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Recipients:
University College London

Results

Exploring gene therapy approaches for neuroblastoma using a patient's own gamma delta T cells. 13 Nov 2014

Neuroblastoma is a rare childhood malignancy with tumours developing from the sympathetic nervous system. Approximately 50% of patients are affected by high-risk disease characterised by widespread metastasis. Five-year survival is only 40% despite highly aggressive multi-modal treatment regimes. Novel therapies that effectively target malignant cells whilst sparing normal tissues are therefore a research priority. Adoptive cellular therapy with T-cells engineered to express a Chimeric Antigen R eceptor (CAR) combine the antigen specificity of a monoclonal antibody together with T-lymphocyte cytotoxicity. Current approaches utilise alpha-beta T-cells due there abundance in the peripheral circulation and ease of expansion ex vivo. Gamma delta T-cells (gdT) however have many unique and advantageous properties, including innate killing ability, antibody-dependent cytotoxicity and professional antigen presenting function. When engineered with a CAR, gdT-cells may therefore may confer therap eutic advantage as we hypothesise they will give better tumour responses and better long-lived protection. This pre-clinical project investigates CAR-gdT-cells as a potential novel therapy for high-risk neuroblastoma. The ultimate aim is to engineer gdT-cells that have greater specific cytotoxcity, reduced off-target effects, and the ability to generate secondary immune responses leading to long-lasting anti-tumour surveillance. If successful, we will look to opening a CAR-gdT-cell phase 1 clini cal trial.

Amount: £114,615
Funder: The Wellcome Trust
Recipient: University College London

The impact of epigenetics on DNA-DNA interactions 18 Sep 2015

It has become clear that DNA-DNA interactions are an important component of gene regulation and of complex trait genetics. The impact of DNA variation of these interactions is less well understood. This project will characterise two important loci, the Major Histocompatibility Locus (MHC) and the imprinted H19/Igf2 locus in mice. These loci play key roles in immunity and growth and serve as models for the rest of the genome. We will use Capture-C sequencing to assay DNA-DNA interactions bet ween sites within these two loci and the rest of the genome, and CTCF-binding genome-wide, in two divergent inbred strains (C57BL/6J and CAST/EiJ), and in reciprocal crosses of these two strains. We will repeat these assays in reciprocal crosses of C57BL/6J and the knockout C57BL/6N-Ercc5tm2a(EUCOMM)Hmgu/BcmMmucd. The experiment will tell us which loci genome-wide interact with these loci. In particular, we will be able to test a prediction from our previous work that physical interactions occur between the MHC and H19/Igf2, and that genetic perturbations at the loci disturb these interactions. These experiments will provide important proofs of principle of links between imprinted loci and the MHC.

Amount: £98,476
Funder: The Wellcome Trust
Recipient: University College London

Detecting tumour resistance to treatment with positron emission tomography. 27 May 2015

Ovarian cancer is the fifth leading cause of cancer-related deaths among women in the United States and Europe, making it one of the most common cancers affecting women. Ovarian cancer initially responds well to surgical resection and/or platinum-based chemotherapy, leaving the patient disease free. However, tumours often recur as lethal, platinum-resistant disease. Aldehyde dehydrogenase (ALDH) has been identified as a biomarker of chemoresistance in this patient population. I will develop nove l positron emission tomography (PET) imaging agents with high specificity and selectivity for visualising therapy resistance in preclinical models of ovarian carcinoma, based on the measurement of aldehyde dehydrogenase activity. Additional biomarkers of drug resistance, such as the drug efflux transporter MDP1, are also known to have a major impact on the pharmacological behavior of most of the drugs in use today. We will further compare the lead ALDH imaging agent to a previously validated PET radiotracer, designed at UCL for the noninvasive assessment of MDP1 activity, to determine their clinical utility. Following clinical translation, an imaging biomarker of treatment resistance will help stratify patients into those suitable for second-line therapy, with high likelihood of response, allowing long term personalised patient management and the possibility of reducing mortality and morbidity.

Amount: £1,137,496
Funder: The Wellcome Trust
Recipient: University College London

Natural killer cell subsets in the liver: phenotype, function and role in obesity-induced liver disease. 29 Oct 2014

Organ-specific natural killer (NK) cells form a distinct lineage from their circulating counterparts and have specialist physiological functions. In the last year, a liver-specific NK subset has been identified in mice. Whether an equivalent population exists in human liver is not yet known, nor is the function of these cells known in either humans or mice. My goal is to address these questions with specific reference to NASH. I will examine liver transplant perfusates by flow cytometry for the transcription factors that define the liver-specific NK subset, and for relevant surface markers. I will then investigate whether any of the subsets identified are liver-specific using in vitro lymphocyte differentiation assays and by comparing their representation in donor- versus recipient-derived NK cells from explanted livers. I will perform ex vivo assays for expected functions such as cytokine production and cytotoxicity. Microarray analysis will also be used to identify any novel function s. Using marginal tissue from liver resections, I will determine whether NK subset frequency and function differs between NASH livers and controls. To test the hypothesis that liver-specific NK cells affect the progression of NASH, I will examine disease severity in Tbx21[fl/fl]Ncr1[icre] mice, which specifically lack these cells.

Amount: £782,599
Funder: The Wellcome Trust
Recipient: University College London

The development of neuronal circuits controlling sleep/wake behaviour in zebrafish models of autism. 19 Nov 2014

The main goal of the proposed research is to understand how the development of hypothalamic neuronal circuits that control complex behaviours such as sleep is disturbed in zebrafish models of autism. For this purpose I will harness a combination of powerful genetic tools available in zebrafish, cutting edge neuroimaging techniques and high-throughput behavioural analysis. The Rihel lab, in collaboration with the Giraldez labs at Yale, has identified diverse sleep/wake phenotypes in zebrafis h mutants harbouring mutations in genes associated with autism. I will test the hypothesis that these sleep phenotypes are due to the altered development and functionality of hypothalamic sleep circuits. I will examine the specification, patterning and connectivity of sleep relevant neuron population located in the hypothalamus, basal forebrain and brain stem using in situ hybridisation, immunostaining and transgenic zebrafish lines. Furthermore, I will image and compare the dynamic activity of developing zebrafish brains of wild-type and mutant larvae to determine the functional integrity of sleep circuits. Differentially active neurons will then be laser-ablated or optogentically/pharmacologically manipulated to directly test their specific sleep/wake circuit function and their contribution to the autism sleep phenotype.

Amount: £250,000
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

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

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

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

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

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

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

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

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

Amount: £501,781
Funder: The Wellcome Trust
Recipient: University College London

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

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

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

Open access publishing costs 2014/15. 15 Sep 2014

Not available

Amount: £540,000
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

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

Investigating the role of RNA interference in retinal development and as an agent of degeneration 31 Jan 2017

Genetic diseases affecting the retina, are the leading cause of blindness in the developed world. Despite the wide knowledge of the genetic factors which result in retinal dystrophies, (more than 200 genes have been identified as playing a role) such conditions remain untreatable. In monogenic retinal dystrophies the age of onset of photoreceptor cell death and rate of sight loss varies, yet the pathogenic gene mutation is present throughout life. Why some cells die at a given point in time and others do not, is unknown. This project aims to investigate the role of endogenous micro RNAs (miRNA) in retinal development and the relationship between miRNA dysregulation and retinal dystrophy. Specific miRNAs will be inactivated using the CRISPR/Cas9 system and the effects on photoreceptor differentiation and optic cup lamination determined. Furthermore, retinal organoid cultures derived from Type I Usher (a syndromic retinopathy) patient induced-pluripotent stem cells (iPSC; derived by reprogramming skin fibroblasts), will be used to establish whether miRNA dysregulation is indicative of an early disease state and whether CRISPR/Cas9-based gene correction can return dysregulated miRNA levels to normal. Finally, the effects of delivering certain miRNAs to a mouse model of retinal dystrophy on early disease phenotype will be established.

Amount: £24,581
Funder: The Wellcome Trust
Recipient: University College London

Local control of ventral subicular circuitry and its alteration by social isolation 31 Jan 2017

The overall aim of this project is to use viral tracing, electrophysiology and optogenetics to investigate the local circuitry of the ventral subiculum (vS), and how this circuit is altered by social isolation stress – a common route to affective disorders such as depression and anxiety. I will first investigate the anatomical distribution of neurons in vS that project to the prefrontal cortex or the NAc. These have been shown to be distinct parallel populations with unique circuit functions, but very little is known about their detailed local circuit organisation. Next I will use optogenetics, electrophysiology and viral tracing to determine the functional connectivity of the local circuit that defines the differential activity of these projections. Despite strong hypotheses that local control is key in this circuit, how this is acheived mechanistically remains unknown. Finally, I will determine how this detailed projection-specific circuitry is altered by social isolation - a manipulation that drammatically alters vS circuitry - and aim to provide more specific targets for in vivo manipulations aimed at reversing isolation-induced behavioural deficits. Overall, these experiments will provide for the first time mechanistic insight into the function and organisation of vS circuitry, from individual synaptic connections, to circuit function.

Amount: £30,524
Funder: The Wellcome Trust
Recipient: University College London

Investigation of the regulatory hot-spots identified for type 2 diabetes 05 Sep 2017

The complex causal chain between a gene and its effect on susceptibility cannot be unravelled until the casual changes have been localised in the DNA sequence. By exploiting high-resolution population-specific genetic maps, we have recently identified 111 additional disease-susceptibility locations, 93 of which are cosmopolitan (in Europeans and African-Americans) and 18 are European specific. We also refined previously identified T2D signals and showed that many of these are also risk loci in African-Americans. The novelty of our results is two-fold: 1) We obtain a precise location for the implicated functional variant(s) and 2) We were able to identify that the majority of the disease locations appear to confer risk of T2D by acting as expression quantitative trail loci (eQTL) that regulate adipose expression levels of a large number of cis-regulated genes. Our aim is to further characterise in detail all the 111 novel and previously found loci by effectively integrating all our causal location estimates together with cell-specific regulatory annotation and chromatin modifications. In addition, we will investigate all our disease and co-localised eQTL locations for tissue specificity (so far we have only used adipose) by performing gene expression analyses in other tissues relevant to T2D.

Amount: £99,945
Funder: The Wellcome Trust
Recipient: University College London

Sexy glia: developmental plasticity during glia-derived neurogenesis 11 Jul 2017

The overall goal of this proposal is to elucidate the cellular and molecular mechanisms that regulate natural glia-to-neuron cell-fate switches. Stably differentiated cells can sometimes display a remarkable degree of plasticity and switch fates to another differentiated cell type, in a process termed transdifferentiation. In the vertebrate nervous system, radial glia act as neural progenitors during embryogenesis. Suprisingly, stably differentiated glia can also act as neural progenitors during adult neurogenesis. We have recently discovered two cases in which stably differentiated glial cells undergo a glia-to-neuron cell-fate switch during sexual maturation in the nervous system of C. elegans, allowing us to study these events at the single-cell level in a genetically tractable system. We will combine classic genetic approaches with state-of-the-art molecular and next-generation sequencing approaches to characterise the molecular and epigenetic changes that occur during natural glia-to-neuron transdifferentiation. We will elucidate the role of cell division in this process, identify novel molecular regulators and determine the reprogramming abilities of the factors we identify. Unleashing the neurogenic potential of glia offers tremendous therapeutic possibilities.

Amount: £1,453,931
Funder: The Wellcome Trust
Recipient: University College London