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Recipients:
University College London
University of Oxford

Results

Divergent roles of Smad1 and Smad2 in patterning the early mammalian embryo. 16 Jul 2012

The TGF? secreted growth factors bone morphogenetic protein (BMP) and nodal play crucial roles in cell fate specification during vertebrate gastrulation. BMPs, acting via Smad1/5/8 induce 'posterior' or extra-embryonic mesoderm (including the germ cell lineage), whereas nodal signals through Smad2/3 specify the 'anterior' primitive streak and its derivatives. Genetic studies in mice suggest that dose-dependent signaling via Smad1/5/8 and Smad2/3 plays complementary roles in regulating cell fate allocation during gastrulation. Ablation of Smad1 primarily disrupts specification of extra-embryonic mesodermand formation of the germ cell lineage, whereas Smad2 functional loss results in defective gastrulation and enhanced formation of extra-embryonic mesoderm. The underlying causes of these complex tissue disturbances remain ill-defined.Information about Smad-regulated transcripts in the embryo is missing. To identify downstream Smad transcriptional targets, Smad1 and Smad2 mutant embryos will be characterized using a new panel of tissue-specific marker genes and profiled by microarrays and RNA-seq. These in vivo experiments will be complemented by investigation of the differentiation potential of mutant embryonic stem (ES) cells towards distinct cell fates in vitro. The transcriptional networks downstream of Smad1 and Smad2 in the early mammalian embryo also govern human development and disease.

Amount: £159,340
Funder: The Wellcome Trust
Recipient: University of Oxford

The importance of Nef-mediated HLA class I downregulation in HIV-1 and HIV-2 infection 25 Jun 2012

The human immunodeficiency virus (HIV) utilises a number of techniques to evade the immune system and survive in the host. HIV-1 negative factor (Nef) has previously been shown to mediate downregulation of class I human leukocyteantigen (HLA-I) molecules from the surface of cells, which is believed to facilitate evasion of cytotoxic attacks by CD8+ lymphocytes. Furthermore, HLA-B molecules are known to be more resistant to downregulation than HLA-A, whilst HLA-C is not downregulated. Studies so far have primarily used Nef derived from laboratory strains of HIV such as HIV-1SF2, rather than Nef isolated from infected patients. This project aims to explore the role of Nefin a cohort of patients with HIV-1 infection, and correlate the extent of HLA-downregulation with clinical data and progression. Nef from both elite controllers and progressors will be studied. In this cross-sectional investigation, the variability of Nef within the cohort and individual patients will be characterised, and the extent to which the protein mediates HLA-downregulation will be determined using flow cytometry. This phenomenon will also be studied in a well-characterised cohort of patients infected with HIV-2, of which very little is known regarding Nef-mediated HLA-downregulation.

Amount: £159,340
Funder: The Wellcome Trust
Recipient: University of Oxford

Role of interleukin 33 in intestinal homeostasis 25 Jun 2012

This research project will focus on the identification of the role of interleukin 33 (IL-33) in intestinal homeostasis. IL-33 belongs to the IL-1 family and has been shown to mediate both pro-inflammatory and anti-inflammatory processes depending on the disease context. Although IL-33 is produced in high amounts in the intestine little is known about its role ininflammatory bowel disease (IBD) development and progression. In this project I will use in vitro and in vivo systems, including knock-out and reporter mouse strains, in order to describe IL-33 signalling in the gut. Recent studies suggest that intestinal regulatory T cells (Tregs) express high levelsof IL-33R and that this pathway contributes to their function. I will build onthese studies to identify key downstream pathways activated by IL-33 in Treg cells that promote their function and how these are regulated by pro-inflamamtory mediators. Altogether the results of this study may lead to identification of potential novel therapeutic targets in IBD.

Amount: £159,340
Funder: The Wellcome Trust
Recipient: University of Oxford

Developing a novel single dose prime-boost vaccine against malaria 25 Jun 2012

The main goal of this project is to develop a new vaccine delivery platform for a single dose prime-boost immunisation regime that would be applicable to current and future vaccines requiring a prime-boost approach. This novel platform is based on the technological advance of the production ofmicrocapsules from biodegradable polymers, which can act as vehicles into which the vaccine can be incorporated and then subsequently released in a delayed time fashion. After achieving the optimal conditions for the microcapsules and the encapsulated vaccine, the aim is to mix the unencapsulated vaccine with the encapsulated booster vaccine dose and then administer both as a single injection. The new methodology will be tested with our current candidate malaria vaccine regime of heterologous immunisation using different viral vectors as a proof of concept. Using this approach, the vaccine delivery efficiency would be optimised by reducing the number of doses required from multiple into a single dose immunisation regime. Reducing the number of repeated injections would mean reduced costs, fewer clinic visits and a higher compliance rate among vaccinees. A successful single dose formulation could provide strong evidence for the initiation of clinical trials of the new technology with considerable benefitsfor future vaccine development

Amount: £159,340
Funder: The Wellcome Trust
Recipient: University of Oxford

Investigation of signal integration by non-catalytic tyrosine phosphorylated receptors in leukocytes 25 Jun 2012

This work will investigate signal integration in cells through analysis of non-catalytic tyrosine-phosphorylated receptors (NTRs). NTRs are a recently described group of leukocyte cell-surface receptors [1, 2] that share a numberof features, including: i) they contain, or associate with adaptor molecules that contain, tyrosine residues that are phosphorylated by extrinsic kinases such as Lck; ii) they have relatively small extracellular domains (<20nm); iii) they bind surface-associated ligands. I will focus on analysis of interactions between NTRs containing immunoreceptor tyrosine-based activating motifs (ITAMs) and those containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Key goals of the research include: 1) To develop a system for analysis of signal integration at the cell surface 2) To determine whether matched sizes of receptor/ligand pairs are required for signal integration of ITIM- and ITAM-containing receptors 3) To determine the importance of the length of the intracellular tail of ITIM-containing NTRs for inhibitory efficiency

Amount: £159,340
Funder: The Wellcome Trust
Recipient: University of Oxford

Investigation of cross-reactive antibodies against Plasmodium falciparum-infected erythrocytes 25 Jun 2012

The main objectives of the proposed project are twofold; firstly, to identify monoclonal antibodies that broadly react against variant surface antigens on erythrocytes parasitized by diverse Plasmodium falciparum strains, and secondly, to identify the conserved epitopes of the surface antigens that are recognized by these antibodies. Although antibodies against variant surface antigens have been linked to protection against malaria, the prevailing viewpoint is that antibodies against these antigens generated in the course ofinfection are predominantly variant-specific. However, there has been evidencesuggesting some partial cross-reactivity of antibodies, and our preliminary work supports the possibility that broadly cross-reactive antibodies may existin adults who are clinically immune to malaria. This project aims to identify such antibodies by screening large numbers of sera from immune adults against diverse parasite strains. When cross-reactive sera are identified, we will request for blood samples from the individual donors and isolate and transformB cells producing monoclonal antibodies of interest. We will then proceed to identify the corresponding conserved target sites on the antigens, which will be potential targets for vaccine development.

Amount: £159,340
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural and Functional characterisation of chlamydial inclusion proteins. 25 Jun 2012

The project aims to study the structure and function of two chlamydial inclusion proteins. Chlamydia is a major human pathogen, causing sexually transmitted disease and trachoma (a form of blindness). To replicate inside host cells, chlamydia build a specialised intracellular compartment called an inclusion, which is segregated from the host endocytic system but selectively engages key host organelles and secretory traffic. To achieve this, Chlamydiae deliver a family of hydrophobic inclusion proteins (Incs) into the inclusion membrane, but very little is kown about their structure and function. Exploiting our ability to purify these membrane proteins, the project aims to fully understand i0 the bases of membrane tubulation by IncC, ii) the nature of the novel endoplasmic reticulum retention signal within IncB, iii) the host targets if IncC and IncB and their roles during bacterial infection. the arising data will allow new insights into the molecular mechanism of this medicallu important pathogen.

Amount: £162,047
Funder: The Wellcome Trust
Recipient: University College London

Modulation of the folding energy landscape of a nascent polypeptide by interactions with the ribosome surface. 25 Jun 2012

He we propose identifying and developing a fast-folding protein domain as the new ribosome-nascent chain complex (RNC) system, and using a series of destabilising mutations to determine the effect of ribosome attachement on the foding eneregy landscape. Key goals in this project are the establishment of a suitable RNC system; development of NMR methodology for the study of surface interactions; and ultimately measurement of the effect ofribosomal attachment on the protein folding energy landscape.

Amount: £162,047
Funder: The Wellcome Trust
Recipient: University College London

Biophysical and structural investigations of DNA repair modulation by viruses. 25 Jun 2012

Viral proteins subvert various cellular processes to optimise the propogation or stable sojourn of virus genomes. Viral stealth and replication strategies can be compromised by uracil-DNA glycosylase (UDG) activity, making UDG a kown target of viruses infecting both prokaryotes and eukaryotes. In viruses of prokaryotes, UDG is silenced by the diverse protein inhibitors: a deeper investigation of structural diversity in this realm would benefit methodology in low homology bioinformatics, our understanding of protein evaluation, and inform the development of novel inhibitors of DNA repair enzymes. In human HIV-1 infections, UDG is targeted to the proteosome by association with the viral accessory protein Vpr. As a strategy for dealing with incoming virus genomes, it is possible that the UDG's ancillary role in somatic hyper-mutation may be reprised in combination with the anti-viral deoxycytidine deaminase, APOBEC3g (A3G). The HIV-1 accessory proteins Vif (targeting A3G), and Vpr, are therefore appealing anti-viral targets, and therapeutic molecules could likely be developed through biophysical and structural knowledge to their respective interactions. We aim to develop systems to identify novel viral predictors of UDG and to produce viral proteins using Vpr [and Vif with relevance to A3G] stably for biophysical and structural analyses via NMR and x-ray crystallography.

Amount: £162,047
Funder: The Wellcome Trust
Recipient: University College London

The Role of Exported Malaria Parasite Proteins in Pathogenesis. 25 Jun 2012

Understanding the molecular mechanism of protein export by the malaria parasite and the role of exported proteins in parasite survival.

Amount: £162,047
Funder: The Wellcome Trust
Recipient: University College London

The Secret Life of Proteins - Computational and Experimental Studies of Moonlighting Proteins. 25 Jun 2012

The aim of the project is to further our understanding of protein moonlighting (multiple unrelatedfunctions of a single protein). During this project we will explore a number of questions that relate to the molecular mechanisms and properties that allow or enhance the moonlighting potential of a protein. the project will concentrate on computational approaches wit the aim of producing testable predictions, which we then hope to veryify with experimental studies.

Amount: £162,047
Funder: The Wellcome Trust
Recipient: University College London

Nonlinear modelling of courtship behaviour in Drosophila melanogaster. 25 Jun 2012

The proposed research aims to develop mathematical models to help in understanding the relationship between genes, neuronal circuits, and behaviour. A nonlinear model of Drosophila courtship behaviour will be developed to guide experimental studies by providing testable predications about both neural activity and behaviour. Three projects are proposed, modelling different aspects of courtship. The first project aims to model courtship song, in particular switches between two modes of song: sine and pulse. It will be investigated whether switches in male song are related to locomotion changes in the female. The second project aims to develop and evaluate a model of courtship behaviour. A male fly courts a female by tapping, abdomen quivering, singing and licking. Switches between these behaviours seem random. A nonlinear model may account for these switches. A comprehensive computational model will be used to investigate the underlying neural basis of courtship in the fly. The third project aims to extend the model developed in the second project by including experience as a critical parameter. This bridges courtship and memory research in the fly and suggests the possibility of modulation of innate behaviour by individual experience.

Amount: £159,340
Funder: The Wellcome Trust
Recipient: University of Oxford

Recognition of dynamic patterns during auditory scene analysis. 25 Jun 2012

To make sense of complex auditory input signals, the mammalian auditory systemmust group the elements of those signals together into identifiable auditory 'objects' or 'streams'. Neither the perceptual rules that govern this groupingnor the neuronal mechanisms by which it is achieved are fully understood. Thisproject proposes to investigate the role of stimulus directionality in sound grouping. We hypothesise that the auditory system is able to identify the directionality of sounds (specifically, increasing or decreasing pitch, level or spatial azimuth) and use this as a cue to group together sounds with similar direction. This hypothesis will be tested through psychoacoustic experiments. We also propose to investigate the neuronal mechanisms underlyinggrouping by directionality. We hypothesise that neuronal populations in the auditory system explicitly represent the directionality of stimuli, and will record neuronal responses in the ferret auditory system to test this. We will investigate whether this is a predictive code, where future values of the stimulus are predicted by the direction of change of past values and neuronal responses are modulated by the deviation of the stimulus from the predicted value. Using parallel neuronal recordings, we will also investigate whether this representation provides a possible basis for the perceptual grouping effects observed psychoacoustically.

Amount: £159,340
Funder: The Wellcome Trust
Recipient: University of Oxford

Development of diencephalic asymmetries in zebrafish and chick embryos. 25 Jun 2012

While most of the body is symmetrical with respect to the midline, a few functions, including higher order behaviours and cognitive functions in the brain, have evolved to be concentrated on one (left or right) side. Although the molecular mechanisms underlying left/right asymmetry of body organs are now fairly well understood, we still know little about how lateralised brain functions arise during development. Recent research has discovered that the parapineal, an asymmetrically positioned group of neurons in the left diencephalon, is essential for development of asymmetries in the adjacent epithalamus, but little is known about the molecular mechanisms of this regulation. Also, no region equivalent to parapineal has yet been discovered in most vertebrates including birds and mammals, whereas the molecular pathways leading to epithalamic asymmetries are likely to be conserved. This project explores how epithalamic asymmetries develop in two different species - zebrafish and chicken, first by establishing the molecular mechanisms by which the parapineal regulates this process in zebrafish, then by studying

Amount: £162,047
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. 25 Jun 2012

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

Amount: £162,047
Funder: The Wellcome Trust
Recipient: University College London

Morphogenesis underlying choroid fissure fusion. 25 Jun 2012

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

Amount: £162,047
Funder: The Wellcome Trust
Recipient: University College London

PDGF as a cell autonomous regulator of Epithelial-to-Mesenchymal-Transition (EMT) in neural crest cells. 25 Jun 2012

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: £162,047
Funder: The Wellcome Trust
Recipient: University College London

Blastema formation and skeletogenesis during arm regeneration of the brittle star Amphiura filiformis: cellular and molecular characterization. 25 Jun 2012

The aim of this research project is to understand the initial stages of brittle star arm regeneration in terms of stem cell involvement, cell specification and the earliest activation of the skeletogenic gene regulatory network. The brittle star is a marine organism with a unique capability for regenerating whole arms post-amputation or after injury. To determine whether the regenerative blastema, a mass of proliferative cells giving rise to the entire structure, is composed of stem cells or dedifferentiating cells, molecular tools will be employed for their characterization. Stem cell markers and lineage tracing techniques will be used to identify the nature of the cells, their origins and migratory behaviour. The regenerating arm of the brittle star is contains several skeletal structures and the second aim of this project is to understand the cohort of signalling pathways involved in the early specification of the cell lineages which will develop into this adult tissue. This will be achieved by using molecular techniques and a candidate gene approach for studying the genes that have already been well-characterised in the closely-related sea urchin, , for which a complete gene regulatory network for the embryonic development of skeletogenic cells has been published.

Amount: £162,047
Funder: The Wellcome Trust
Recipient: University College London

The influence of spatial and temporal context on information integration during human decision-making. 25 Jun 2012

Decisions often require integration of information from different sources. Integration and choice are shaped by the temporal and spatial context in whichinformation occurs. We propose a series of experiments involving behavioural and neurophysiological recordings that are aimed at characterising these contextual influences and pinpointing their neural substrates. The proposed experiments involve a new paradigm (the 'two streams' task) in which discretesamples of information are presented in two parallel streams, after which participants judge the relative information provided by each stream. Coupled with high-resolution imaging methods such as electroencephalography (EEG), magnetoencephalography (MEG), and functional magnetic resonance imaging (fMRI), and with formal modelling of the decision process, this will allow us to characterise how the processing of each new sample of information is modulated by information presented beforehand (temporal context) and in the opposing stream (spatial context). Neural recordings will allow us to identifythe brain regions were information processing is modulated, with a focus on the parietal and medial prefrontal cortices. We hypothesise that contextual influences on information integration arise from well-described phenomena in the cognitive science literature, such as perceptual priming, spatial attention, and conflict monitoring and resolution, and give rise to suboptimalbiases in decision-making.

Amount: £159,340
Funder: The Wellcome Trust
Recipient: University of Oxford

Cortical mechanisms underlying human behavioural control. 25 Jun 2012

Our brains devote substantial resources towards making profitable choices by often selecting courses of actions with high value, and seldom those with low value. The orbitofrontal cortex has been shown to represent an internal model of the world that allows it to make precise associations between stimuli and rewards and to flexibly guide a goal-oriented behaviour. The hippocampus also has a model of the environment, however it remains debatable if it is restricted to spatial representations only, or if it has a more general role. Interestingly, both of these brain areas have been shown, separately, to make very similar inferences that influence future behaviour. However, their interactions for guiding goal-oriented behaviour are not sufficiently understood. During my DPhil, I aim to study the interactions between the orbitofrontal cortex and the hippocampus using non-invasive human neuroimagingtechniques. My key goals are to dissociate between their functional roles and underlying mechanisms for making stimulus-stimulus and stimulus-reward associations and to explore how these associations are represented in the brain.

Amount: £159,340
Funder: The Wellcome Trust
Recipient: University of Oxford