing the burden of AMD on the individual and society by changing the way treatment is delivered within five to seven years.

Amount: £1,666,193
Funder: The Wellcome Trust
Recipient: University College London

Image-guided neurosurgical treatment of epilepsy 16 Apr 2015

One third of individuals developing epilepsy are uncontrolled with medication. If epilepsy arises from one part of the brain, surgical removal of this area can be curative. This needs to be balanced by the risk of causing new deficits such as paralysis or impaired speech. Improved diagnostic methods, and surgical precision, will improve the benefit/risk ratio of epilepsy surgery, and increase treatment availability. At University College London, teams led by Professor John Duncan and Professor Sebastien Ourselin have developed software to visualise the whole range of 3D brain imaging, including normal architecture, abnormalities of structure and function, arteries, veins, critical brain areas and nerve pathways, and the skull. This increases the safety and precision of implantation of the electrodes necessary to pinpoint the brain tissue that needs to be removed to cure the epilepsy. This project aims to implement automated planning of electrode trajectories and robotic systems for placing the electrodes into the brain. It will also establish methods for automated 3D planning of neurosurgical resections, so that surgery is optimal and quicker. Consequently, curative neurosurgery will be available more quickly to more individuals. The surgical advances pioneered here will be applicable in future to other procedures, such as taking biopsies and tumour surgery.Note this is a HICF award but funded solely by the Trust as a Translation Fund project

Amount: £1,757,340
Funder: The Wellcome Trust
Recipient: University College London

Medicine Corner - costed extension 20 Apr 2015

This extension funding will cover the engagement by SNEHA of two consultants. One will assist with Dharavi Biennale activities as the project winds down. Both will work on Medicine Corner, the Wellcome Collection's programme of cultural activity exploring Indian medicine, health and wellbeing.

Amount: £6,300
Funder: The Wellcome Trust
Recipient: University College London

Histories of sickle cell anaemia, race and health in postcolonial Britain, c.1950-1995 . 12 May 2015

Following an extensive historiographical survey and archival research, I will complete an 80,000-100,000 word original thesis. This will be made up of an introduction, setting out historiographical and historical context and establishing my methodology and definitions, and five thematic chapters. The first chapter will deal with the genetic research undertaken on SCA by British scientists such as J B S Haldane and Antony Allison, examining the papers of these and others in UCL Special Collection s. The second chapter will examine the experience of SCA patients and activists as they lobbied the state and health service at archives from the Runnymede Trust and Black Cultural Archive, as well as oral history research. The third chapter will explore the activities and training healthcare professionals undertook to understand the disease, examining journal articles, training films and awareness programmes, held in archives such as the Wellcome Collection and LSHTM. The fourth chapter will ex amine government provision and policy for the treatment of SCA, investigating Commons debates in the Hansard, financial reports and policy development. A fifth chapter will place the disease in its context with the politicised issue of immigration. These strands will be drawn together with a substantive conclusion.

Amount: £90,020
Funder: The Wellcome Trust
Recipient: University College London

Studying the impact of alpha-synuclein mutations on mitochondrial dynamics and synaptic function in neurons. . 26 Feb 2015

Dysfunction of alpha-synuclein protein is the critical event in the pathogenesis of Parkinson's disease and a full understanding of the mechanisms of synuclein-triggered pathology is required to develop new treatments for this devastating condition. Evidence from cell and animal models suggests that disease-causing mutations in alpha-synuclein principally lead to dysfunction in two key cellular compartments: mitochondrial and synaptic. However, whether compromised synaptic energy supply or calci um buffering due to impaired mitochondrial dynamics and function underpins neuronal and synaptic Parkinson's pathology remains unclear. In this project I will investigate the impact of alpha synuclein mutations on mitochondrial fission/fusion and trafficking dynamics in axons and presynaptic terminals, and the relationship of these to synaptic function. This will be investigated using state-of-the-art imaging approaches in primary neurons from rodent models of alpha-synuclein dysfunction and in human neurons, differentiated from established Parkinson's patient-derived induced pluripotent stem (iPS) cell lines. Abnormalities detected in this survey will be studied mechanistically at the molecular level. These abnormalities will also form the basis of high-throughput screens of modifiers of mitochondrial dynamics in human and rodent neurons with wildtype or mutated alpha-synuclein, in order to identify potential novel therapeutic targets for Parkinson's disease.

Amount: £427,791
Funder: The Wellcome Trust
Recipient: University College London