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Open access publishing costs 2014/15. 15 Sep 2014

Not available

Amount: £718,235
Funder: The Wellcome Trust
Recipient: University College London

Neurobiology of speech communication:cognition, plasticity and social interactions 03 Dec 2014

Functional imaging studies (PET and fMRI) have revealed that human speech is processed along distinct (though interacting) streams, in ways that are analogous to the functional and anatomical auditory streams seen in animal primate studies. I am proposing a series of studies in which aspects of human speech perception and production are investigated, to identify the neural basis of low level and higher-order control of speech perception, the neural basis of production and perception of speech in different masking contexts, and plasticity and individual differences in speech processing. I am particularly interested in how we can apply these results to the understanding of clinical issues (e.g. aphasic stroke and cochlear implantation), and will address the latter with studies of cochlear implant users and simulations. I also aim to extend this work to consider how the importance of social factors, such as how communicative intent affects the neural regions recruited in addition to those involved in the linguistic processing of speech. This is an attempt to integrate the neurobiology of speech perception and production with themes in social neuroscience, and important link to establish, given the central role of speech as a communication tool.

Amount: £311,157
Funder: The Wellcome Trust
Recipient: University College London

The Spatio-Temporal Role of Dpp in Regulating Growth 23 Jun 2014

<p>One of the main questions still puzzling developmental biologists today is how morphogens direct the patterning and growth of different tissues. To address this question, I plan to study the Bone Morphogenetic Protein 2/4 (BMP2/4)-like ligand Decapentaplegic (Dpp) in <em>Drosophila </em>melanogaster. In the wing imaginal disc, Dpp is secreted from a stripe of cells that is located at the boundary between the anterior (A) and posterior (P) compartments and is thought to form a ong-range signalling gradient. In turn, this gradient regulates the activation of target genes that correctly position wing veins along the AP axis. Many studies have focused on unravelling the mechanism by which Dpp patterns the wing imaginal disc and how this signalling feeds into growth. However, the function of Dpp in regulating growth and proliferation still remains unclear. I will use a conditional allele to genetically remove Dpp from the wing disc at different developmental time points and assess the effect on wing disc growth. My long-term plans include finding a novel way to modulate Dpp signalling (i.e. through optogenetic techniques). By doing this, I hope to gain insight into how morphogens provide cells with positional information in a developing organ.</p>

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

Biomedical Vacation Scholarship. 23 Jun 2014

Not available

Amount: £34,000
Funder: The Wellcome Trust
Recipient: University College London

London's anti-vivisection hospitals 1896-1935. 13 May 2014

London's anti-vivisection hospitals were created to cater for the needs of patients who disapproved of vivisection and vivisectionists. Whether animal experimentation was a productive mode of scientific enquiry was held to be secondary to its moral perils: those who vivisected showed themselves too hard-hearted to be good doctors. Thus patients who attended an anti-vivisection hospital might receive better treatment overall if staff were more compassionate and respectful of patient autonomy. Unp ublished hospital archives and other sources will be used to build up a picture of the work of Londons anti-vivisection hospitals and the financial difficulties that led them to abandon their antivivisection principles. Were their ideals popular with patients but thwarted by opposition from mainstream practitioners committed to advancing the cause of scientific medicine, or were they a non-viable concern that had to be sustained by donations from patrons whose views they promoted? The study will examine the conflict between utilitarianism and virtue ethics. Was the morally virtuous doctor no longer a significant concept in the early-twentieth century or had the nature of virtue changed from personal integrity to public service?

Amount: £42,000
Funder: The Wellcome Trust
Recipient: University College London

Innate immune governance of the fate of inflammatory monocytes in tuberculosis. 25 Jun 2014

Circulating monocytes contribute to tissue resident macrophages at inflammatory foci. Existing data suggest that differential innate immune host-pathogen interactions govern the fate of monocytes and functional heterogeneity of macrophages to influence the outcome of disease in models of Mycobacterium leprae and Mycobacterium marinum infection. I aim to address the question that innate immune interactions also influence the fate and function of monocytes recruited to foci of Mycobacterium tuberc ulosis (Mtb) infection, and inform our understanding of alternative outcomes of tuberculosis (TB) in which macrophages play an important role. In this fellowship, I will test the hypothesis that inflammatory monocytes associated with virulent Mtb strains differentiate to macrophages that support greater mycobacterial growth than those associated with avirulent strains. I will specifically investigate the role of Toll-like receptor 2 dependent innate immune responses to Mtb on the fate inflammato ry monocytes and extend these experimental models to identify the molecular mechanisms which support monocyte survival and influence intracellular mycobacterial restriction. In parallel, I will assess the physiological significance of my in vitro model by testing the hypothesis that transcriptional signatures of monocytes differentiated in vitro by Mtb stimulated innate immune responses are reflected in macrophages at the site disease in human TB.

Amount: £234,234
Funder: The Wellcome Trust
Recipient: University College London

Refinement of gene and cell therapies for inherited immunodeficiencies based on human interventions and developing technologies . 08 Jul 2014

Significant recent advances in gene transfer technology together with improved understanding of basic disease biology have led to remarkable clinical successes in several inherited immunodeficiencies and metabolic disorders, and the realisation that advanced gene and cell therapies can eventually be applied more widely. However, clinical studies have also revealed some initially surprising limitations of technology both generic and specific to individual disease targets. The objectives of this a pplication are to use knowledge gained through experimental studies and first generation clinical trials to acclerate the implementation of more refined approaches. The specific goals are: 1. to examine the efficacy and safety of ongoing first-into-man clinical trials of gene therapy in primary immunodeficiency through detailed molecular and immunological analysis of treated patients. 2. to translate knowledge gained from relevant animal modelling and clinical trials into more refined strate gies in terms of gene delivery and expression. 3. to develop state-of-the-art vector technologies including retroviral gene addition, gene editing, and regulated transgene expression. 4. to explore the feasibility of gene therapy in other disease targets. 5. to understand disease-specific limitations to successful and safe application of gene transfer technology through modelling in relevant laboratory model systems of disease. 7. to establish a streamlined pipeline from concept to clinical application, and thereby to accelerate the adoption of novel cell and gene therapies as standards-of-care for patients with primary immunodeficiencies and other tractable rare diseases.

Amount: £2,394,728
Funder: The Wellcome Trust
Recipient: University College London

Local cyclic AMP signalling in synaptic plasticity. 04 Jun 2014

The second messenger cAMP can trigger long-term potentiation of synapses following electrical or hormonal stimulation. cAMP is elevated within different subcellular compartments, depending on the stimulus, where its primary intracellular receptor protein kinase A (PKA) is anchored in proximity to its substrates. I will investigate three poorly understood elements of local cAMP signalling. First, I will engineer synthetic PKA regulatory and catalytic subunits to enable identification of PKA subst rates and anchoring proteins associated with different forms of long-term potentiation. Second, using temporally-controlled crosslinking, I will test a novel hypothesis for explaining how different sub-neuronal populations of PKA are isolated from one another. Third, I will combine structural, biophysical and electrophysiological methods to determine how the AKAP79 postsynaptic complex coordinates local cAMP and calcium signals. The research will benefit from collaborations with proteomics exper ts in Zurich, and ion channel specialists at UCL. Taken together, this work will advance understanding of the molecular basis of synaptic plasticity, and generate technologies that can be applied in other biological systems including the heart. The research is relevant to disease as the synapse is a locus for pathological mutations, and modifying cyclic AMP signaling is a potential avenue for disease intervention.

Amount: £837,024
Funder: The Wellcome Trust
Recipient: University College London

Basal ganglia network degeneration and cortical network compensation in Huntington's disease. 18 Feb 2014

Background: Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin gene. Neuronal degeneration occurs initially in the striatum and progresses to other subcortical and cortical structures. HD gene carriers may be split into pre-manifest or manifest groups based on the unified Huntington's disease rating scale total motor score. Extensive white matter loss occurs prior to the onset of overt motor symptoms in the pre-manifest stage. Aims: Us ing diffusion tractography in pre-manifest HD and controls, I will evaluate longitudinal change in structural basal ganglia connectivity. Differences in functional cortical and sub-cortical brain networks will be characterised using resting state fMRI. By combining tractography and resting state fMRI I will investigate the correspondence between functional and structural networks. Associations with symptomatology and disease burden will also be evaluated. Methods: Diffusion tractography and r esting state fMRI will be analysed using graph theory in 110 pre-manifest HD and 112 controls, at one time point. Basal ganglia connectivity will be assessed at two time points. Implications: Understanding how HD affects basal connectivity and brain networks will shed light on pathogenesis and compensatory mechanisms in HD and other neurodegenerative diseases.

Amount: £165,423
Funder: The Wellcome Trust
Recipient: University College London

Defining the role of Lrig1- dependent EGFR signalling pathway inhibition in airway homeostasis and lung cancer development. 21 Nov 2013

The EGFR pathway is important in cell division, proliferation, angiogenesis and apoptosis. Aberrations of this pathway occur in lung cancer, with increased activity one of the earliest changes seen in preinvasive squamous cell lung cancer. Lrig1 is a membrane- associated negative regulator of EGFR signalling and has recently been shown by the host laboratory to have a tumour suppressor role; it negatively regulates proliferation at cell-cell contact and is lost in preinvasive lung cancer but p resent in normal airway epithelium. Intriguingly I have shown Lrig1 is associated with known progenitor populations in developing murine airways. My proposal establishes the role of Lrig1 in airway homeostasis, development and repair and delineates how its loss results in cancer development. I hypothesise Lrig1 expression controls airway cell homeostasis and its loss is sufficient to initiate pre-invasive lung cancer My key objectives are:- 1. To delineate the role of Lrig1 expression in normal, repairing and cancerous human and murine airways 2. To determine the role of Lrig1 in airway homeostasis and lung cancer initiation 3. To identify the mechanisms by which Lrig1 regulates epithelial growth and cancer initiation, and to generate therapeutic candidates

Amount: £287,812
Funder: The Wellcome Trust
Recipient: University College London

The NKG2D pathway in hepatitis B associated hepatocellular carcinoma in a highly endemic setting 25 Nov 2013

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide; there is an urgent need to better understand mechanisms underlying its immune surveillance to allow their therapeutic manipulation. Animportant pathway implicated in tumour surveillance is the expression of the activatory receptor NKG2D on NK cells, interacting with NKG2D ligands (NKG2DL)induced on cancer cells. I hypothesise that a major factor influencing HCC development and prognosis in the context of chronic hepatitis B virus infection (CHB) is a deficit in NKG2D-mediated NK cell cytotoxicity. This could result from loss of NKG2DL expression by HCC and/or secretion of solubleNKG2D ligands, leading to NKG2D downregulation on NK cells and reduced cytotoxicity. I propose to investigate these mechanisms using direct ex vivo analysis of NKG2D/NKG2DL expression in peripheral blood and liver biopsy samples from a cohort of patients with CHB +/- HCC collected in a high prevalence setting (PROLIFICA study, The Gambia). Functional experiments probing and artificially enhancing NKG2D interactions will be carried out

Amount: £325,613
Funder: The Wellcome Trust
Recipient: University College London

Structural vulnerabilities and maternal health among Mexican indigenous populations. 11 Dec 2013

This research will ask how structural inequalities operate symbolically and through everyday activities to put indigenous people more at risk of harm and explore how this can be addressed through interventions. To address this I will conduct an in-depth study of maternal health in Mexican indigenous communities from the conceptual position of structural violence and develop an intervention strategy. The project will begin with a review of research on structural violence relating to women's h ealth in order to identify a set of structural risk factors and mechanisms. The ethnographic element will centre on in-depth interviews with twenty pregnant women and twenty key informant interviews. I will explore how social, cultural, economic and political structures operate to curtail agency by limiting individual decision making processes. Data will be analysed for theoretical interpretation and will feed into a series of Design Focus Groups through which stakeholders and community members will develop an intervention strategy that addresses the fall-out of structural inequalities on community and structural levels. Goals are: 1)Conduct an ethnography of maternal health from the positionality of structural violence 2) Develop an intervention strategy to address this on community and structural levels.

Amount: £345,811
Funder: The Wellcome Trust
Recipient: University College London

The role of c-Jun in controlling the repair-supportive phenotype of Schwann cells in injured nerves. 17 Jan 2014

<table> <tbody> <tr> <td>Work in the Jessen and Mirsky laboratory, using a mouse in which the transcription &nbsp; factor c-Jun has been inactivated in Schwann cells only (c-Jun-cKO mouse), &nbsp; shows that the Schwann cell response to nerve injury depends on activation of &nbsp; the transcription factor c-Jun in Schwann cells, and that this protein &nbsp; specifies the phenotype of the Bunger repair cell, a cell essential for nerve &nbsp; regeneration. Consequently, nerve repair is severely compromised in c-JuncKO &nbsp; mice. This project will address the following issues: 1) Establish an in &nbsp; vitro model of the regeneration deficit in c-Jun-cKO mice, using adult DRG &nbsp; neurons and Scwann cells from injured nerves. 2) Use this model to analyse &nbsp; Schwann cell factors that control axon growth and neuronal survival. 3) Test whether &nbsp; axonalregeneration and neuronal survival can be improved by enhancing Schwann &nbsp; cell c-Jun expression. 4) Determine whether the diminishing ability of distal &nbsp; nerve tosupport repair with time after injury ( the deterioration of the &nbsp; distal stump ) is due to instability of the Bungner repairsupportive &nbsp; phenotype, and its gradual attenuation. 5) Test whether the repair-supportive &nbsp; Schwann cell phenotype</td> </tr> </tbody> </table>

Amount: £40,094
Funder: The Wellcome Trust
Recipient: University College London

Morphogenesis underlying choroid fissure fusion. 17 Jan 2014

<table> <tbody> <tr> <td>Coloboma is a defect in the morphogenesis of the eye that results from failureof &nbsp; choroid fissure closure. It is among the most common congenital defects in &nbsp; humans and can significantly impact vision. However, very little is known &nbsp; about the developmental mechanisms regulating choroid fissure fusion. &nbsp; Therefore, I aim to resolve the cellular and molecular mechanisms underlying &nbsp; choroid fissure closure by high-resolution 4D confocal imaging of zebrafish &nbsp; retinal cells during fusion. In particular, I will investigate how cell cycle &nbsp; progression regulates the epithelial remodelling that accompanies fusion.</td> </tr> </tbody> </table>

Amount: £41,769
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

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

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

Probing the inhibitory neurosteroid binding site on the GABAA receptor 17 Jan 2014

<table> <tbody> <tr> <td>Neurosteroids are naturally occurring potent modulators of type A GABA receptors in the&nbsp;brain. Although there are many neurosteroid metabolites, these can be characterised into two distinct classes - those that potentiate GABAA &nbsp; receptor function and those that inhibit. Previously we deduced where &nbsp; potentiating neurosteroids bind on the GABAA receptor, but the inhibitory neurosteroids remain unaffected if this site is disrupted. This concurs with &nbsp; the belief that such inhibitory neurosteroids bind to another discrete site &nbsp; onthe GABAA receptor. Its discovery will allow the function of the inhibitory &nbsp; neurosteroids to be explored in the brain. We will select a GABA receptor &nbsp; thatlacks sensitivity to inhibitory neurosteroids and use this structure in &nbsp; combination with GABAA receptor subunits to make chimeric and eventually &nbsp; pointmutated receptors to identify the inhibitory neurosteroid binding site. &nbsp; Once the site is found, we will disrupt its function and then observe the &nbsp; consequences for inhibitory synaptic and tonic inhibition. Overall, this &nbsp; studywill use structural, electrophysiological, imaging, pharmacological and &nbsp; molecular approaches with GABA receptors. This study will bring much need &nbsp; clarity to the role and importance of inhibitory neurosteroids in the brain.</td> </tr> </tbody> </table>

Amount: £14,903
Funder: The Wellcome Trust
Recipient: University College London

Predicting language outcome and recovery after stroke (PLORAS) 04 Jun 2014

The main goal is to provide proof of principle for a clinically useful tool that will predict recovery of language abilities after stroke. There are three separate but interacting lines of research, to be conducted in parallel: (A) Using structural neuroimaging and behavioural assessments, we will identify lesion and non-lesion factors that are most likely, and least likely, to cause long term communication difficulties. The influence of the identified factors will be tracked over months and years following the stroke to understand how recovery unfolds over time. (B) Using functional neuroimaging and dynamic causal modelling, we will map the brain areas that are activated when the patient is speaking or comprehending speech. This will provide a mechanistic understanding of the language pathways that are able to support recovery after damage to the normal system. (C) We will develop an easy-to-use web-basedsystem that will provide patients, their carers and clinicians with the likely time course of recovery on the basis of probabilistic summaries ofother patients in our database who have corresponding brain damage according to the carefully constrained criteria developed in (A).

Amount: £156,004
Funder: The Wellcome Trust
Recipient: University College London

Open access award 2013/14. 16 Sep 2013

Not available

Amount: £500,000
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

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