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Recipients:
University College London
Award Year:
2008

Results

Two-component signalling systems in NT-26 - arsenite utilizing bacterium. 29 Aug 2008

NT-26 is arsenite-utilizing bacterium whose whole genome sequence has recently become available. Capitalizing on our previous studies on regulation of enzyme arsenate oxidase and the availability of the genome information the aims of this project are: To carry out gene annotation, identify and analyse the sequence of all two-component signaling system pairs in bacterium NT-26; To explore the cross-reactivity between various two-component signaling pathways in this organism; To investigate arsenite binding within AroS histidine kinase; To initiate crystallization and structure determination of selected domains from the identified signaling proteins.

Amount: £148,911
Funder: The Wellcome Trust
Recipient: University College London

Bridging disulfides with halomaleimides. 29 Aug 2008

The repertoire and functionality of proteins in mammal cells is greatly enhanced by post-translational modifications. These include the addition of polymers and small groups to the protein, the formation and change of the orientation of single bonds and the modification of amino acids. The possibility to artificially mimic the cells' ability to modify proteins yields great opportunities to gain a deeper insight into function and regulation but would also lead to the creation of new applications with a diagnostic and clinical background. One of the main obstacles yet to overcome in the synthetic modification of proteins is the poor selectivity exhibited by the methods that are available at present. In order to sustain the ability of a protein to bind its interaction partner or to accomplish its designated role it is vital that any artificially modification interferes as little as possible with its structure and its function. This can only be achieved if the applied chemistry allows the attachment of one or more functional molecules at one or more well-defined sites with high selectivity. Cysteine is widely considered the easiest amino-acid to selectively modify, due to its high nucleophilicity. However cysteines present in proteins often have a catalytic function or are inaccessible due to their incorporation in disulfide bonds. Free cysteines can be generated by subjecting proteins containing disulfides to mild reducing conditions, but solvent exposed disulfide bridges often fulfil the role of a stabilising feature of the structure and their breakage often leads to denaturation. One possible approach to preserve the protein structure would be the reconnection of the two cysteines after the reaction. We are proposing to develop a new class of reagents, the dihalomaleimides (e.g. dibromomaleimide), for this purpose (Scheme 1). Each cysteine from the disulfide can displace one of the bromines on the maleimide to afford the bridged product. By varying the R group we can, in a highly controlled manner, incorporate a range of functional moieties onto the protein.

Amount: £148,911
Funder: The Wellcome Trust
Recipient: University College London

Influenza A: Understanding changes in selective constraints occurring during host shifts. 29 Aug 2008

The proposed aims are to: 1) Develop methods of phylogenetic analysis that will allow us to identify changes in selective constraints that occur during host shifts in influenza. 2) Identify locations where such selective constraint shifts have occurred during shifts from avian to human hosts, and the nature of these changes. 3) Expansion of the model to include the selective constraints in swine influenza. 4) Establishment of measures of 'avianicity', 'humanicity', and 'swinicity', the propensity of a virus or genomic segment to undergo host shifts to humans or swine, respectively. 5) Identify whether the viral strains that underwent host shifts were random or exceptional, whether it was a question of mutations that made such a shift more likely, or rather random opportunism. 6) If time permits, develop other models that characterise the changing nature of the selective constraints in other circumstances.

Amount: £148,911
Funder: The Wellcome Trust
Recipient: University College London

Probing ribosome-nascent chain complexes by NMR spectroscopy and molecular dynamics. 29 Aug 2008

Protein synthesis occurs on ribosomes within all living organisms. The newly synthesized 'nascent chain' emerges from the ribosome one amino acid at a time and explores conformations that eventually lead to its folded structure. This project aims to use structural methods, in particular NMR spectroscopy combined with molecular dynamics simulations to determine structures of emerging nascent chains on their parent ribosomes. Biochemical/biophysical studies have shown that nascent chains can obtain native-like structure on their ribosomes and display activity. We have shown [e.g. 1 ,2] that NMR can uniquely provide structure and dynamics of ribosome nascent chain complexes (RNCs), allowing monitoring the emergence of folded structure. Among the RNCs to be considered here will be the biosynthesis of a disease-associated intrinsically disordered proteins (lOPs). We will answer questions such as how they avoid aggregation/degradation, what conformations are sampled on the pathway, how these differ from those in isolated solution, whether molecular chaperones interact with them, and whether protein targets of these proteins can interact with them before their ribosomal release. Protein conformational diseases include a range of degenerative disorders in which specific peptides or proteins - often lOPs - misfold and aberrantly self-assemble, often in the form of amyloid fibrils. These include Alzheimer's, Parkinson's, and Huntington's diseases. a-synuclein is a well-studied and increasingly prominent protein, the aggregation of which is linked to the pathogenesis of Parkinson's disease. Indeed, a-synuclein is the major component of Lewy bodies, the protein-rich aggregates found post-mortem in the brains of patients suffering from Parkinson's disease or a number of related diseases. By preparing a-synuclein-RNCs, high-resolution snapshots of the conformational properties sampled by asyn as it is synthesized on the ribosome will be obtained as well as it's interactions with the molecular chaperone, Trigger Factor (TF). Such structural data will be combined with novel MD simulations to provide a detailed structural/dynamical information the ensemble of structures sampled during the progressive emergence of the nascent chain and it's interactions with the ribosome. Additionally, the pathological conversion of misfolded proteins into cytotoxic species is modulated by interactions with several proteins, among them molecular chaperones such as the Trigger Factor (TF}, which will also be studied. This work will provide detailed insights into protein folding at the level of synthesis and will have applications to understanding protein misfolding and its links to biology and the onset of disease.

Amount: £148,911
Funder: The Wellcome Trust
Recipient: University College London

Computational studies of the usher outer-membrane assembly platform involved in pilus biogenesis. 29 Aug 2008

a. Model the complete usher structure (dimeric form) from p pili in its native environment (periplasm and OM) using tools such as cryo-electron microscopy density fitting, homology modelling and solvation methods. b. Apply standard molecular dynamics (MD) simulations on various components of the usher within their native environment. c. Use SMD and ABF methods to understand and quantify the conformational changes that occur in the usher protein upon translocation of pili subunits across the membrane. d. Develop a web-based resource that will summarize all the experimental and computational structural and biophysical data on the p and type 1 pi lis systems.

Amount: £148,911
Funder: The Wellcome Trust
Recipient: University College London

Vacation Scholarships 2008. 27 May 2008

Not available

Amount: £22,800
Funder: The Wellcome Trust
Recipient: University College London

Investigating dendritic computation in pyramidal cells. 17 Apr 2008

1) Measure voltage in the dendrites and spines of cortical pyramidal cells during back propagating action potentials (BAP) and synaptic input. 2) Investigate the properties of synaptic integration in pyramidal cells with different spatio-temporal patterns of excitatory synaptic input, with the aim of exploring the conditions that produce linear and nonlinear synaptic integration. 3) Examine how inhibitory synaptic input influences synaptic integration in pyramidal cells with a particular focus on whether inhibition can affect nonlinear dendritic processes.

Amount: £148,655
Funder: The Wellcome Trust
Recipient: University College London

'The influence of network activity on the spatiotemporal receptive fields of mouse V1 neurons'. 17 Apr 2008

The project will investigate the influence of neuronal population activity on receptive field properties of individual neurons in mouse visual cortex at different developmental ages in order to understand how this region of the brain becomes specialised for sensory processing. Particular emphasis will be made on characterising the synaptic mechanisms which shape receptive fields in response to different types of visual stimuli.

Amount: £148,655
Funder: The Wellcome Trust
Recipient: University College London

'Mechanisms of transplanted photoreceptor precursor migration and integration'. 17 Apr 2008

To examine the mechanisms by which transplanted photoreceptor precursor cell migrate into the recipient retina and to compare these mechanisms with those by immature photoreceptors in embryonic development

Amount: £148,655
Funder: The Wellcome Trust
Recipient: University College London

Inhibitory processes in human voluntary action. 17 Apr 2008

The phenomenon of the conscious intention to act is an elusive but interesting aspect of cognition. Actions can be classified as being either stimulus driven or voluntary (Goldberg, 1985). In this context, stimulus driven actions are those that are done in response to an external stimulus. This external stimulus, through an association however arbitrary, unequivocally specifies the movement to be done. Voluntary actions, on the other hand, do not appear to be elicited by any obvious external stimulus. Instead, they arise as a result of the integration of many different sources of information. (Cunnington et al., 2002, Haggard, 2008). According to one recent model, three main components characterise voluntary action (Brass and Haggard, 2008). These are decisions regarding not only the identity (what) and the timing (when) of the action, plus a final check that allows withholding a prepared action (whether decision). This final ?veto? or Intentional Inhibition (II) would be important not only as a self-control mechanism, but also in situations where the task environment has changed. As actions are planned with some anticipation, it is reasonable to expect an online checking mechanism to be advantageous for flexible and appropriate behaviour. Experimental paradigms designed to address voluntary action are very often subject to criticism. Because experiments should be reproducible and interpretable, they tend to be simple, artificial in nature and of a low ecological value (Libet et al., 1983, Haggard and Eimer, 1999, Lafargue and Duffau, 2008). A genuine ?urge? to perform an action is hard to generate in the laboratory environment. Objective methods for studying intentions and convincing measures of the subjective experience of intention are thus relatively scarce. Increasing interest has arisen in the potential mechanisms for II, but in order to experimentally address II, one needs to achieve four things: - generate the urge to perform a movement, - induce participants to prepare to make the movement - allow them to choose to refrain from doing the movement at the very last moment, and - have an appropriate measure of this inhibition. By definition, there is no behavioural outcome to this kind of paradigm. Despite this methodological problem, some experimental paradigms have yielded robust results. Brass and Haggard (2007) asked participants to prepare a button press and to inhibit the prepared action in some trials. They have shown the selective activation of a brain area, associated with an endogenous cancellation function. An area of the anterior frontomedian cortex (dFMC), rostral to the presupplementary motor area (preSMA), was activated more when subjects had to cancel a prepared action than when they carried on with it. We propose to develop a more naturalistic and physiologically plausible paradigm for intentional inhibition, based on inhibiting the urge to scratch following electrically induced itch. In this proposed paradigm, although the urge to move is driven by a specific itch stimulus, the inhibition of the scratching is self-generated, and related to the urge to scratch. This combination therefore represents a significant improvement to the traditional paradigms of II used thus far.

Amount: £148,655
Funder: The Wellcome Trust
Recipient: University College London

Interaction of Decision-making and Action Planning in the Human Brain. 17 Apr 2008

The current project aims at a more detailed understanding of how the brain translates decisions into actions. Traditionally, decision-making and action planning are considered (and studied) as separate processes that occur largely independently, with brain processes leading to a decision required to precede those involved in planning the resulting action [1,2]. Recent evidence suggests that in a large number of cases, decision-making occurs in an action-dependent way, sharing common neural resources with action selection [3-6]. For example, decision-related neural signals can be observed in areas traditionally assigned to ?motor processes? (e.g. superior colliculus: [7]; frontal eye field: [8]; premotor cortex: [9]. In the human brain, the interplay between decision-making and action planning remains to be determined. In particular, it remains is unclear (1) whether different systems subserve decisions that are related or unrelated to specific actions [10], and (2) how different decision variables influence and enter the motor system when the decision is linked to a particular action. The proposal addresses these timely questions, using a combination of non-invasive neuroimaging, electrophysiological recording, and neurostimulation techniques in healthy human adults.

Amount: £148,655
Funder: The Wellcome Trust
Recipient: University College London

Higher resolution cardiovascular epidemiology: unique insights from linking the national cardiac event register with primary care records and highly phenotyped cohorts. 16 Jul 2008

Background Our understanding of the aetiology of coronary disease in populations has been limited by low resolution in three key dimensions: phenotyping different coronary syndromes, the timing and evolution of risk, and the interplay between different risk factor domains. This uncertainty motivates each of our aims: Aim I Curation of novel research platform We will establish, validate and curate for the wider research community new, internationally unique, large-scale resources based on link ing the national myocardial infarction register to the rich longitudinal primary care record and highly phenotyped cohorts in the UCL genetics consortium. We will focus on stable angina, unstable angina, non-STEMI and STEMI (about 146,000 linked cases). Aim II Research To what extent are risk factors for specific chronic or acute coronary syndromes different from those of undifferentiated coronary disease aggregates? Across short and long-term risk periods, in aetiologic and prognostic set tings, we will address major aetiological domains including: social and psychosocial factors, physical environment, inflammation, biological markers and genetics. Aim III Training and education We will develop, deliver and evaluate new training opportunities at short course, MSc and PhD level to spawn a new cadre of academics trained in exploiting multiple sources of EPR for health research.

Amount: £1,159,056
Funder: The Wellcome Trust
Recipient: University College London

Development of a novel mammography system based on X-ray phase contrast imaging 11 Apr 2008

The objective of this proposal is to build a laboratory prototype X-ray phase contrast imaging (XPCi) system so that the potential of the technique can be demonstrated to interested commercial partners by imaging ex-vivo breast tissue. Synchrotron radiation (SR) experiments have demonstrated that XPCi solves one of the basic problems of diagnostic radiology, i.e. poor image contrast due to small X-ray absorption differences. This problem is particularly significant in mammography where most lesions have absorption characteristics close to those of healthy tissue. XPCi overcomes this limitation because it uses a different physical effect, i.e. refraction/interference of X-rays rather than their absorption. Exploitation of these effects has led to an increase in image contrast and lesion detecability as reported by clinical radiologists. A novel technique, recently developed by the applicants, makes the advantages of XPCi attainable with conventional x-ray sources and detectors. The technique uses coded apertures placed either side of the tissue to be imaged that splits the beam into micro-shafts of photons. These individual beams are aligned with the edges of pixels to ensure that when phase effects occur they cause significant changes in the pixel response. Unlike SR based XPCi this technique can be used with polychromatic, divergent X-ray beams and hence will allow XPCi based upon a conventional mammography source to be transferred into clinical practice. It is this technology that will be exploited and evaluated in the current proposal.

Amount: £460,735
Funder: The Wellcome Trust
Recipient: University College London

Assessing the challenges faced by health systems in providing paediatric Cotrimoxazole prophylaxis in resource limited countries. 15 May 2008

HIV exposed infants are 16 times more likely to die in their second six months of life than unexposed infants, largely due to respiratory infections. Cotrimoxazole prophylaxis significantly reduces both mortality and morbidity. In Zimbabwe it is estimated that only 11% of exposed infants are prescribed cotrimoxazole and the extent to which it is correctly taken is unknown. The aim of the project is to describe the process and obstacles to provision of cotrimoxazole prophylaxis for HIV exposed infants in three sites in Zimbabwe, focusing on issues related to drug supply and adherence. This information will be used to develop an evidence-based intervention for improving its provision. The study will be conducted in three phases in two Zimbabwean health centres, one urban, one rural: 1) guidelines and standard operating procedures for PMTCT, cotrimoxazole prophylaxis and aftercare of HIV infected mothers will be studied; 2) implementation activities at study clinics including identification of HIV infected mothers, procedures for ensuring babies are prescribed cotrimoxazole and adhere to treatment will be assessed as will aftercare for HIV positive mothers; 3) the findings will be disseminated to stakeholders to identify solutions and develop an evidence based intervention relevant for Zimbabwe and the wider region

Amount: £35,697
Funder: The Wellcome Trust
Recipient: University College London

Assessing the challenges faced by health systems in providing paediatric Cotrimoxazole prophylaxis in resource limited countries. 16 Sep 2008

HIV exposed infants are 16 times more likely to die in their second six months of life than unexposed infants, largely due to respiratory infections. Cotrimoxazole prophylaxis significantly reduces both mortality and morbidity. In Zimbabwe it is estimated that only 11% of exposed infants are prescribed cotrimoxazole and the extent to which it is correctly taken is unknown. The aim of the project is to describe the process and obstacles to provision of cotrimoxazole prophylaxis for HIV exposed infants in three sites in Zimbabwe, focusing on issues related to drug supply and adherence. This information will be used to develop an evidence-based intervention for improving its provision. The study will be conducted in three phases in two Zimbabwean health centres, one urban, one rural: 1) guidelines and standard operating procedures for PMTCT, cotrimoxazole prophylaxis and aftercare of HIV infected mothers will be studied; 2) implementation activities at study clinics including identification of HIV infected mothers, procedures for ensuring babies are prescribed cotrimoxazole and adhere to treatment will be assessed as will aftercare for HIV positive mothers; 3) the findings will be disseminated to stakeholders to identify solutions and develop an evidence based intervention relevant for Zimbabwe and the wider region

Amount: £73,801
Funder: The Wellcome Trust
Recipient: University College London

Imaging Brains, Changing Minds. 16 Apr 2008

'Imaging Brains, Changing Minds' is a radio drama that uses the fictional experiences of characters in the past, present and future to explore the far-reaching impact of brain imaging technologies on the way we construct, treat and legislate the interior lives of others. The drama will be broadcast to an international audience on Resonance 104.4fm and further disseminated via a podcast on the web. A series of live readings from the drama and panel discussions about the issues it explores will be accompanied by a film of images of the brain, recorded in different eras and with different technologies.

Amount: £29,931
Funder: The Wellcome Trust
Recipient: University College London

Methyl-CpG-binding protein 2 (MeCP2) and the Control of Neuronal Plasticity in Nociceptive Pathways. 16 Sep 2008

Our previously published research suggested that noxious stimulation relieved gene repression by MeCP2, leading to the expression of a number of genes in specific populations of dorsal horn neurons and increased pain sensitivity. This proposal is an investigation of the regulation of persistent pain sensitivity by modulation of MeCP2 activity but is more generally concerned with the role of MeCP2 in the regulation of neuronal plasticity. We will study MeCP2 activity following activation of pai n pathways concentrating on both the phosphorylation of MeCP2 as a mechanism for gene de-repression as well as the inhibition of MeCP2 translation by activity-dependant regulation of microRNA miR-132. We will also study the influence of MeCP2 target genes on persistent pain states and the effects of MeCP2 gene deletion on pain signalling. Specifically, we will investigate the pain phenotype of pre-symptomatic mice that are either MeCP2 male nulls or female heterozygotes . The use of female heterozygotes has the advantage that MeCP2 is deleted in a mosaic fashion throughout the central nervous system allowing us to study the behaviour of adjacent neurons which are either normal or lack MeCP2.

Amount: £266,332
Funder: The Wellcome Trust
Recipient: University College London

Control of synaptic transmission by scaffold proteins. 28 May 2008

The aim of the first study is to determine if AKAP79/150 is involved in voltage-gated Ca2+ channel regulation in the SNc. AKAP79/150 anchors protein kinase A (PKA), protein kinase C (PKC) and protein phosphatase 2B (PP2B) for regulation of membrane proteins and receptors. Three lines of mice have been engineered with mutations in the AKAP79/150-binding sites for either PKA, PKC or PP2B. Measurements of pacemaking in the SNc in the different breeds of mice will be integrated with studies in cu ltured cells that will include simultaneous electrophysiological and time-lapse imaging recordings of voltage-gated Ca2+ channel signalling. A structural investigation of voltage-gated calcium channel signalling will be initiated in the last year of the fellowship. Both AKAP79/150 and certain members of the membrane-associated guanylate kinase (MAGUK) family can bind CaM and are present in the postsynaptic density (PSD). In this situtation they could potentially orchestrate a rewiring of si gnalling pathways in the PSD following Ca2+ influx and subsequent CaM activation. A second related study will aim to test this hypothesis. RNAi-based experiments in cultured cells will examine the effect of mutation of the CaM-binding site in AKAP79/150, and a proteomic/systems biology investigation to investigate whether CaM activation affects MAGUK valency.

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

Vestibular representation in the mammalian cortex . 28 May 2008

Every sensory modality has spatial aspects and all vertebrates have a sensory organ dedicated to sensing linear and angular acceleration. I will examine how vestibular input is processed in the hippocampus and associated cortical areas and how it shapes network and single cell activity underlying complex cognitive processes such as spatial navigation. First, I will combine large-scale extracellular recordings with precise measurement of vestibular cues in awake, freely moving animals. I will ana lyze which populations (principal cells, interneurons, grid cells, place cells) are affected by vestibular cues and their contribution to network oscillations. I will also gather stimulus statistics for natural movement to use in the second part. Second, I will combine in vivo whole cell recordings with extracellular recordings in anesthetized animals to examine how vestibular input is coded on the sub- and supra-threshold level in single neurons of the hippocampus and associated cortical areas. This will help understand contribution of single neurons to network oscillations and the representation of the vestibular sense. The anticipated results will help clarify the neural basis of vestibular perception and provide the first steps towards understanding the mechanisms by which the vestibular sense is represented and integrated in the mammalian cortex.

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

Defining the role of vascular endothelial growth factor (VEGF-A) in commissural axon guidance at the optic chiasm 26 Jun 2008

The co-ordinated patterning of nerves and blood vessels is essential for normal physiological function. This functional integration has its basis in development, but the mechanisms that control the co-patterning of nerves and vessels remain poorly understood. The overarching aim of this proposal is to elucidate the contribution of the archetypical angiogenesis factor vascular endothelial growth factor (VEGF-A) and blood vessels to axon guidance in the central nervous system. Our pilot data p rovides convincing evidence that the VEGF-A isoform VEGF164 and its receptor neuropilin 1 (NRP1) play an essential role in retinal ganglion cell (RGC) axon pathfinding at the optic chiasm, where RGC axons decussate to set up the binocular visual pathways. These findings provide the first evidence for a role of VEGF-A in axon guidance in vivo and identify a classical vascular growth factor as a major player in the establishment of contralateral visual projections. We now wish to extend these fi ndings to establish the precise role of VEGF-A at the optic chiasm. In particular, we wish to determine if VEGF-A acts directly on the growth cones of RGC axons or if physical interactions between nerves and blood vessels underlie the role of VEGF-A in axon guidance.

Amount: £148,775
Funder: The Wellcome Trust
Recipient: University College London