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Recipients:
University College London

Results

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

Decisions and dopamine in frontal cortical circuits. 19 Nov 2014

This proposal has three aims. Firstly, I will investigate whether the phasic activation of dopamine neurons projecting to different brain structures, namely NAc versus mPFC, could cause distinct effects on perceptual decision making. To do so, I will use optogenetic tools to stimulate dopamine neurons of a mice engaged in visually guided decision task. Secondly, I will study how the projection-pathway specific dopamine activity modulates frontal cortical responses. In doing so, I will record the activity of single neurons in different parts of mPFC while optically stimulating dopamine neurons projecting to different target structures. Finally, I will investigate dopamine-related frontal cortical dynamics underlying perceptual decisions. By combining two-photon microscopy and genetic tools, I will examine the simultaneous activity of several dopamine receptor expressing neurons in mPFC while the mice is engaged in the perceptual decision task. If successful, these studies will support t he proposal that projection-pathway specific and cell-type specific modulation of neuronal circuits shape the decision process. As such, this research will provide important insights about the neurobiology of goal-directed behaviour and will open new directions in the study of cortico-basal ganglia dynamics.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

Systematic identification and characterisation of poxvirus lateral body constituents using quantitative proteomics and advanced superresolution microscopy. 19 Nov 2014

The aim of this research program is to elucidate the molecular components of poxvirus lateral bodies and determine their role in the viral life cycle. Poxviruses are large, enveloped, double-stranded DNA viruses characterised by their complex structure and cytoplasmic replication site. All poxviruses, deposit two protein rich structures, termed lateral bodies, into the cell cytoplasm during infection. The development of poxviruses as vaccine vectors and oncolytic agents, as well as on-going zoon otic poxvirus outbreaks and the potential threat of smallpox bioterrorism, warrant continued research on these important pathogens. This study will focus on the prototypic poxvirus, vaccinia. Taking a novel interdisciplinary approach, I will use advanced technologies that allow for high-throughput mass spectrometry identification and then superresolution visualisation of lateral body constituents. This will be followed by characterisation of their roles in the viral life cycle and immunomodulati on using a variety of virology, cell biology, biochemistry, and microscopy technologies. This research will provide detailed understanding of how poxviruses use their lateral bodies to package and then deliver cell modulatory factors into the host cytosol during infection. This will elucidate the function of these poorly understood viral structures and may identify cell- or immune-modulating viral components with powerful potential therapeutic applications.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

A Two-day Conference on the Human Right to Health, Universal Health Coverage and Priority Setting. 27 Oct 2014

This grant would be used to fund a two-day conference exploring the various tensions between what the UN refers to as the progressive realisation of the human right to health, the international effort to secure universal health coverage and the inevitable need to set priorities between different treatments and services. The conference would bring together three research centres within UCL (the Institute of Global Health, the Institute of Global Governance and the Centre for Philosophy, Justi ce and Health) to hear new evidence from researchers, policy-makers and practitioners from both the UK and abroad. The conference would: i) explore existing policy drives towards HRH, universal health coverage and priority setting activities; ii) reflect upon conceptual and ethical tensions between such policies; and iii) assess the feasibility of solutions aimed at resolving this tension. The conference's main output would be a consensus statement, drawn up by Benedict Rumbold and circula ted to delegates before the meeting and discussed by attendees on Day Two of the conference itself, setting out the delegates thoughts on the next steps towards remedying the current conflict between HRH, the drive towards Universal Coverage and priority setting.

Amount: £4,760
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

Investigation into LRRK2 vesicular trafficking pathways to provide further insight into Parkinson's disease pathogenesis. 12 Jan 2015

How do Parkinson’s disease causing mutations in LRRK2 impact vesicular trafficking within the trans-golgi network (TGN)? In addition, what is the functional nature of LRRK2- arfaptin-2 and ARL6IP1 interactions within this pathway?

Amount: £80,000
Funder: The Wellcome Trust
Recipient: University College London

FunVar: Impacts of Genetic Variations on Protein Functions and Functional Pathways. 25 Jun 2014

We will maintain and extend our integrated resources by developing new computational platforms. FunVar will analyse the impacts of genetic variants on the structures/functions of proteins and the networks in which they participate. DISASTR will exploit FunVar to provide web-based reports of impacts for all known, human, disease-associated variants. This will require development and further integration of our resources CATH-Gene3D (Orengo group), a unique, internationally renowned domain stru cture classification, with the functional resources of the Thornton group. CATH-Gene3D classifies ~30 million protein sequences into evolutionary superfamilies and provides information on functions (eg GO). It also describes biological roles by reporting protein interactions/networks. Functional resources in the Thornton group provide complementary data eg protein-ligand interactions (PDBsum) and catalytic residues (CSA). We will provide a unique perspective by focusing on domain structu re and accurately considering the functional role of the domain in its biological context eg complexes/networks. Our resources are unique in classifying domains into functional families. DISASTR will be a new and unique catalogue reporting structural/functional impacts for publicly available genetic variations linked to classified diseases. We will also establish a FunVar webserver for clinicians/biomedical researchers to learn the impacts of novel variants.

Amount: £536,722
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

Investigating the immune response to somatic corneal stem cell allografts 21 Nov 2013

This project will examine the interaction between tissue specific stem cells and the immune system using the eye as a model. This is a critical aspect of cellular therapy about which little is known. Two populations of corneal stem cells will be used, LESC and CSSC. The specific objectives are: 1. To determine the immunological characteristics of LESC and CSSC in terms of their ability to activate or suppress T cell mediated immune responses. This will be achieved by detailed phenotypic anal yses of the stem cell populations together with in vitro functional immunological assays. 2. To create a mouse model of LSCD in which LESC and CSSC allograft rejection can be studied. 3. To demonstrate the mechanisms of allograft rejection following LESC and CSSC transplantation in the mouse model. 4. To investigate whether the immunomodulatory properties of CSSC can confer improved cell survival onto LESC allografts when both cell types are co-transplanted. 5. To determine whether co-trans plantation of LESC and CSSC from different allogeneic donors is a viable therapeutic option or whether co-transplantation requires a common allogeneic donor for both cell types. The findings will guide immunosuppressive regimes and strategies in corneal cell therapy.

Amount: £828,795
Funder: The Wellcome Trust
Recipient: University College London

Probing the synaptic mechanisms of human genetic neurological disorders 29 Aug 2014

We are interested in how mutations that lead to human neurological disorders (particularly epilepsy) impact neuronal function. Much of our previous work has focused on how mutations change intrinsic neuronal excitability, but epilepsy is increasingly being associated with genes which are also predicted to perturb synaptic activity, and the aim of this project is to probe whether a subset of mutations linked to similar genetic epilepsy disorders have similar consequences for pre-synaptic properties. We will develop a lentiviral tool that will express a fluorescent protein (e.g. RFP) and a cDNA or shRNA to mimic a genetic disorder in a subset of cultured neurons. Recordings will be from untransduced post-synaptic cells, limiting the possibility of post-synaptic genetic effects contaminating readouts of the impact of mutations on synaptic release. We will also investigate whether incorporation of an activating opsin is sufficient for light based stimulation of the pre-synaptic neurons only. By incorporating cellspecific promoters, this project will also allow us to test the hypothesis that mutations that cause seizures have distinct effects in interneurons and excitatory neurons, including how they couple excitation to transmitter release. This project will dissect the synaptic mechanisms of disease, and correlate them with subsets of neurons.

Amount: £162,584
Funder: The Wellcome Trust
Recipient: University College London

PDGF as a cell autonomous regulator of Epithelial-to-Mesenchymal-Transition (EMT) in neural crest cells. 17 Jan 2014

A defining characteristic of neural crest (NC) cells is the epithelial-to?mesenchymal transition (EMT) they undergo to segregate from the neural tube to start migration. EMT is a cellular process converting non-motile epithelial cells to motile mesenchymal cells, showing strikingly common characteristics in metastatic cancer cells and NC cells. Preliminary data suggests that PDGF signalling is required cell-autonomously for NC cell migration in Xenopus laevis embryos whereas PDGF loss-of-function is sufficient to inhibit EMT in in vitro cultures. The proposed project aims to investigate cellular and Molecular mechanisms governed by PDGF during EMT of NC and to extrapolate the gained knowledge onto cancer cell metastasis. We will perform high-resolution time-lapse video analysis of NC EMT comparing gain-of-function and loss-of-function of PDGF in vivo and in vitro. Further study will aim to identify the pathways and downstream targets triggered by PDGF signalling. Finally the gained knowledge will be used to study EMT in cancer cell lines and a transparent zebrafish model allowing the live-imaging

Amount: £41,973
Funder: The Wellcome Trust
Recipient: University College London

How do cells interpret the multiple signals they receive into the complex behaviours of gastrulation? 15 Jul 2013

During early development the embryo generates a complex architecture from multipotent cells. One of the first events is the establishment of bilateral symmetry: during gastrulation, cells rearrange themselves as they acquire different fates, all controlled by signals from different subpopulations of cells. Although we know many of the players, we know surprisingly little aboutwhich particular signal regulates which cell behaviour, or how cells integratesignals to generate regional complexity. Using the chick embryo as a model, wewill first create an atlas of cell behaviours and signalling activity in normal embryos and during experimentally-induced twinning. Subsequently, we will investigate the individual contribution of each of the pathways, and combinations thereof, to these complex cellular decisions, using gain- and loss-of-function experiments in normal embryos and fragments. Finally, we aim to integrate this knowledge by creating an agent model with predictive power, relating signalling to cellular behaviours during normal development and twinning. Together this project will disentangle the roles of different signals in establishing polarity, assigning cell fates and selecting from a vast array of possible cell behaviours during amniote gastrulation, which are also relevant to human twinning.

Amount: £163,023
Funder: The Wellcome Trust
Recipient: University College London

Role of clathrin light chains and other binding partners in generating functional diversity of clathrin heavy chains. 24 Jun 2013

This project aims to study clathrin heavy chain (CHC) binding interactions andhow these interactions diversify clathrin function. CHCs trimerise into a triskelion and can assemble into cage-like lattices on cellular membranes to sequester specific cargo for vesicular transport. There are two isoforms of clathrin heavy chains. Whereas CHC17 binds clathrin light chains (CLC), equivalent binding partners for CHC22 remain to be identified. CLCs modulate CHC17 cage assembly and mediate binding to Hip proteins, which recruit actin to the plasma membrane. Upregulation of both CLCs and Hip proteins are associated with forms of metastatic cancer. In this project, we will focus on three aspects of clathrin interactions: (1) We will investigate how CLC isoforms alter CHC17 clathrin trimer stability, tensile strength and disassembly - physical properties that can govern clathrin function and cargo selectivity (2) We will develop a high-throughput screen for an inhibitor of CLC-Hip interaction. This will provide the platform for drug development and research in metastatic cancer (3) A list of candidates for CHC22 interactions,derived from known binding partners, will be tested and binding regions will be mapped. This will give insight in CHC22 cellular function and allow for inhibitor screening for these interactions.

Amount: £163,023
Funder: The Wellcome Trust
Recipient: University College London

Neuronal and glial energy use and supply 11 Feb 2013

Processing and propagation of information by neurons is energetically expensive. We will investigate the following aspects of energy supply and demand in the grey and white matter of brain slices: (1) how sodium pumping by neurons (which consumes most brain ATP) is regulatedin response to sodium load and is related to oxygen consumption, (2) how a lowered energy supply affects information transfer across synapses, (3) which cortical synapses are mainly responsible for increasing energy supply when neurons are active, and (4) how energy is supplied to developing oligodendrocytes (glial cells) duringmyelination.

Amount: £8,500
Funder: The Wellcome Trust
Recipient: University College London

Retinal repair using ESC-derived cone photoreceptor precursors. 18 Dec 2012

Retinal degenerations leading to loss of photoreceptors are a major cause of untreatable blindness; in particular theloss of cone photoreceptors reduces visual acuity in patients. The Ali laboratory has previously demonstrated proof of principle for cone photoreceptor transplantation into the adult wildtype and degenerate retina. They have shown that cone photoreceptor transplantation is feasible provided the donor cell population are correctly staged post-mitotic coneprecursors, isolated at the peak of cone genesis. As far fewer cones are present in the murine retina compared to rod photoreceptors, a more appropriate strategy to generate cone photoreceptors for transplantation is the use of mouse ES cells. The recent publication of a 3D retinal differentiation protocol closely mimicking the developing neural retina not only provides a model system with which to test the specification of photoreceptors towards a cone cell fate, but also enables the generation of large numbers of photoreceptors for transplantation studies. We hypothesise, that detailed investigation of the developmental signals leading to the acquisition of cone photoreceptor cell fate will lead to improved generation of stem cell-derived cones. This cell population will present a potential to be transplanted to the degenerate retina in order to restore cone-mediated visual responses.

Amount: £27,735
Funder: The Wellcome Trust
Recipient: University College London

Characterisation of genes regulated by S-nitrosylation of HDAC2 during radial neuron migration. 11 Feb 2013

The generation of the laminar structure of the cerebral cortex relies on the radial migration of post mitotic neurons. This proceeds under the control of extremely precise regulatory networks requiring input from multiple extracellular signalling pathways and the co-ordinated expression of nuclear factors that result in specific programmes of gene expression. Recently, in the Riccio lab, we have shown that S-nitrosylation of HDAC2 is required for polarization and radial migration of cortical neurons during the formation of the cerebral cortex. A screen was carried out to identify genes regulated by S-nitrosylation of HDAC2 during cortical neuron migration. Druing this project, 2 candidate genes identified by this screen will be selected and their role in cortical development will be characterised. Key goals which have been set in order to achieve this include the following: 1) Verifying that these genes are upregulated in response to HDAC2 S-nitrosylation. 2) Characterisation of candidate genes expression in vivo 3) Analysis of candidate gene promoter and interaction with HDAC2 4) Characterisation of the function of the candidate genes in cortical neuron polarization and migration, which will include the generation of 2 knockout mouse lines.

Amount: £33,208
Funder: The Wellcome Trust
Recipient: University College London

Neural coding with the tripartite synapse. 10 Jul 2013

In our quest to decipher the brain circuit machinery astroglia have emerged as an important third participant of the signal exchange between pre- and postsynaptic neurons. To understand principles of information processing in such tripartite circuits represents a conceptual challenge. How the multiple modalities of intracellular astrocyte signalling translate into meaningful communication with neurons remains poorly understood. Our long-term aim is therefore to understand how generation, pr opagation and storage of informative signals in tripartite brain circuits form memories and shape a physiological response, in health and disease. We will take full advantage of the on-going methodological revolution in sub-cellular real-time imaging, coupled with pharmaco- and optogenetic approaches ex-vivo and in-vivo and aided by biophysical and neural-network modelling. The five-year strategy will build upon our recent discoveries which have unveiled novel principles of synaptic organisat ion and plasticity including the regulatory role of astrocytic signalling. Firstly, we will employ our novel FLIM-based Ca2+ imaging technique to decipher the code of causalities arising between the synaptic identity and Ca2+ homeostasis machineries at tripartite connections. Secondly, we will establish how the diverse neural signals are integrated and possibly stored by non-excitable astroglia operating their Ca2+-wave communication medium. Thirdly, we will explore and expand the classical rule s of synaptic plasticity to meta-plasticity of the tripartite synapse. Fourthly, we will establish how the operational assemblies of nerve and glial cells interact to support a physiological function. Finally, we will attempt to formulate how astroglial signalling impinges on functional modalities of theoretical neural networks.

Amount: £2,768,760
Funder: The Wellcome Trust
Recipient: University College London

Establishing the Role of the FoxG1 transcription factor in normal and glioma-derived neural stem cells. 16 Sep 2013

Glioblastoma (GBM) is the most common and lethal primary brain tumour. GBMs contain a population of cells that display characteristics of neural stem cells. Understanding the action of the lineage specific transcription factors responsible for orchestrating self-renewal in this population and in their normal stem counterparts offers promise in identifying therapeutic targets. Through pilot studies comparing gene expression in normal NS cell cultures with GBM-derived NS (GNS) cells we have ident ified FOXG1 as a brain-specific transcription factor that is consistently overexpressed in GNS cells. Previous studies have implicated FOXG1 in control of cell cycle and differentiation pathways (p21 and Bmi-1). The aim of this project is to define the function and transcriptional targets of FOXG1 in these malignant and non-malignant contexts. I will make use of established and well characterised NS and GNS cell lines as the model system and use intracranial xenotransplantation as an in vivo a ssay of tumour formation. The objectives are: 1) Monitor the changes in FOXG1 mRNA and protein during differentiation. 2) Perform gain-of-function studies using 'tuneable' overexpression. 3) Perform loss-of -function studies using the latest genome editing technologies (TALENs). 4) Define genome-wide transcriptional targets of FOXG1 using chromatin immunoprecipitation and deep sequencing (ChIP-Seq).

Amount: £13,325
Funder: The Wellcome Trust
Recipient: University College London