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Recipients:
University College London
Award Year:
2016

Results

Albumin to prevent infection in Acute-on-Chronic Liver Failure (ATTIRE) 30 Sep 2016

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: £271,437
Funder: The Wellcome Trust
Recipient: University College London
Amount: £14,500
Funder: The Wellcome Trust
Recipient: University College London
Amount: £12,000
Funder: The Wellcome Trust
Recipient: University College London

Role of grid cell replay in consolidation and navigation 11 Feb 2016

<table> <tbody> <tr> <td>I aim&nbsp;to build a neural level understanding of how information about the&nbsp;environment is stored, updated, and retrieved from memory. To this end I will&nbsp; study spatial memory and its representation in the rodent hippocampal&nbsp; formation. The results from experimental work including multi-site single&nbsp; unit recordings, pharmacological and optogenetic interventions, along with &nbsp; behavioural manipulations, will be combined with state of the art&nbsp; computational modelling. In turn computational work will suggest&nbsp; and refine further experimental&nbsp; manipulations. This joined-up approach is necessary to close the existing gap &nbsp; between our current neural-level understanding of the brain and cognitive &nbsp; functions.&nbsp; My key goals are to &nbsp; understand: 1) How entorhinal and hippocampal spatial representations are &nbsp; modulated by the level of certainty an animal has about the spatial &nbsp; configuration of its environment. 2) The role of cholinergic modulation in &nbsp; signalling environmental novelty, and more generally spatial u ncertainty. In &nbsp; particular, the effect of cholinergic modulation on theta-frequency &nbsp; rhythmicity and the scale of spatial representations. 3) How changes in the &nbsp; scale of the entorhinal spatial representation may contribute to, and even &nbsp; trigger, memory formation.</td> </tr> </tbody> </table>

Amount: £143,293
Funder: The Wellcome Trust
Recipient: University College London

Novel multichannel "SMART" neuroprobe - Enhancement 08 Apr 2016

<table> <tbody> <tr> <td>Neuroscience is entering an exciting period when it will be possible to decipher the neural codes underlying perception and cognition. Novel genetic, molecular, physiological, optical and behavioural approaches will allow the monitoring &nbsp; of activity across ensembles of neurons in behaving rodents, and the&nbsp; manipulation of this activity in a temporally and spatially precise manner.&nbsp; For the first time we will establish causal links between patterns of neural activity and behaviour, and carry out decisive tests of both new and long-standing hypotheses about the computational properties of neural circuits. Members of the consortia seek to understand the patterns of neural&nbsp;activity underlying sensory, motor and cognitive representations, and the rules by which they are assembled. The core of the present proposal is the &nbsp; development and testing of a major stepchange in silicon-based electrode &nbsp; technology to rapidly accelerate the pace of this work by greatly increasing &nbsp; the simultaneous sampling of extracellular electrical signals within and &nbsp; across multiple brain regions.</td> </tr> </tbody> </table>

Amount: £273,651
Funder: The Wellcome Trust
Recipient: University College London

A phase I clinical trial of DARC 30 Sep 2016

Preclinical development of a novel diagnostic for glaucoma. Glaucoma is the major cause (15 per cent) of irreversible blindness worldwide. A recent UK report suggested 10 per cent earlier detection of glaucoma would save £1billion/year in treatment costs alone.Professor Francesca Cordeiro and colleagues from the Institute of Ophthalmology at University College London, have been given Translation Award support to fund the preclinical development of their Detection of Apoptosing Retinal Cells (DARC) Technology. DARC is a novel technique that utilises the unique optical properties of the eye to allow direct visualisation of dying nerve cells. If successful, early diagnosis and treatment would mean that DARC will increase patient benefit and decrease burden of care costs.

Amount: £271,521
Funder: The Wellcome Trust
Recipient: University College London

Two-photon imaging and optogenetics in the mouse midbrain 08 Jun 2016

<p>The brain processes and responds to information from the outside world using neurons - cells that are wired up in a network like a computer. Neurons receive input on so-called dendrites - long extensions resembling tree branches - which have properties that allow them to transform information before it reaches the output end of the neuron. Understanding how the brain processes information requires knowing how individual neurons and dendrites integrate input. In the primitive brain areas that con trol instinctive behaviours, neurons have a small number of dendrites, which simplifies the goal of fully understanding how each neuron processes information. In this project I aim to find out how the dendrites of primitive&nbsp; neurons integrate input. I will work on a mouse brain circuit involved in aggression, and begin by examining the integration properties of dendrites. I will then investigate how specific brain areas are connected to these dendrites and study how they processes information a rriving from each area. In the last stage I will use genetic methods to study the specific neurons that control aggression. The results of these experiments will provide insight specifically into how aggression neurons integrate input, and more generally into how primitive&nbsp; brain areas process information</p>

Amount: £171,360
Funder: The Wellcome Trust
Recipient: University College London

Request for enhancement funding LonDowns 11 Feb 2016

<table> <tbody> <tr> <td>Most&nbsp;studies treat Down syndrome (DS) as a single entity. Our novel aim is to focus on individual differences and subgroups at the cellular, genetic and cognitive levels to explain why the DS phenotype varies so much. For example, &nbsp; despite all DS individuals presenting with Alzheimer's Disease pathology, only a subgroup develops dementia. Is this due to cellular, molecular,&nbsp;genetic and/or cognitive differences?&nbsp; Can we identify these differences not only in adulthood, but also in infancy? If so,&nbsp;early diagnosis and &nbsp; intervention can be targeted. To study DS cognition longitudinally, we will &nbsp; develop comparable assessments for DS infants, adults and mouse models, to characterise deficits associated with hippocampal, cerebellar and frontal&nbsp;regions. Uniquely, we will correlate&nbsp;cognitive/genetic profiles with defects in neurogenesis, neurite/synapse &nbsp; plasticity, mitochondrial dysfunction, A-beta accumulation within &nbsp; participants neurons, differentiated from iPSC.&nbsp; We will create a Biobank&nbsp; and genotype/phenotype database as &nbsp; platforms for add-on pharmacologic/metabolomic/imaging projects, and clinical &nbsp; trials. This project aligns methods with other DS studies globally, but is &nbsp; unique in encompassing different age cohorts, integrating human cognitive &nbsp; development, ageing, neurobiology, genetics, cellular and mouse modelling.&nbsp; It is strategic for improved health, and &nbsp; timely, as therapies for DS cognitive deficits and decline are now realistic.</td> </tr> </tbody> </table>

Amount: £152,400
Funder: The Wellcome Trust
Recipient: University College London

A computer assisted system to reduce auditory hallucinations unresponsive to antipsychotic medication 30 Sep 2016

About 25% of people with schizophrenia continue to suffer with persecutory auditory hallucinations despite drug treatment. Their capacity to work and make relationships is grossly impaired, often for the rest of their life. Professor Julian Leff from University College London and colleagues at Speech, Hearing and Phonetics, UCL have developed and evaluated a novel therapy based on computer technology which enables each patient to create an avatar of the entity (human or non-human) that they believe is talking to them. The therapist promotes a dialogue between the patient and the avatar in which the avatar progressively comes under the patient's control. This translation award aims to refine the system, streamline the technology to make it more user-friendly and evaluate the system by a randomised controlled trial conducted by an independent team of researchers at the Institute of Psychiatry, King's College London.

Amount: £34,060
Funder: The Wellcome Trust
Recipient: University College London

Development of a novel bioartificial liver device for the treatment of patients with liver failure 30 Sep 2016

In the UK, over 16,000 patients a year die of liver failure. Their livers have the capacity to repair and regenerate, but do not have time to do so. A device temporarily replacing liver function would save lives and reduce the necessity for liver transplantation worldwide. Dr Clare Selden and her team at UCL have developed a prototype 'bio-artificial liver' (BAL) to address this unmet need. Its key element comprises functioning liver cells in an external bioreactor. Plasma from a patient with liver failure will be passed through the bioreactor, contacting the alginate encapsulated liver cells, so that the cells replace those functions that the sick liver cannot perform. The machine will buy time for a patient's liver to improve or, if damage to the liver is irreversible, may buy time until liver transplantation can be arranged. The technology combines alginate encapsulation of a human liver cell line and subsequent culture of the encapsulated cells in a fluidised bed bioreactor - providing a convenient, manipulatable biomass in a form which maximises mass transfer between cells and perfusing plasma. The team have Translation Award funding to complete the design, specification, performance characterisation and manufacture of this fully biocompatible BAL.

Amount: £66,434
Funder: The Wellcome Trust
Recipient: University College London

Partnering for Equitable STEM Pathways for Youth from Minoritized Communities. 07 Nov 2016

<p>Minoritized Youth, addresses fundamental equity issues in informal STEM learning (SL+ priority D, Equity, diversity and access to informal learning settings). The major goal of our Partnership is for practitioners and researchers, working with minoritized youth, to develop new understandings of how and under what conditions minoritized youth participate in Informal STEM Learning (ISL) over time and across settings, and how they may connect these experiences towards pathways into STEM. We will: 1) Develop new understandings of ISL pathways that are equitable and transformative for minoritized youth; 2) Co-develop high leverage practices and tools that support these equitable and transformative ISL pathways (and the agency youth need to path-make); and 3) Strengthen and increase professional capacity to broaden participation among youth from minoritized communities in STEM through ISL. Our work is grounded in longitudinal youth participatory ethnographies, surveys, and design-based implementation research methodologies.&nbsp; Our major goal responds to three challenges at the intersections of ISL research and practice in the US/UK: 1) lack of shared understanding of how minoritized youth perceive and experience ISL opportunities across the US/UK, and the practices and tools needed to support empowered movement through ISL; 2) limited shared understanding and evidence of core high-leverage practices that support minoritized youth in progressing within and across ISL, and 3) limited understanding of how ISL might be equitable and transformative for minoritized youth seeking to develop their own pathways into STEM. We focus on minoritized youth, ages 11-14, for whom there are wide and persistent gaps in representation in STEM, and for whom STEM careers and pursuits remain elusive.&nbsp; The project will be carried out by RPPs in 4 cities: London &amp; Bristol, UK and Lansing, MI &amp; Portland, OR, US, involving university researchers (Kings College, University College London, Michigan State University, Oregon State University) practitioners in science museums (@Bristol Science Centre, Brent Lodge Park Animal Centre, Impressions 5, OMSI) and community-based centers (STEMettes, Knowle West Media Centre, Boys &amp; Girls Clubs of Lansing, and Girls, Inc.).</p>

Amount: £749,245
Funder: The Wellcome Trust
Recipient: University College London

Complex Urban Systems for Sustainability and Health (CUSSH) 06 Oct 2016

<p>The CUSSH programme will deliver strategically vital global research on the complex systemic connections between urban development and health. Based on transdisciplinary methods, it will develop critical evidence on how to achieve the far-reaching transformation of cities needed to address vital environmental imperatives for population and planetary health in the 21st century. <br />Its core components include:</p> <ul> <li>a systematic review of evidence on potential solutions;</li> <li>the development and application of methods for tracking the progress of cities to towards sustainability and health goals;</li> <li>the development and application of models to assess the impact on population health, health inequalities, socio-economic development and environmental parameters of alternative urban development strategies to support policy decisions;</li> <li>iterative in-depth engagements with stakeholders in partner cities in low-, middle- and high-income settings, based on participatory methods, to test and deliver the implementation of the transformative changes needed to meet local and global health and sustainability objectives.</li> </ul> <p><span>Through these steps, the project will provide transferable evidence on how to accelerate actions essential to achieving population-level changes in such areas as energy provision, transport infrastructure, green infrastructure, water and sanitation, and housing. Associated public engagement and training, based on principles of co-generation of research, will be embedded throughout.&nbsp;</span></p>

Amount: £149,988
Funder: The Wellcome Trust
Recipient: University College London

Unravelling the molecular complexity behind ocular maldevelopment 06 Dec 2016

<p><strong>Aim:</strong> Investigating the relationship between genotype, gene expression and phenotype of <u>m</u>icrophthalmia, <u>a</u>nophthalmia&nbsp;and ocular <u>c</u>oloboma&nbsp;(MAC), which collectively causes one-third of life-long blindness and severe visual impairment in children worldwide.</p> <p>&nbsp;</p> <p><strong>Research questions: </strong>What are the pathogenic variants underlying MAC? How do molecular subtypes correlate with phenotype and stratify clinical risk?&nbsp; What molecular pathways are involved in human eye development? What is the relationship between genotype and gene expression in microphthalmia?</p> <p>&nbsp;</p> <p><strong>Key goals and methodology:</strong></p> <ol> <li>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.</li> <li>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.</li> <li>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.</li> </ol> <p>&nbsp;</p> <p><strong>Outcomes:</strong> 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.&nbsp;</p>

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

Using visual dysfunction to understand dementia in Parkinson’s disease 06 Dec 2016

<p>Dementia affects half of patients with Parkinson&rsquo;s disease (PD) but there are no robust measures to predict who is at highest risk. Visual hallucinations are highly distressing to patients and carers but are poorly understood. This Fellowship will use visuo-perceptual dysfunction to predict dementia and understand hallucinations in PD.</p> <p>I have developed a novel test using skewed images to detect visuo-perceptual deficits in Parkinson&rsquo;s patients. I have also developed a web-based platform to enable this and other visual tests to be accessed by large numbers of patients with PD.</p> <p>In this proposal I will use visual perceptual tests combined with neuroimaging over time to determine the sequence of visuo-perceptual deficits in PD. I will relate these to changes in hallucinations. I will use my web-based platform to identify clinical and genetic associations with visual deficits and determine their role in predicting dementia in PD.</p> <p>Goals</p> <p>1. Characterise changes in visuo-perception as PD progresses and correlate deficits with brain atrophy.</p> <p>2. Relate MRI structural connectivity changes with disease progression.</p> <p>3. Examine clinical and genetic associations of visual dysfunction in PD.</p> <p>4. Test whether transcranial stimulation can improve visuo-perceptual function in PD.</p> <p>5. Determine how visual hallucinations become distressing as PD advances.</p>

Amount: £1,223,282
Funder: The Wellcome Trust
Recipient: University College London

Control and enzymatic activation of the APC/C ubiquitin ligase system 30 Nov 2016

<p>CDK1 and APC/C are two key regulatory enzymes controlling the cell division, growth, differentiation and death, through phosphorylation and ubiquitylation, respectively. Although it has long been apparent that phosphorylation modifies APC/C function, the challenges posed by the need for functional assays to study this control puts the elucidation of the molecular basis of phosphorylation control beyond our grasp. We have recently overcome these limitations with a pipeline that uses reconstituted recombinant APC/C in <em>Xenopus</em> cell free extracts to show how CDK1 activates the APC/C through coordinated phosphorylation of Apc3 and Apc1. We will now extend this pipeline with targeted assays that will determine how phosphatases regulate these phosphorylation events. Because we have found that the disordered loop domains of APC/C subunits are targets for both post-translational modifications (PTMs) and interacting partners, including protein phosphatases, we will study how the loop domain controls the APC/C. Cell cycle specific and stress-dependent PTMs and binding proteins will be identified and we will determine their impact upon APC/C-dependent ubiquitylation. This approach of combining high throughput reconstitution mutated apo-APC/C in extracts from which any component of interest can be depleted offers a unique opportunity to gain an unprecedented insight into APC/C function and control.&nbsp;</p>

Amount: £1,547,248
Funder: The Wellcome Trust
Recipient: University College London

Explaining Language Outcome and Recovery After Stroke (ELORAS) 30 Nov 2016

<p>My aim is to develop a theoretical model of language processing that explains inter-patient variability in outcome after stroke. My hypotheses are that the same language task (e.g. describing a picture) can be sustained by different sets of brain regions (and neuronal pathways) and that inter-subject variability in neuronal pathways for the same language task reflect an individual&rsquo;s inherent potential and prior experience.&nbsp; My investigations will (1) use functional neuroimaging to characterize inter-subject variability in neuronal pathways in a range of language tasks; (2) cluster healthy individuals and stroke patients into different groups according to the neural systems used for the same task; and (3) compare the identified groups on a multitude of demographic, behavioural and &nbsp;structural imaging measures.&nbsp; The results will identify the factors that distinguish which neuronal pathways a subject typically uses and which neural pathways are available to support recovery. The work will provide: (i) greater understanding of the neuronal pathways sustaining recovery; (ii) improved accuracy and precision in our prognoses for whether and when patients with aphasia will recover after stroke, and (iii) a new patient stratification system that can be used to design effective, individualised therapeutic interventions.</p>

Amount: £2,701,886
Funder: The Wellcome Trust
Recipient: University College London

Endothelial cell behaviours in vascular health and disease 30 Nov 2016

<p>At the interface between blood and tissues, vascular endothelial cells (ECs) provide signalling hubs for vascular adaptation to physiological needs. Quiescent ECs form a non-thrombotic surface that facilitates the exchange of gases, molecules and cells between blood and tissues, but they respond to hypoxia-induced signals with vascular expansion and regulate leukocyte extravasation in response to injury. Our unpublished observations indicate that the cell surface receptor neuropilin 1 (NRP1) relays signals from the extracellular environment to the endothelial nucleus to enable such context-dependent responses. Thus, we hypothesise that NRP1 integrates growth factor and extracellular matrix signalling with gene transcription programmes to balance EC behaviours that enable vascular growth and to prevent the senescent and proinflammatory endothelial phenotype common to many chronic diseases. To determine how vascular growth and homeostasis depend on NRP1-mediated pathways, we will investigate novel mechanisms by which NRP1 conveys signals for tissue vascularisation, protects ECs from premature senescence and regulates gene transcription for vascular growth and homeostasis. The knowledge gained will significantly advance our understanding of how extracellular signals are integrated with gene regulation to control EC behaviour, and will likely uncover pathways for therapeutic intervention in diseases with vascular dysfunction.</p>

Amount: £1,436,838
Funder: The Wellcome Trust
Recipient: University College London

Organization of large neuronal populations during behavior 30 Nov 2016

<p>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?</p> <p>&nbsp;</p> <p>Until recently, these questions were barely answerable: one could only record from tens or hundreds of neurons, and during single behaviors. &nbsp;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.</p> <p>&nbsp;</p> <p>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.</p>

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

The mechanisms of photoreceptor cell death 30 Nov 2016

<p>Problems of protein homeostasis (proteostasis) that lead to protein misfolding, improper traffic and aggregation are associated with many forms of neurodegeneration. The neurodegeneration retinitis pigmentosa (RP) offers an excellent paradigm to study why proteostasis is critical for neuronal function and survival. Rhodopsin mutations cause dominant RP and disturb proteostasis, yet the underlying disease mechanisms and effective therapies remain elusive. I will exploit recent advances in gene editing technology and stem cell biology to produce new animal and patient derived models of the most common rhodopsin mutations in the UK. I will use these to address my key goals, i) to define any common disease mechanisms between the different classes of mutation, and ii) identify new therapeutic approaches for rhodopsin RP. I will use a combination of genetic and chemical manipulation of the major cell stress and degradation pathways, and identify the partner proteins of rhodopsin mutants using unbiased proteomic analyses. These complementary studies will be based on a series of interlinked hypotheses to determine how rhodopsin mutations disturb protein homeostasis and if this can be restored. The findings will have broader implications not only for other forms of retinal degeneration, but also neurodegenerative disease where proteostasis is disturbed.&nbsp;</p>

Amount: £1,529,466
Funder: The Wellcome Trust
Recipient: University College London

Transforming brain recordings with next-generation probes 30 Nov 2016

<p>Thanks to the Wellcome Trust and other leading international institutions, we have developed and proved the viability of a new generation of recording probes that will transform electrophysiology. These &ldquo;Neuropixels&rdquo; probes transcend past approaches, recording hundreds to thousands of neurons simultaneously. Several key steps are now necessary to maximize the impact of this new technology, enabling its widespread use in the neuroscience community. We must develop radically new recording equipment and software, provide training, and build a collaborative community of users (<strong>Aim 1</strong>). To allow this community to fully exploit the potential of this technology, we must extend it to a larger range of applications: multi-shank probes, wireless recording for freely moving animals, and optrodes for use with optogenetics (<strong>Aim 2</strong>). Meanwhile, we will obtain ground-truth data to calibrate error rates, and begin the development of a tool to automatically identify brain regions based on electrophysiological characteristics (<strong>Aim 3</strong>). This project integrates software and hardware engineering, fabrication efforts, neurophysiology tests, and behavioral and anatomical techniques. It thus requires a collaboration between laboratories with different skill sets, and a unique nanoelectronics research partner, IMEC. The results of this collaboration will transform the field of neuroscience.</p>

Amount: £2,287,189
Funder: The Wellcome Trust
Recipient: University College London