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Results

A cell culture model to find drugs that may be useful to treat dementia. 15 May 2017

I am an undergraduate Neuroscience Msci student studying at the University of Bristol. I am undergoing an industrial trainee year, with Alzheimer’s Research UK University College London drug discovery institute (AR-UK UCL DDI), as part of my course. The AR-UK UCL DDI is a newly established unit in UCL, with core funding from Alzheimer’s Research UK. Its goal is to discover new approaches and therapies for dementia, a core symptom of a number of important diseases ("neurodegenerative diseases" of the brain such as Alzheimer’s disease). With the increasing aging population these neurodegenerative diseases are becoming a huge individual, societal and economic problem. The AR-UK UCL DDI currently has 12 scientists and will increase to about 24, and is equipped to enable the scientific experiments and studies to be performed.My industrial trainee year with the AR-UK UCL DDI will allow me to experience neuroscience in the research setting with an opportunity to use techniques commonly used in the field. The placement will provide a very practical learning in a professional environment, challenging me both personally and academically. It will also expose me to the process of working towards developing new therapies. I will be able to develop my interpersonal skills alongside vital experience working in lab with experienced colleagues. I will take the confidence and skills built during the placement into my final year and in my future studies and career as I hope to do a PhD after my undergraduate course.Project details: Neurons are key cells of the brain. Synapses are the key points that neurons communicate to each other, and are thought to be the basis of learning and memory. In neurodegeneration the neurons and the synapses decrease in number and ability to function, leading to progressive memory loss, dementia and eventually, death. Therefore ways of protecting the neurons and synapses, and maintaining their function, could be useful therapeutic approaches. The project will involve growing neurons in a cell culture dish; it is possible to do this by obtaining the neurons from mouse brains. The neurons are able to form synapses in the culture dish, which mimic the synapses that would be naturally formed in the mouse brain. I will use these cultured neurons to develop ways of measuring the number of synapses. It will be possible to measure the number of synapses by using fluorescently tagged antibodies that bind specifically to neuronal proteins that localise to synapses, and then use microscopy to count the number of those synapses. Once I have set up this system, I will be able to add various small molecules (compounds) and drugs and identify any that are able to increase the number of the synapses. Such small molecules or drugs could be the starting point for developing new therapies for dementia.

Amount: £7,000
Funder: The Wellcome Trust
Recipient: University College London

Overcoming constraints on T cells in the HBV-infected liver 05 Dec 2016

My request for enhancement funding arises from the component of my existing award focused on developing T cell immunotherapy of hepatitis B and hepatocellular carcinoma using patient samples. We recently made important contributions to the testing of genetically redirected T cells for a first-in-man treatment of HBV-related hepatocellular carcinoma1. We are also collaborating with academic and pharmaceutical partners to develop immunotherapeutic vaccines aiming to boost antiviral T cells for hepatitis B control. However, these approaches remain limited by the profound exhaustion and other immune constraints imposed on T cells by high-level antigenic stimulation in the tolerogenic liver. Front-line candidates to revive T cells are checkpoint inhibitors such as PD-1 blockade. However, we have found that genetic knockdown of PD-1 can initiate detrimental effects in virus-specific T cells (Fig.1). The emerging concept that PD- 1 may actually be required to support long-term maintenance of T cells in the setting of persistent antigenic stimulation is underscored by recent work in murine models2, 3 and by our finding that liver-resident PD-1+T cells can remain highly functional (Pallett, in preparation). These discoveries underscore the need to investigate more fundamental drivers and mediators of T cell failure as alternatives or additions to checkpoint inhibition.

Amount: £175,008
Funder: The Wellcome Trust
Recipient: University College London

Advancing Psychiatric Mapping Translated into Innovations for Care: PsyMaptic-A 05 Dec 2016

My current and previous Wellcome Trust Fellowships (Henry Wellcome, 2009-13; Henry Dale 2014- present) focus on important aetiological questions about psychotic disorders, using epidemiological data. Psychotic disorders are a debilitating set of mental health disorders, characterised by hallucinations, delusions and cognitive deficits. My research demonstrates that these disorders have a robust, replicable social aetiology, with higher incidence rates observed in young people,1–3 men,1–3 ethnic minorities2–7 and people exposed to greater social disadvantage.8–11 In my previous fellowship, I established the largest epidemiological study of first episode psychosis [FEP] in England since 1999, to demonstrate that these substantial mental health inequalities also exist in more rural populations (East Anglia)3,12; rates are over twice as high as expected,3,13 with deprived rural communities experiencing the highest psychosis incidence. This study has generated new Page 5 of 18 aetiological clues, for example by showing that people at "ultra-high risk" of psychosis are exposed to similar social and spatial markers of social disadvantage as FEP patients,14 implicating an aetiological role for social adversities prior to onset. I have also demonstrated that migrants face greatest FEP risk when immigrating in childhood,15 an important period of sociocognitive development. I am attempting to replicate this in my current Fellowship, in a larger longitudinal cohort using Swedish national register data. Using this data, I have already shown that refugees are at elevated psychosis risk compared with other migrants from the same region of origin,7 providing further insights into the possible social determinants of psychosis. Epidemiological data can also inform mental health service planning. In England, Early Intervention in Psychosis [EIP] services assess and treat people with suspected FEP, offering evidence-based multidisciplinary care to improve downstream clinical and social outcomes, shown to be highly costeffective.16 Unfortunately, original policy implementation guidance17 made no provision for the heterogeneity in incidence described above, with services commissioned on a uniform expectation of 15 new cases per 100,000 people-per-year. This was at least half the true incidence,1,3 and over three times lower than the overall referral rate for all suspected FEP, including "false positive" (nonFEP) referrals,3 who still require appropriate psychiatric triage and signposting, and consume additional EIP resources not factored into original guidance. In response, I demonstrated that epidemiological estimates of psychosis risk could be used to better predict the expected FEP incidence in the population at-risk in England,13 nationally and regionally. The tool, known as PsyMaptic, has had substantial impact on policy and commissioning since it was freely-released in 2012 (www.psymaptic.org).16,18–22 Most recently, it has been used to inform national EIP workforce calculations23 following the introduction of Access and Waiting time standards,19 as part of the Department of Health’s commitment to achieving parity of esteem between mental and physical health by 2020.24 Whilst I have demonstrated, via PsyMaptic, that it is possible to translate epidemiological data into effective public mental health,25 some vital methodological limitations require empirical attention. I therefore seek Wellcome Trust enhancement funding to answer four empirical questions to develop and apply novel statistical prediction methodologies to generate sustainable, dynamic populationbased models of future mental health need.

Amount: £204,479
Funder: The Wellcome Trust
Recipient: University College London

Human Immune Response Variation in Tuberulosis 11 Jul 2017

I aim to discover novel mechanisms by which differences in human immune responses influence the outcome of Mycobacterium tuberculosis (Mtb) infection. I hypothesise that host-genetic polymorphisms lead to variation in immune responses that determine the clinical outcome of Mtb infection by affecting host-cell restriction of mycobacterial growth. We will use transcriptional profiling at the site of tuberculin skin tests (TST) to make comprehensive molecular and systems level assessments of in vivo human immune responses to a standardised mycobacterial challenge. In order to identify human immune responses that increase risk of disease in people exposed to Mtb, we will test the hypothesis that the TST transcriptome will reveal immune phenotypes associated with progression of LTBI to active TB. We will test the role of host genetics by identifying genome-wide expression quantitative trait loci (eQTL) associated with variation in the TST transcriptome. We will then recall participants by genotypes associated with selected traits to undertake in vitro mechanistic studies in primay immune cells. We will validate the causal association between genetic and phenotypic variations, and test their impact on Mtb restriction by macrophages. The findings will inform clinical risk stratification, vaccine design and development of host directed therapies for TB.

Amount: £1,660,537
Funder: The Wellcome Trust
Recipient: University College London

Mechanisms and Regulation of RNAP transcription 11 Jul 2017

This grant focuses on four lines of scientific enquiry converging on RNAP function Characterisation of the molecular mechanisms underlying RNA polymerase and basal factors that facilitate transcription initiation, elongation and termination by using multidisciplinary approaches in vivo and in vitro. This includes using bespoke transcription assays, structure elucidation and a global characterization of the occupancy and transcriptomes. Identification of novel gene-specific factors and characterization of the proteomes of transcription preinitiation- and elongation complexes in vivo. Identification and characterization of RNAP-associated proteinaceous- and RNA regulators. Characterisation of the structure and function of archaeal chromatin formed by A3 and 1647 histone variants. A biophysical characterization of protein-DNA interactions and a whole-genome view of histone occupancy. Focus on the impact of chromatin on RNAP as it progresses through the transcription cycle, and the role of elongation factors to overcome the inhibitory effect of chromatin. Characterisation of factors that modulate RNAP during virus-host interactions. Virus (RIP)- and host (TFS4)-encoded RNAP-binding factors function as global inhibitors of transcription and their mechanism is reminiscent of antibiotics. Using two virus libraries of we want to screen for novel RNAP-binding regulators and use them as molecular probes to dissect RNAP function.

Amount: £2,029,869
Funder: The Wellcome Trust
Recipient: University College London

LRG1 and dysfunctional vessel growth 05 Apr 2017

Neovascularisation plays a key role in the pathogenesis of diseases such as cancer and diabetic retinopathy. Neovessels are frequently disorganised, poorly perfused and leaky resulting in hypoxia, oedema and ineffective delivery of therapeutics. Until recently, most therapeutic strategies have focused on the inhibition or ablation of these vessels but recent evidence suggests that re-directing abnormal vessel growth towards normality is clinically beneficial. Vascular normalisation has gained traction as a therapeutic concept, but its application to human disease is severely hampered by our limited understanding of the factors that subvert normal angiogenesis. A fundamental conundrum is that many of the molecular drivers of normal vascular development are also responsible for pathogenic angiogenesis, indicating that in disease there are additional factors corrupting this process. We recently discovered a secreted pro-angiogenic factor, leucine-rich alpha-2-glycoprotein-1 (LRG1), that is up-regulated in pathogenic settings and disrupts vessel growth, and we have shown that inhibition of LRG1 results in vessel normalisation. In this study, we will investigate the mechanisms that drive pathological angiogenesis, and test the hypothesis that LRG1 subverts endothelial-mural cell interactions by interfering with or redirecting key signalling pathways. The work will increase our understanding of pathological angiogenesis and pave the way towards new therapies.

Amount: £856,820
Funder: The Wellcome Trust
Recipient: University College London

LRG1 and dysfunctional vessel growth 05 Apr 2017

Neovascularisation plays a key role in the pathogenesis of diseases such as cancer and diabetic retinopathy. Neovessels are frequently disorganised, poorly perfused and leaky resulting in hypoxia, oedema and ineffective delivery of therapeutics. Until recently, most therapeutic strategies have focused on the inhibition or ablation of these vessels but recent evidence suggests that re-directing abnormal vessel growth towards normality is clinically beneficial. Vascular normalisation has gained traction as a therapeutic concept, but its application to human disease is severely hampered by our limited understanding of the factors that subvert normal angiogenesis. A fundamental conundrum is that many of the molecular drivers of normal vascular development are also responsible for pathogenic angiogenesis, indicating that in disease there are additional factors corrupting this process. We recently discovered a secreted pro-angiogenic factor, leucine-rich alpha-2-glycoprotein-1 (LRG1), that is up-regulated in pathogenic settings and disrupts vessel growth, and we have shown that inhibition of LRG1 results in vessel normalisation. In this study, we will investigate the mechanisms that drive pathological angiogenesis, and test the hypothesis that LRG1 subverts endothelial-mural cell interactions by interfering with or redirecting key signalling pathways. The work will increase our understanding of pathological angiogenesis and pave the way towards new therapies.

Amount: £857,450
Funder: The Wellcome Trust
Recipient: University College London

Integrative structural biology of protein folding during biosynthesis on the ribosome 05 Apr 2017

Central to the activity of all living systems is the need for polypeptide chains to acquire their biologically-active structures and avoid the competing events of misfolding. It is well established that the majority of proteins begin to acquire structure as highly-dynamic nascent chains during biosynthesis on the cell’s protein biosynthesis machinery, the ribosome. A detailed molecular understanding of how this native structure is acquired and how misfolding is avoided during biosynthesis is sparse. We will build on our capacity to derive structural and dynamic mechanistic information of the fundamental process of co-translational folding: we will produce a multi-scalar analysis extending from in vitro to in vivo to provide a comprehensive, high-resolution description of emerging nascent chains (NC) during biosynthesis. Our research will integrate NMR and cryo-EM to answer emerging questions regarding the observation that the ribosome itself can modulate folding processes, and also act as a hub for the recruitment and co-ordination of auxiliary proteins that can assist NC folding and modification processes. Structure-based design, incorporating protein engineering and ribosome modification will dissect NC folding mechanisms and understand how misfolding is avoided. This underpins aims to reshape co-translational folding, targeting the ribosome and NC at the earliest stages of protein-biosynthesis.

Amount: £2,034,461
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

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

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 Xenopus 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.

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

Endothelial cell behaviours in vascular health and disease 30 Nov 2016

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.

Amount: £1,436,838
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

The mechanisms of photoreceptor cell death 30 Nov 2016

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.

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

Unravelling the CTLA-4 immune checkpoint: from cell biology to clinical application. 30 Nov 2016

The CTLA-4 pathway is a key immune regulator whose absence or mutation leads to profound autoimmunity. CTLA-4 and its relative CD28 have opposing inhibitory and stimulatory functions respectively and interact with two ligands CD80 and CD86. Despite the key role of this pathway in immune regulation and high profile therapies in tumour immunology, our understanding of how CTLA-4 functionally interacts with its two natural ligands is remarkably incomplete. The aim of this proposal is to generate a robust molecular, cellular and functional framework for CTLA-4 biology which can be used to understand the impact of disease mutations, which are being identified as a result of next generation sequencing programmes, and generate knowledge which can underpin new approaches to manipulation of this key immune axis. We will address three key aims: 1). What is the cellular machinery used by CTLA-4 to capture and transfer ligands between cells? 2). How do CTLA-4 interactions with its natural ligands influence its function? 3). How do clinically identified mutations inform our understanding of the CTLA-4 pathway?

Amount: £1,653,759
Funder: The Wellcome Trust
Recipient: University College London

A multi-user FACS facility at the University of Leicester 06 Jul 2017

We request funds to purchase a BD FACSAria Fusion cell sorter enclosed within a Class-II microbiological safety cabinet (MSC) to establish a multi user cell sorting facility. The FACSAria Fusion is a highly flexible and advanced flow cell based flow cytometer that can perform multi-parameter four-way sorting. The Aria flow cell-based detection method provides greater fluorescence sensitivity than alternative stream-in air based cell sorters, which is critical for many of the proposed studies. We have requested funds for a four laser (blue/red/violet/yellow-green) 18-parameter instrument to enable high dimension analysis of the cells during sorting. The violet laser will enable use of highly sensitive brilliant violet fluorochromes and the yellow-green laser will allow greater use of multiple fluorescent proteins. The instrument can also perform single cell index sorting into 384-well plates, which will enable our research teams to undertake single cell transcriptomics projects and sort CRISPR/Cas9-mediated gene edited cells. The instrument is fully integrated into the biosafety cabinet enabling work to be undertaken with primary patient samples and hazard group 2 pathogens. Maintenance, assisting new users and staff training are essential for such a complex instrument, we have therefore requested funding for an experienced grade 7 manager for a 4-year period.

Amount: £290,555
Funder: The Wellcome Trust
Recipient: University of Leicester

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

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. Its core components include: a systematic review of evidence on potential solutions; the development and application of methods for tracking the progress of cities to towards sustainability and health goals; 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; 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. 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.

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

4 year PhD in Neuroscience 30 Sep 2017

Not available

Amount: £2,850,000
Funder: The Wellcome Trust
Recipient: University College London
Amount: £2,814,500
Funder: The Wellcome Trust
Recipient: University College London