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University College London

Results

Open access award. 20 Sep 2011

Not available

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

Properties of GABAergic inhibition in the prefrontal cortex. 12 Jul 2011

The molecular mechanisms underpinning GABA receptor mediated synaptic and tonic inhibition in the prefrontal cortex (PFC) will be investigated. Dysfunction of the PFC is implicated together with GABA neurotransmission in numerous neurodevelopmental disorders. The main objective of this project is to analyse the basic mechanisms involved in inhibitory transmission in the PFCand understand how these can be modulated by dopaminergic and serotoninergic pathway activation and by neurosteroids. We will target PV-positive GABAergic interneurons and their target pyramidal neurons in layer II/III of the PFC. Inhibitory transmission will be studied using acute and organotypic brain slice preparations as well as dissociated neuronal cell cultures. The underlying mechanisms will be explored using biochemical, chemical, electrophysiological, imaging (single particle tracking), pharmacological and molecular approaches involving mutated GABA receptors and photo-active receptor ligands. Our understanding of inhibition in the PFC will be used in conjunction with mouse models to try and corroborate their significance with

Amount: £157,778
Funder: The Wellcome Trust
Recipient: University College London

Investigating the potential of the adult epicardium as a stem cell niche, the lineage heterogeneity of the he response epicardium-derived progenitors and the response to injury-induced signalling. 20 May 2011

To characterise the lineage heterogeneity of adult epicardium-derived progenitor cells and to investigate the potential of the epicardium as a stem cell niche; thus identifying the characteristics, that can be altered pharmacologically as a novel approach to regenerative medicine. As well determine whether epicardial activation in response to injury is "organ wide" or localised to the infarct site, to investigate the efficacy of aged epicardium for cardiac repair and to determine injury-induced signals and factors that result in the activation of the epicardium for further mechanistic studies identifying key specific pathways and to design therapeutic agents to activate EPDCs.

Amount: £20,382
Funder: The Wellcome Trust
Recipient: University College London

The role of auxiliary transmembrane proteins in AMPA receptor targeting in neurons. 06 Jun 2011

To investigate the types of AMPA receptor auxiliary proteins that regulate targeting of the receptors to axonal and presynaptic sites, to determine whether these differ from auxiliary proteins involved in receptor targeting at postsynaptic sites, and to understand their role in the regulation of transmitter release.

Amount: £23,306
Funder: The Wellcome Trust
Recipient: University College London

Regulation of N type calcium channel expression, trafficking and modulation. 31 Aug 2011

Voltage-gated calcium channels are essential to numerous aspects of the function of excitable cells. In neurons they are involved in the release of neurotransmitters, and in a number of other processes in which a rise in intracellular Ca2+ is the primary signal. Two very important neuronal subtypes of calcium channels are N-type (CaV2.2) and P/Q-type (CaV2.1), with the former being particularly important at peripheral synapses and neuro-effector junctions, in the autonomic and sensory nervous systems. In nociceptive dorsal root ganglion neurons they are a therapeutic target for anti-nociceptive drugs. The function of these voltage-gated calcium channels may be modulated by several means, for example their expression is controlled by the auxiliary ß as well as a2d subunits, and in the short term they are inhibited by the activation of G-proteins via a variety of G-protein coupled receptors. Over a number of years, my group has examined the properties of cloned calcium channels, expressed both in non-neuronal heterologous expression systems and in neurons. The key goals of the current proposed programme of work relate to four interlinked themes involving CaV2.2 calcium channels: (i) examination of CaV2.2 calcium channel mRNA trafficking and stability, since the mRNA for these channels has particular trafficking motifs in it, (ii) examination of CaV2.2 calcium channel protein trafficking and the role of the auxiliary ß subunits and (iii) study of the mechanism of G-protein modulation of plasma membrane CaV2.2 calcium channels. Finally (iv) we will study the pathophysiological consequences of mis-assembly of CaV2.2 calcium channels. The last theme could also generalise to CaV2.1 calcium channels and may relate to the calcium channelopathy, episodic ataxia-type 2, which is caused by mutations in this channel that are often truncating mutations

Amount: £333,308
Funder: The Wellcome Trust
Recipient: University College London

Thymus transplantation for the treatment of Complete DiGeorge syndrome. 07 Mar 2011

Without intervention, complete DiGeorge syndrome (DGS) results in fatal immunodeficiency, as a result of absent thymic stromal function. Recent therapies focus on transplantation of non-MHC-matched thymic epithelium. This project will investigate the importance of MHC-restriction in immune reconstitution and self-tolerance in DGS patients treated with transplantation of thymic epithelium. To test if appropriate MHC expression in thymic epithelial transplants is necessary for efficient T-cel l immunity and tolerance-induction, we will compare the ability of T-cells from DGS transplant patients to activate and proliferate in response to MHC (+antigen) of host- or donor-origin. We will also establish in vitro and mouse in vivo models to address this question. We will compare tolerance induction in human thymus reaggregate cultures in which the epithelial and haematopoietic components are either MHC-matched or mismatched. To assess the impact of MHC-matching on immune reconstitution i n vivo, we will generate models in which athymic mice reconstituted with human haematopoietic stem cells, are transplanted with human thymic epithelium, expressing either MHC matched or non-matched to the haematopoietic component. In addition, to test if a gene-therapy approach to MHC-matching would be beneficial, we will test if we can improve reconstitution by lentiviral-transduction of matched MHC into thymic epithelial cells.

Amount: £408,095
Funder: The Wellcome Trust
Recipient: University College London

Change detection in human auditory cortex. 07 Oct 2010

The project consists of a series of brain imaging (MEG and fMRI) and psychophysics experiments based on a new paradigm designed to reveal the factors that determine listeners sensitivity to changes in an unfolding acoustic scene. Our stimuli contain unpredictable step-changes ( temporal edges ) in the pattern of fluctuation representative of a wide range of acoustic changes. By carefully manipulating stimulus statistics preceding and following the temporal edge and recording brain and behavio ural responses, we probe the cortical networks that underlie the detection of these events. Our findings to date have already provided important new insights about change processing in the human brain, previously unobserved with classical paradigms such as the mismatch negativity (MMN). Proposed experiments (1 fMRI, 6 MEG, and 2 psychophysics) are designed to broaden our understanding of the stimulus attributes and contextual factors that underlie change detection and sketch-out the processes involved: What acoustic factors does auditory cortex monitor to detect change? Which neural systems underlie change detection and what computations do they implement? How are they affected by the perceptual state of the listener (focus of attention and decision bias)? How is low-level change detection in auditory cortex used by listeners when making decisions about sound events?

Amount: £137,436
Funder: The Wellcome Trust
Recipient: University College London

Differential leukocyte counts and the prognosis of specific coronary phenotypes. 23 Nov 2010

Background: Leukocyte counts are routinely measured in coronary disease and are related to prognosis, but the shape, strength and significance of such relationships, particularly with regard to prognosis of specific coronary phenotypes, are unclear. In addition, there is a need for better risk prediction tools for stable angina. Aims: To investigate the association of counts of leukocyte subtypes with prognosis in patients with stable coronary disease. To examine differences in the shape and strength of the association by start point and endpoint, to assess whether any inference can be made for causality. To develop and validate a risk prediction model for patients with stable coronary disease, and assess the incremental value of leukocyte counts in such a model. To use prognostic risk information for stable coronary disease to explore variation in drug treatment effects. Methods: Analysis of new bespoke prospective cohort study (recruiting patients from cardiology clinics and a ngiography lists), and analysis of large database of linked routinely collected data including the General Practice Research Database (GPRD, 4.7 million patients), the Myocardial Infarction National Audit Project (MINAP, 25,000 episodes linked to GPRD), Hospital Episode Statistics (HES) and death registrations.

Amount: £270,211
Funder: The Wellcome Trust
Recipient: University College London

FTO and appetite regulation. 25 Nov 2010

A single nucleotide polymorphism, rs9939609, in the first intron of the fat mass- and obesity associated gene (FTO) confers the greatest genetic risk for obesity. Subjects homozygous for the at-risk A allele exhibit reduced satiety, increased energy intake and energy-dense food preference. The mechanisms underlying these obesity-prone eating patterns remain unknown. Hypothesising a link between FTO and the gut hormone system, I undertook studies to investigate this. I found that non-obese human subjects carrying the A allele have increased reward responsiveness, an obesity-prone behaviour. Moreover, AA subjects exhibited an attenuated reduction in postprandial hunger and aberrant suppression of the hunger hormone ghrelin. In mice, I found that gastrointestinal FTO expression and circulating ghrelin levels are positively correlated suggesting a regulatory role for FTO on ghrelin. I now wish to build upon these findings with key goals of the proposed work being to investigate: i) the neurobiological effects of FTO rs9939609 using fMRI. ii) the regulatory relationship between FTO and ghrelin. iii) the effect of FTO rs9969309 on appetite and gut hormones in obese patients. The proposed work will offer insights into how FTO results in obesity and may result in the development of genotype-tailored treatment strategies for the at-risk population.

Amount: £235,682
Funder: The Wellcome Trust
Recipient: University College London

Trying and Trying and Trying extension. 21 Feb 2011

Gethan Dick will work with six UCL scientists to write six song poems, each one based on the experience and research of a single scientist. She will then work with six bands, each with their own fans and community of interest, to record the pieces. The songs will be made available for free on CD at a number of venues around London and wider afield, as well as via popular download sites. The final CD will feature text and images from each scientist as a response to the song poem about their work.

Amount: £2,725
Funder: The Wellcome Trust
Recipient: University College London

Development of a novel bioartificial liver device for the treatment of patients with liver failure 28 Jul 2011

In the UK, over 16,000 patients a year die of liver failure. Their livers have the capacity to repair and regenerate, but do not have time to do so. A device temporarily replacing liver function would save lives and reduce the necessity for liver transplantation worldwide.Dr Clare Selden and her team at UCL have developed a prototype 'bio-artificial liver' (BAL) to address this unmet need. Its key element comprises functioning liver cells in an external bioreactor. Plasma from a patient with liver failure will be passed through the bioreactor, contacting the alginate encapsulated liver cells, so that the cells replace those functions that the sick liver cannot perform. The machine will buy time for a patient's liver to improve or, if damage to the liver is irreversible, may buy time until liver transplantation can be arranged. The technology combines alginate encapsulation of a human liver cell line and subsequent culture of the encapsulated cells in a fluidised bed bioreactor - providing a convenient, manipulatable biomass in a form which maximises mass transfer between cells and perfusing plasma. The team have Translation Award funding to complete the design, specification, performance characterisation and manufacture of this fully biocompatible BAL.

Amount: £2,025,379
Funder: The Wellcome Trust
Recipient: University College London

Tomography of type IV secretion system complexes 14 Jun 2010

4.1 Visualisation of available T4SS subcomplexes by ET. Constructs encoding core- and mega-complexes of the pKM101 T4SS plasmid will be transformed into BL21 DE3 and B/r E. coli strains for inducible expression. Samples of induced BL21 DE3 cells will be high-pressure frozen, freezesubstituted into organic solvents and embedded in a plastic resin. Different freeze-substitution protocols will be tested, so as to determine the optimal temperature steps, identify the most suitable fixatives, stains and resin, together with their concentrations, giving rise to the smallest loss of ultrastructure and the best contrast, as assessed by TEM. Room temperature ET will be performed on ultrathin sections of thus prepared resin blocks. The same approach will initially be applied to every new T4SS system or its overexpressed portion. Although the stains and fixatives used in this strategy would almost certainly lead to some structural artefacts, they also greatly improve contrast and are hence desirable for the initial detection of T4SS complexes. This will facilitate the subsequent artefact-free visualisation of T4SS assemblies embedded in vitreous ice, when the strict low electron dose regime severely constraints the signal-tonoise ratio and contrast. Simultaneously, all constructs will also be transformed into B/r H266 cells which when grown in minimal media do not exceed ~0.6 ?m in diameter and are hence suitable for whole-cell CET (24). Tomograms will be recorded at cryogenic temperatures at 300 keV. Low-pass and other types of filtering, together with various denoising methods will also be used. The challenging task of cryo-sectioning will further be attempted on any complexes successfully observed either in plastic-sections or in whole cells (25). 4.2 Approaches to localization of T4SS complexes in tomograms Due to a relatively small size of currently overexpressable and stable T4SS complexes and the possibly low level of constitutive T4SS expression (26), their unambiguous detection under electron microscope will be assisted by using different electron-dense high-contrast labels. Both post- and pre-embedding immunogold labelling will be used to tag an extracellular Flag-tag introduced between ?-helices 2 and 3 of VirB10 in VirB10-containing complexes (9). In this technique, the antigen-specific primary antibody is detected with a suitable secondary antibody conjugated to nano-size gold particles of defined diameter, which can be easily observed under electron microscope. Additionally, a recently developed iron-loaded ferritin-label will be translationally fused to individual T4SS subcomplex subunits and the resulting construct expressed in fur gene knockout B/r H266 E. coli strain, hence providing 3-dimensional information, as opposed to immunogold technique where labelling is limited to section surfaces (24). In addition to electron-dense labelling, determination of positions of T4SSs or of their smaller complexes in the bacterial membrane will be attempted by tracking of extracellular conjugative pili, which are constitutively expressed by exponentially growing E. coli harbouring derepressed T4SS operons. One example of such system is the R1-16 plasmid (27), which will be studied by ET in BL21 DE3, TOP10 or thin B/r cells. If required, discrimination of T4SS pili from bacterial flagella will be achieved through bacteriophage-display approach (28). R1-16 is a deletion mutant of plasmid R1-19, which itself is a derepressed high conjugation frequency mutant of plasmid R1, a close relative of the extensively studied, archetypal F-system (27). 4.3 Cloning of inducible T4SS subcomplexes Despite the possible localization of constitutively expressed T4SSs being restricted to the double-membrane, trace levels of their expression renders them unlikely to be observed in an exposure area of a tomogram. This problem becomes particularly profound for averaging of reconstituted individual sub-volumes, where large numbers are required for better structural characterization. This limitation imposes a need for efficient inducible overexpression of functional T4SS machines. Achievement of this goal would also prove indispensible for numerous functional studies on Type IV secretion. During the proposed PhD research, work will therefore focus also on restriction-free and other approaches to clone the functional T4SS operon of the self-transmissible R388 system (29) downstream of inducible promoters. Overexpression of A. tumefaciens T4SS genes with acetosyringone for ET studies will also be investigated and assessed by the presence of T4SS pili under TEM. In the event of successful detection and purification of new T4SS subcomplexes through pull-down experiments, single particle EM studies will be undertaken. Successful visualization of a wild-type T4SS would open a wide range of possibilities to study its functional and associated structural dynamics.

Amount: £153,066
Funder: The Wellcome Trust
Recipient: University College London

Defining circuits of the basal ganglia circuits for human action selection and instrumental learning. 14 Jun 2010

An unanswered question in human cognition is the precise role of the basal ganglia (BG) will much recent emphasis on reward processing and reward learning. In recent work we have shown that a disposition to act is strongly encoded in BG. Given these findings it is opportune to re examine the precise role of the basal ganglia in action selection and instrumental learning. 1. Effective connectivity in the direct and indirect pathway is enhanced and reduced, respectively, when an action is required compared to when there is no requirement for action. 2. Increased reward enhances activity the direct pathway for Go trials, and enhances activity in the indirect pathway for NoGo trials. 3. Instrumental reinforcement learning involves changes in effective connectivity in these pathways.

Amount: £153,066
Funder: The Wellcome Trust
Recipient: University College London

Olig2 phosphorylation and the regulation of neural stem cell fate 14 Jun 2010

During development of the central nervous system (CNS), neuroepithelial stem cells (NSCs), residing in the ventricular zones (VZ) of the embryonic brain and spinal cord, divide and differentiate to generate all the neurons and glial cells (astrocytes and oligodendrocytes) of the mature CNS. Typically, neurons form before glia. In the ventral spinal cord, for example, embryonic NSCs of the pMN progenitor domain generate several subtypes of motor neurons (MNs) before switching abruptly (at E12.5 in mouse) to production of oligodendrocyte precursors (OLPs). The OLPs then migrate away from the VZ into all parts of the spinal cord before associating with axons, differentiating into post-mitotic oligodendrocytes (OLs) and synthesizing myelin. We aim to address how NSCs switch at a predetermined time from neuron to glial production ? specifically, the mechanism of the MN-OLP fate switch in the ventral spinal cord. Broadly, the proposed project aims to characterize the role and regulation of the basic helix-loophelix transcription factor Olig2 in the MN-OLP fate-switch. Recent work from the Richardson lab showed that a specific serine residue (S147) in Olig2 is phosphorylated during MN specification and de-phosphorylated at the switch to OLP production. What triggers de-phosphorylation of Olig2 at the time of the MN-OLP switch? The sequence surrounding S147 conforms to a protein kinase-A target site, but the identity of the putative phosphatase responsible for dephosphorylation has not been established. What are the targets and co-factors of Olig2 in its different phosphorylated states that coordinate the temporally-defined switch in NSC fate? And what are the functions of the other predicted Olig2 phosphorylation states? This project will involve three distinct lines of investigation. 1: Characterizing the expression of candidate phosphatases/phosphatase inhibitors in the ventral spinal cord at the time of the MNOLP fate-switch. 2: Identifying target genes of Olig2 in its phosphorylated and de-phosphorylated states. 3: Characterizing the developmental function of another Olig2 phosphorylation site, S263, a potential target of p38 mitogen-activated protein kinase (MAPK).

Amount: £153,066
Funder: The Wellcome Trust
Recipient: University College London

Identifying mechanisms of mechanosensation in the Drosophila notum that contribute to the control of epithelial junction remodelling 14 Jun 2010

When two epithelial cells make contact they form a stable cell adhesion complex that finally results in the formation of an epithelium. However when two mesenchymal cells make contact the outcome is completely different: they do not form a permanent adhesion complex and very frequently they move away from each other in a behavior called contact inhibition of locomotion [1]. Intriguingly, cell adhesion molecules such as cadherins are known to be involved in both kinds of cell interaction. The formation and dynamics of the adhesion complex in epithelial cells has been extensively studied [2], but the study of cell-cell interactions and cell adhesion in mesenchymal cells has been rather neglected. The aim of this project is to compare cell adhesion complex formation between epithelial cells and between mesenchymal cells, in order to understand the different outcomes of these two cell interactions. This knowledge would help us to better understand important processes such as epithelial-to-mesenchymal transition and contact inhibition of locomotion; two cell behaviors that are central to both cancer metastasis and cell migration during embryo development. We will use two embryonic cell populations whose behavior has been very well characterized in our lab: neural crest (as a mesenchymal cell type) and placode cells (as an epithelial cell type). Most of the experiments will be performed using Xenopus cells cultured in vitro, but we will also analyze cell behavior in vivo, using zebrafish and Xenopus embryos. The cell adhesion complex has been well characterized in epithelial cells, and several key molecules have been described, such as cadherins, catenins, and elements of the cytoskeleton like actin and myosin. In addition, the regulation of small GTPases, such as RhoA and Rac, has been shown to be essential for the formation and maintenance of epithelial junctions. In this project, we will study in placode (epithelial) and neural crest (mesenchymal) cells: i) the dynamic localization of molecules of the cell adhesion complex during cell contact ii) the dynamics of small GTPases during cell contact and their regulation by elements of the adhesion complex. iii) From the above experiments we expect to find the key elements that regulate the different outcome of epithelial and mesenchymal cell-cell contacts. Based on these results, we will perform functional studies with these molecules in order to change a mesenchymal cell-cell contact into an epithelial interaction and vice versa.

Amount: £153,066
Funder: The Wellcome Trust
Recipient: University College London

What is the difference between epithelial and mesenchymal cell junctions: understanding the molecular basis of contact inhibition of locomotion and epithelial-mesenchymal transition 14 Jun 2010

When two epithelial cells make contact they form a stable cell adhesion complex that finally results in the formation of an epithelium. However when two mesenchymal cells make contact the outcome is completely different: they do not form a permanent adhesion complex and very frequently they move away from each other in a behavior called contact inhibition of locomotion [1]. Intriguingly, cell adhesion molecules such as cadherins are known to be involved in both kinds of cell interaction. The formation and dynamics of the adhesion complex in epithelial cells has been extensively studied [2], but the study of cell-cell interactions and cell adhesion in mesenchymal cells has been rather neglected. The aim of this project is to compare cell adhesion complex formation between epithelial cells and between mesenchymal cells, in order to understand the different outcomes of these two cell interactions. This knowledge would help us to better understand important processes such as epithelial-to-mesenchymal transition and contact inhibition of locomotion; two cell behaviors that are central to both cancer metastasis and cell migration during embryo development. We will use two embryonic cell populations whose behavior has been very well characterized in our lab: neural crest (as a mesenchymal cell type) and placode cells (as an epithelial cell type). Most of the experiments will be performed using Xenopus cells cultured in vitro, but we will also analyze cell behavior in vivo, using zebrafish and Xenopus embryos. The cell adhesion complex has been well characterized in epithelial cells, and several key molecules have been described, such as cadherins, catenins, and elements of the cytoskeleton like actin and myosin. In addition, the regulation of small GTPases, such as RhoA and Rac, has been shown to be essential for the formation and maintenance of epithelial junctions. In this project, we will study in placode (epithelial) and neural crest (mesenchymal) cells: i) the dynamic localization of molecules of the cell adhesion complex during cell contact ii) the dynamics of small GTPases during cell contact and their regulation by elements of the adhesion complex. iii) From the above experiments we expect to find the key elements that regulate the different outcome of epithelial and mesenchymal cell-cell contacts. Based on these results, we will perform functional studies with these molecules in order to change a mesenchymal cell-cell contact into an epithelial interaction and vice versa.

Amount: £153,066
Funder: The Wellcome Trust
Recipient: University College London

Revisiting Jebel Moya: Social and biological evolution in south-central Sudan 30 Nov 2009

Description of the project and its relevance Jebel Moya is a combined cemetery and settlement locality in the south-central Sudan which was excavated in the early 20th century by the founder of the Wellcome Trust, Sir Henry Wellcome. The excavation was overseen by different field directors, employing variable excavation, recording and surveying techniques, over the course of the four seasons from January 1911 - April 1914. Plans for further expeditions were first placed on hold by the outbreak of World War I and subsequently ended by Sir Henry's death in 1936. Around a fifth of the estimated 10.4 hectares of deposits were excavated. It still stands as one of the largest British excavations ever undertaken in Africa and one of the largest cemeteries yet excavated in North-East Africa. Overall, 2792 graves were excavated and recorded. A site report was eventually published by Frank Addison in 1949, followed by Ramkrishna Mukherjee, C. Rao and J. Trevor's 1955 analysis of the osteological remains. Limited re-analyses have since been conducted. Rudolf Gerharz (1994), Isabella Caneva (1991) and Joel Irish (2007). Gerharz only utilised the information contained in Addison's 1949 report, particularly the limited Registrar of Graves, to propose a new tentative chronology; he never re-examined any of the excavation records and materials firsthand. Caneva examined a small sample of pottery, curated at the British Museum, from the earliest settlement period. Irish looked at the remaining teeth to test Mukherjee's hypothesis on population heterogeneity. No previous study has re-examined the excavation records and materials to test the validity of the original site reports, and to re-analyse the social implications of the individual burial assemblages and distribution of graves. Furthermore, there has been no attempt to ascertain the probability of conducting radiometric dating on either the osteological or pottery remains, for example using Accelerator Mass Spectrometry (organic materials) and Thermoluminescence (inorganic materials, including pottery). My accompanying paper from Sudan & Nubia (2009) provides a critical overview of the previous publications mentioned above, details my investigations to date, demonstrates that there remains much information to glean from studies of the materials - both skeletal and associated artefacts - and presents preliminary ideas resulting from analysing the grave card data which I am cataloguing into the first ever electronic database for the site. In addition, I am re-examining the excavated grave, settlement and skeletal materials firsthand. The majority of the grave objects' positions are recorded on the grave and anatomical cards, and also in Addison's register of graves. These factors are also being entered into the database under together with data on the strata, attitude of the burials and the condition of the skeletal remains. Furthermore, Dr Kevin MacDonald (Institute of Archaeology, UCL) will be assisting me in the Petrie and British Museums to analyse the associated settlement and grave pottery which is of chronological, spatial and social interest; this has never been comprehensively undertaken before. Moreover, as a result of research presented at the May 2009 Sudanese Archaeological Research Society's conference (British Museum), Professor Abdel Rahman Ali extended an open invitation to visit the National Museum of Sudan (Khartoum) and work on the housed Jebel Moya materials which remain unstudied. The accompanying Table 1, derived from Frank Addison's registrar of graves in his 1949 publication, summarises the distribution of the artefacts from Wellcome's expedition which are primarily held in museums in Cambridge, Khartoum and London.I will also be using the information provided in the archived records on the skeletal and associated grave artefacts to reconstruct behavioural patterns, social structures and population histories. The previous Jebel Moya publications did not adequately integrate different subsets of data, resulting in an incomplete reconstruction of the social and biological transformations which occurred over the millennia. Theoretical modelling of social and biological evolution has advanced considerably in the 60 years since Addison's publication. Mortuary systems can provide information on social variability through analysing spatial dimensions, in comparison with biological and cultural affiliations: human (biological) bodies are loci of identity at individual and group levels, and are situated within the wider culturally constructed landscape. Places were defined and made significant not just by their physical location but also by materiality, including the skeletal remains. There are two additional avenues which my research encompasses: bone chemistry and DNA analyses. The human skeletal and faunal remains are curated in the Duckworth Laboratory, Cambridge, and some are in a condition where bone chemical analyses could be attempted. Such analyses, if successful, would help shed light on marriage patterns and possible migratory patterns by disentangling intra-site and regional relationships, and also provide information on diet. DNA would help test previous hypotheses of genetic closeness in, for example, the proposed elite cemetery from the late first millennium BC. Dr Tamsin O'Connell (Wellcome Trust Research Fellow, MacDonald Institute) and Professor Martin Jones (Department of Archaeology) will be approached for their assistance. A third avenue, that of disease, could be looked at as a possible future research question. Therefore, the interdisciplinary approach which I employ involves interpreting the relationships between mortuary behaviour, memory and material culture by utilising aspects of bioarchaeology (such as radiocarbon dating and isotopic studies), ethnography, Wellcome's expedition records and the archaeological artefacts housed in different museums. The re-examination of the nature of burial distributions will assist in establishing relative chronologies of graves, cultural histories, patterns of pastoral migrations and interactions with the surrounding regions. There is also the possibility of conducting radiometric dating on appropriate skeletal remains in order to arrive at a firmer chronology than what is currently available. These avenues for research are also detailed in the sub-section 'What can be done with the data' in my accompanying paper.

Amount: £8,300
Funder: The Wellcome Trust
Recipient: University College London

Automated high-dimensional outcome prediction in stroke 19 Mar 2010

Stroke is a significant cause of death and disability around the world yet patient outcomes are not improving as fast as those for similar conditions such as heart disease.A major cause is the difficulty in providing targeted care in a patient group with hugely diverse treatment needs. Dr Parashkev Nachev of the UCL Institute of Neurology, London has been given a Translation Award to develop a system for predicting outcomes in order to provide advance information on the optimal treatment for each patient. The system uses automated brain image analysis with high-dimensional computer-aided inference and exploits the finely specialized anatomical architecture of the brain, capturing the relation between the pattern of brain damage and the outcome in the patient with high fidelity. The Translation Award to Dr Nachev will be used to develop the technology to the point of direct clinical application.

Amount: £392,444
Funder: The Wellcome Trust
Recipient: University College London

Mass Spectrometry Studies of Type IV Secretion Systems. 21 Jul 2009

The emergence of methicillin-resistant Staphylococcus aureus (MRSA), responsible for difficult to treat infections in humans has led to the identification of broad-host-range plasmids carrying antibiotic resistance, conjugated through Type IV Secretion Systems (T4SSs). The T4SS is one of several types of secretion systems that mediates the transport of macromolecules across cellular membranes [1-2]. They are extremely versatile: found in both Gram-negative and Gram-positive bacteria as well as some archaea, they are responsible for secreting a wide range of substrates, including monomeric proteins, multisubunit protein toxins and nucleoprotein complexes. 1) Determine the composition and interacting proteins of the complex using mass spectrometry-based proteomics. 2) Identify the stoichiometry of the complex. 3) Define distance restraints between interacting proteins.

Amount: £152,244
Funder: The Wellcome Trust
Recipient: University College London

The role of Prox1 in the cardiac ent and lymphatic vasculature during development and disease. 29 May 2009

The role of Prox1 in the cardiac lymphatic vasculature during development and disease a) The hypotheses: i) Prox1 is crucial for cardiac lymphangiogenesis; ii) the development of the cardiac lymphatic system is essential for cardiac morphogenesis and function during development; iii) the developmental lymphangiogenesis programme is reinitiated after injury-induced inflammation in the heart. Thus, the aims of the project are as follows: 1. Characterization of the cardiac lymphatics in wild-type mice 2. Characterization of the cardiac lymphatics in conditional Prox1-mutants (Tie2Cre;Prox11oxPnoxP; Nkx2.5Cre;Prox 11oxPnoxP; WT1 Cre;Prox 11oxPnoxP) 3. Characterization of morphological or functional cardiac defects in conditional Prox1-mutants 4. Determination of whether Prox1 acts cell-autonomously, non cell-autonomously, or both and possible secreted downstream factors 5. Determination of defects in lymphatic endothelial cell (LEC) specification and/or migration in a cardiac context. 6. Examination of neo-lymphangiogenesis in Ml-induced wild-type and Prox1-mutant adult hearts 7. Examination of inflammation progression/chronic inflammation in wild-type and Prox1-mutant hearts post Ml

Amount: £152,244
Funder: The Wellcome Trust
Recipient: University College London