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Recipients:
University College London

Results

Optimisation of carrier materials for the delivery of olfactory ensheathing cells in spinal cord injury 27 Apr 2017

Transplant-mediated repair is a promising method in spinal cord injury (SCI) treatment. This involves transplanting therapeutic cells that promote nerve regeneration at the site of injury. For SCI, one promising therapeutic cell type is olfactory ensheathing cells (OECs). These have been shown to remyelinate demyelinated axons and promote new synapses following injury. They are also easily accessible clinically via trans-nasal endoscopic biopsy, and compelling pre-clinical evidence means that they are now close to being formally tested as part of a first-in-man clinical trial. However, currently these cells are delivered as a simple cell suspension, and this is unlikely to be optimal for creating a permissive and optimised repair environment. Thus, the objective of this project will be to develop and engineer optimised biomaterial scaffolds for OEC delivery. In doing so, it is hoped that a permissive 3D extracellular environment can be created, and the phenotype and behaviour of OECs optimised for spinal cord repair. Promising prospective biomaterials include fibrin, collagen and collagen-fibrin blends. To this end, we will investigate the effect of these promising carrier materials on OEC survival and phenotype, particularly with a focus on changes they may cause on 3D cell morphology.

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

Up and down regulation of MafB gene in the developing chick hindbrain. 27 Apr 2017

The project's aim is to up and down regulate MafB gene, that is expressed in the Nucleus Laminaris (NL) and Nucleus Angularis (NA), in the developing chick hindbrain and ask questions about: 1) formation of nucleus Laminaris and nucleus Angularis in the dorsal hindbrain; 2) other effects on hindbrain development e.g interfering with fgf8 molecule expression, which in turn would affect the development of the cranial motor nerves VI, VII and nVIa. Such experimental techniques as in ovo electroporation, immunofluorescence and in situ hybridization will be used to look at the genes expressed in the auditory brainstem. The in ovo electroporation constructs used will overexpress MafB and also express a dominant negative version of MafB and immunofluoresce analysis will be carried out to test whether the electroporation was successful. The in situ hybridization analysis will be performed to establish the effect of MafB on the expression of such genes like FGF8, Pou6F2, N-cadherin, gamma catenin, cadherin-13 and cadherin-22 in the hindbrain. These techniques would also allow the analysis of the formation of the nucleus Laminaris in the developing hindbrain.

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

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.

Amount: £10,936,087
Funder: The Wellcome Trust
Recipient: University College London

Africa Health Research Institute (GBP record) 6 month partial award 30 Jun 2016

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

Amount: £472,230
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

TREAT-HD: targeting neurodegeneration in Huntington's disease 08 Dec 2015

Despite their immense public health burden, and after considerable investment in therapeutics research, the pathobiology of neurodegenerative diseases remains poorly understood and we lack treatments to prevent or slow their progression. Our vision is to provide a step-change in the understanding of mechanisms underlying neurodegeneration – and recovery – using Huntington’s Disease (HD) as a model. Our three key goals are to: further understanding of HD neuropathology and its response to gene-silencing treatment. We will exploit a unique opportunity to link with the first human trial of an antisense oligonucleotide (ASO) to reduce levels of huntingtin protein. develop a new generation of ASO treatments by targeting levels of the highly pathogenic exon 1 mutant huntingtin protein. determine the earliest potential time window for therapeutic intervention. We will study a novel cohort of young adult HD gene-carriers decades before expected symptom onset to characterise the earliest signs of disease-related brain changes and identify early functional impairment. By examining this model disease in patients, we will gain understanding of general pathological processes shared across protein-misfolding neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Consequently, this work has fundamental implications for the development of treatment strategies beyond HD to more prevalent neurodegenerative diseases.

Amount: £275,628
Funder: The Wellcome Trust
Recipient: University College London

The Countdown to 2030: Global Health and Climate Action 30 Sep 2016

Climate change threatens to undermine the foundations of human wellbeing, and to reverse the last five decades of gains in global health. The 2015 Lancet Commission on Health and Climate Change concludes that the barriers to tackling climate change and improving public health are no longer economic or technological, but largely political. The report also concludes that "tackling climate change could be the greatest global health opportunity of the 21st century", with reduced greenhouse gas emissions yielding substantial health (and economic) gains. The Commission is an institutional collaboration between European and Chinese academic centres, led by University College London, Tsinghua University (Beijing), the University of Exeter, and Sweden’s Stockholm Resilience Centre and Umea University. It published its work on the 23rd of June, 2015 in The Lancet, with 11 launch events around the world. The authors of the Commission report recognise the need to carry their work forward- and to help deliver the required change. They propose a "Countdown to 2030: Global Health and Climate Action" as a mechanism for tracking progress on the implementation of policies designed to respond to climate change and protect public health. This idea draws upon the success of the Countdown to Child Survival, which galvanised evidence, interest and action to improve progress on child mortality over the past decade. The Countdown will exist as an independent, international, and multi-disciplinary coalition of organizations. The combined networks of The Lancet and the partner institutions will be utilized to ensure global reach to academics, policymakers, and the health community. It will produce an annual synthesis report on (i) the health impacts of climate change; (ii) progress in mitigation policies and the extent to which they protect and promote public health; (iii) progress with broader adaptation action to reduce population vulnerability, to build climate resilience, and to implement low carbon, sustainable health systems. The Countdown will continue its collaboration with The Lancet, who commit to publishing these Countdown Reports, as well as a number of related country- or issue-specific articles throughout each year.

Amount: £499,186
Funder: The Wellcome Trust
Recipient: University College London

Created Out of Mind: Shaping perceptions of dementia through art and science 07 Mar 2016

Created Out of Mind will shape public and professional perceptions of dementia through a dynamic fusion of scientific and creative experimentation. Our Hub residency will support the active connection and collaboration of previously disparate cultures (scientists, artists, commissioners/policymakers) and infuse the insights and skills of people living with dementia, communications professionals and collaboration experts. Common (mis-)conceptions of dementia will be challenged through integrated artistic and scientific investigation of less recognised symptoms associated with typical and rare dementias. The project will investigate the neuroscientific, artistic and social bases of artistic engagement, enjoyment and change across multiple art forms. Interdisciplinary discussion, disagreement and creativity will also challenge and develop thinking regarding the principles, priorities, practice, health benefits and methodologically-robust evaluation of arts in dementia. Our inspiration comes directly from the intriguing experiences, heart-rending questions and puzzling uncertainties of people living with dementia. Team members will become creative collaborators whilst maintaining their professional ‘essence’, yielding a richly and meaningfully interconnected network of multi-skilled science/arts researchers, practitioners and communicators. We will also enrich understanding about dementia by raising provocative questions about the healthy brain, our emotional reactions to change in ourselves and others, and the attributes by which we value and define humanity.

Amount: £715,199
Funder: The Wellcome Trust
Recipient: University College London

Metabolic stratification of breast cancer for personalised chemotherapy 01 Sep 2016

Breast cancer is a common term describing several subtypes of the disease, each of which requires specific treatments in order to achieve the maximum response. Previous research by G. Szabadkai’s team indicated that cancer subtypes diverge due to distinct adaptation mechanisms mediated by the mitochondrion, a subcellular organelle. Mitochondria are responsible for providing energy to the cell under normal conditions, but cancer cells hijack this essential component and use it to grow uncontrollably. In this project the team will explore how mitochondria behave in different cancer types, and will categorise cancers according to the genes which govern their behavior in order to inform on their sensitivity to treatment. G. Szabadkai and K. Bryson have devised a mathematical way to quantify mitochondrial gene expression (mGEP) which is the basis of the new classification. To show that this classification has important functional consequences, they will test human tumour samples using methods to evaluate the metabolism of tumours belonging to different genetic subtypes in collaboration with R. Stein and M. Yuneva. Ultimately, the team will evaluate how mGEP and the associated metabolic profile can inform on the sensitivity of tumours to treatment, which will help future efforts to develop a novel diagnostic tool to prevent overtreatment of the disease.

Amount: £154,369
Funder: The Wellcome Trust
Recipient: University College London

A drug target for common ocular inflammatory diseases 13 Jan 2016

Epithelia form cellular barriers such as the corneal epithelium, protecting the eye’s surface, and the retinal pigment epithelium (RPE), a barrier between the blood and the retina. Epithelial defects are major components of common diseases, such as inflammation, infections, diabetes and age-related conditions. Professors Maria Balda and Karl Matter, UCL Institute of Ophthalmology, have developed inhibitors targeting a central regulator of a mechanism activated in such diseases to prevent epithelial and endothelial inflammation, malfunction, and loss of or reduced vision. These pathological conditions are integral components of chronic inflammation and ageing; hence, they become increasingly more common. There are few treatments available and they are not very effective. Therefore, their project addresses an unmet, clinically relevant healthcare need and will potentially benefit a wide range of patients suffering of inflammatory and age-related conditions that become increasingly more common. Balda and Matter research programme thus has a high future potential healthcare impact and directly supports the strategic aim of Moorfields Eye Hospital and the Institute of Ophthalmology to develop new therapies with High-Patient-Impact. (172 word)

Amount: £143,976
Funder: The Wellcome Trust
Recipient: University College London
Amount: £14,500
Funder: The Wellcome Trust
Recipient: University College London

UCL - Neuroscience 30 Sep 2016

Not available

Amount: £133,252
Funder: The Wellcome Trust
Recipient: University College London

Allosteric modulators of nicotine acetylcholine receptors 30 Sep 2016

Nicotinic acetylcholine receptors (nAChRs) are major excitatory neurotransmitters and have been implicated in a number of neurological and psychiatric disorders. The primary aim of the project will be to combine synthetic organic chemistry and pharmacological techniques to examine allosteric modulation of nAChRs. This will build upon recent work in the Sheppard and Millar labs at UCL and will also exploit a refined homology model of the a7 nAChR that was generated as part of a rotation project during the first year of this PhD studentship. It is anticipated that the generation of novel compounds, combined with computer docking studies and molecular pharmacological techniques, will enable a greater insight to be gained into the mechanism of action of nAChR allosteric modulators.

Amount: £2,529
Funder: The Wellcome Trust
Recipient: University College London

The role of the blood nerve barrier in peripheral neuropathies. 30 Sep 2016

The nervous system in maintained in a protective environment by a specialised vasculature. In contrast to the Blood Brain Barrier (BBB), the Blood Nerve Barrier (BNB) is poorly characterised despite having an important role in protecting peripheral nerves and its disruption being associated with neuropathies associated with pathologies such as diabetes and cancer. We have initiated a characterisation of the BNB in the sciatic nerve and have found that it is distinct from the BBB both in its permeability and cellular make-up. Moreover, we have developed a unique transgenic mouse in which ERK signalling in Schwann cells (SCs) in the nerve can reversibly open the barrier, which mimics the normal injury response. This provides a powerful model system for studying in a temporal manner how the BNB can be broken down and reformed. The aims of this proposal are threefold. 1. To characterise the nature of the BNB throughout the PNS and correlate differences with structural changes 2. To determine the role of SC-secreted Semaphorin 3A in the regulation of the BNB. 3. To analyse the expression and role of BBB transporters in the BNB.

Amount: £34,680
Funder: The Wellcome Trust
Recipient: University College London

Unravelling the molecular complexity behind ocular maldevelopment 06 Dec 2016

Aim: Investigating the relationship between genotype, gene expression and phenotype of microphthalmia, anophthalmia and ocular coloboma (MAC), which collectively causes one-third of life-long blindness and severe visual impairment in children worldwide. Research questions: What are the pathogenic variants underlying MAC? How do molecular subtypes correlate with phenotype and stratify clinical risk? What molecular pathways are involved in human eye development? What is the relationship between genotype and gene expression in microphthalmia? Key goals and methodology: Whole genome sequencing of 30 parent-offspring trios with isolated MAC and longitudinal phenotyping. Establish an international reference network to stratify a well-defined cohort to improve care pathways and future research. Temporal comparative analysis of DNA methylome (bisulfite conversion and Illumina Infinium EPIC BeadChips) and transcriptome (65 million reads per sample using Illumina HiSeq-2500) in the developing human eye between 4-9 weeks gestation. Model 3D human microphthalmic optic cups using iPSC technology with isogenic controls using CRISPR/Cas9 gene-editing. DNA methylome and transcriptome analysis to assess disruption of molecular pathways. Outcomes: Establish a molecular framework for ocular maldevelopment. Identify drug targets and develop therapeutics. Improve genetic diagnosis, counselling and management. Elucidate shared molecular mechanisms between embryonic tissue fusion defects and late-onset visual sensory disorders.

Amount: £1,133,875
Funder: The Wellcome Trust
Recipient: University College London

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

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

Amount: £2,669,767
Funder: The Wellcome Trust
Recipient: University College London

Effective public policy for improving sexual health of migrants/refugees 30 Sep 2017

Summary: Identifying and implementing appropriate and effective public policy responses for improving the sexual health of migrants and refugees Global challenges are complex, interwoven "wicked problems" whose solutions require systemic thinking, cross-disciplinary collaboration, and engagement with a range of stakeholder opinions and positions. In this proposal we will address the interlinked problems of inequalities, migration/refugees and global health. Using the tracer example of sexual health (sexually transmitted infections including HIV) we will explore rigorous evidence for interventions to address upstream determinants driving poor health outcomes for refugees/migrants from West Asia/Middle East North Africa (WA/MENA). Results from systematic reviews, realist reviews and mathematical modelling will be synthesised to identify effective interventions which can be translated into policy (in a range of sectors). These policy options will be assessed and refined to enhance their ‘palatability’ – i.e. their legitimacy, feasibility and acceptability with a range of key stakeholders in countries in the WA/MENA region as well as in pan-EU and national level (UK) health institutions.

Amount: £673,516
Funder: The Wellcome Trust
Recipient: University College London

MRF2 National Alliance for Museums, Health and Wellbeing 30 Sep 2017

This project seeks to take forward work begun by the National Alliance for Museums, Health and Wellbeing. Since its establishment in July 2015 the Alliance has engaged with an of audience of 96,000, recruited 400 members, led an All Party Parliamentary Roundtable on Museums and Wellbeing, delivered the first National Museums and Wellbeing Conference and Week, and developed a database of over 600 museum-wellbeing projects. The proposal draws together the shared expertise of a number of allied organisations with interests in wellbeing. By working in partnership we will: share expertise and best practice across our diverse audiences; provide training to help develop the regional workforce; create online virtual training resources for building resilience in museums; provide leadership and advocacy at the highest levels of health and social care policy making; and develop an umbrella organisation across arts and culture to ensure future sustainability and legacy. The Alliance is a consortium led by UCL Museums, National Museums Liverpool, British Museum, Thackray Medical Museum, UK Medical Collections Group, Tyne & Wear Archives & Museums, Manchester Museums and Galleries, University of Leicester Research Centre for Museums and Galleries, Museums Association and National Alliance for Arts, Health & Wellbeing.

Amount: £15,000
Funder: The Wellcome Trust
Recipient: University College London

Physiological and pathological regulation of calcium channel trafficking and function 05 Apr 2017

Voltage-gated CaV2 calcium-channels are essential for presynaptic neurotransmitter release. Knowledge of factors governing the regulation in neurons of N-type (CaV2.2) calcium-channel trafficking and properties is key to understanding their pathological role in neuropathic pain. Both CaV2.2 and the auxiliary subunit alpha2delta-1, which is up-regulated in neuropathic pain models, represent validated pain therapeutic targets. My overarching research aim is to address fundamental questions regarding N-type calcium-channel trafficking and function. For this, we will exploit our key development of a knock-in mouse containing HA-tagged CaV2.2. Firstly, we will analyse expression of CaV2.2 in sensory neurons and spinal cord, and its dysregulation following neuropathic insult. We will examine the role of alpha2delta-1 by making double transgenics with alpha2delta-1 knock-out mice. Secondly, we will dissect the interdependent dual roles of alpha2delta subunits in permitting voltage-dependent activation of CaV2.2 channels and promoting their trafficking, concentrating on the essential requirement for proteolytic maturation of alpha2delta. Finally, we will address the identity and subcellular localisation of the protease involved in alpha2delta processing, since it represents a potential novel therapeutic target in chronic pain. This study will parse out the multiple roles of alpha2delta-subunits in N-type calcium-channel function, and elucidate the molecular mechanism of the alpha2delta-ligand gabapentinoid drugs.

Amount: £1,399,688
Funder: The Wellcome Trust
Recipient: University College London

Organization of large neuronal populations during behavior 30 Nov 2016

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.

Amount: £3,642,870
Funder: The Wellcome Trust
Recipient: University College London