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Funders:
Paul Hamlyn Foundation
The Wellcome Trust
Recipients:
University College London
University of Edinburgh
Amounts:
£500 - £1,000

Results

Funds for administrative support. 26 Apr 2006

Wellcome Trust Cardiovascular Research Initiative. The University of Edinburgh has had considerable recent success in setting up new interdisciplinary centres for biomedical research and the intention of the University to institute a Centre for Research in Cardiovascular Biology (CRCB) was highlighted in the submission for the 1996 RAE well in advance of publicity for the CVRI. The CRCB will be a network of interacting groups within an interdisciplinary 'centre without walls'. A Scientific Advisory Board (SAB) will provide the necessary management structure and administrative support for the Initiative to ensure quality in both research and training. As indicated in our original submission, the SAB will comprise Profs Fox, Haslett, Seckl, Webb and Wyllie, as well as all senior and principal fellows related to the Initiative. Therefore, it is envisaged that Dr Mullins would be a member of the SAB from the outset and that Dr Brown would join in due course. The leader of the Initiative will be Prof Webb, a clinical pharmacologist and clinician in cardiovascular medicine who has a background in cardiovascular science, a major research interest in endothelial function, and whose work bridges clinical and laboratory based-research. This group has the following major responsibilities: In research: To review overall strategy and focus, and set the priorities for research; to review ongoing research programmes and assess new proposals for funding; to assess proposals for senior or principal fellows; and to consider applications from potential visiting research staff. In training: To review ongoing training fellowships; to approve and prioritise new training opportunities and requirements; to consider applications for research leave in the UK or abroad to learn new techniques; to implement a programme of research seminars; and to liaise with the University Faculty of Medicine and, where relevant, with the Postgraduate Dean to address and facilitate clinical training needs, a role which the four clinical professors of medicine who are members of the SAB are particularly well placed to accomplish.

Amount: £45,000
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Balance of funds awarded to Edinburgh CVRI. 26 Apr 2006

Wellcome Trust Cardiovascular Research Initiative. The University of Edinburgh has had considerable recent success in setting up new interdisciplinary centres for biomedical research and the intention of the University to institute a Centre for Research in Cardiovascular Biology (CRCB) was highlighted in the submission for the 1996 RAE well in advance of publicity for the CVRI. The CRCB will be a network of interacting groups within an interdisciplinary 'centre without walls'. A Scientific Advisory Board (SAB) will provide the necessary management structure and administrative support for the Initiative to ensure quality in both research and training. As indicated in our original submission, the SAB will comprise Profs Fox, Haslett, Seckl, Webb and Wyllie, as well as all senior and principal fellows related to the Initiative. Therefore, it is envisaged that Dr Mullins would be a member of the SAB from the outset and that Dr Brown would join in due course. The leader of the Initiative will be Prof Webb, a clinical pharmacologist and clinician in cardiovascular medicine who has a background in cardiovascular science, a major research interest in endothelial function, and whose work bridges clinical and laboratory based-research. This group has the following major responsibilities: In research: To review overall strategy and focus, and set the priorities for research; to review ongoing research programmes and assess new proposals for funding; to assess proposals for senior or principal fellows; and to consider applications from potential visiting research staff. In training: To review ongoing training fellowships; to approve and prioritise new training opportunities and requirements; to consider applications for research leave in the UK or abroad to learn new techniques; to implement a programme of research seminars; and to liaise with the University Faculty of Medicine and, where relevant, with the Postgraduate Dean to address and facilitate clinical training needs, a role which the four clinical professors of medicine who are members of the SAB are particularly well placed to accomplish.

Amount: £14,243
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Reno-selective nitric oxide donor drugs: preliminary toxicology and metabolism studies. 19 Jul 2006

The proposed research is in support of an existing Wellcome Trust Development Award to develop novel renoselective nitric oxide donor drugs fir use in acute renal failure. The Development Award is progressing to schedule and we now ha ve prototype pro-drugs with pharmacological characteristics to suggest that th ey will be renoselective. During recent discussions, Wellcome Trust suggested that we consider conducting a preliminary screen to determine the toxicology a nd metabolism of candidate compounds at an early stage in order to optimise le ad selection for future development. Studies of this type will be outsourced t o a specialised company (CXR Biosciences, Dundee). Studies have been designed to assist lead selection and optimisation based on the potential for adverse m etabolic or safety characteristics of the active metabolite as well as its gen eration from the prodrug in kidney and other tissues. CXR Biosciences have con siderable experience in this area and will use a combination of experiments in human and rat microsomes, hepatocytes and tissue homogenates to establish these key criteria in our compounds for further development, and in optimising th e drug like characteristics of compounds to improve the chances of clinical success.

Amount: £58,750
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Regulation of N type calcium channel expression, trafficking and modulation 20 Oct 2005

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: £1,375,208
Funder: The Wellcome Trust
Recipient: University College London

Understanding the significance of the AIPL1:NUB1 interaction for photoreceptor homeostasis 20 Oct 2005

Mutations in the pineal- and photoreceptor-specific aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) gene cause a devastating disease characterized by congenital blindness called Leber congenital amaurosis (LCA). The molecular basis of disease in LCA caused by AIPL1 mutations is not understood. It has been suggested that AIPL1 may function as a chaperone for phosphodiesterase (PDE) and farnesylated proteins. However, mutations in PDE subunits themselves lead to retinitis pigmentosa (RP) and global defects in the processing of farnesylated proteins were not observed in AIPL1 animal models. We have shown that AIPL1 can modulate the nuclear translocation and inclusion formation of the NEDD8 ultimate buster protein 1 (NUB1) and that this activity is affected by certain pathogenic mutations. NUB1 associates with the proteasome and targets small ubiquitin-like protein (NEDD8 and FAT10) conjugated proteins for degradation, providing a functional link between AIPL1 and the proteasome. However, the role of NUB1 in the retina is unknown. The primary goals of this study are therefore i) to determine the molecular mechanisms involved in the AIPL1-mediated regulation of NUB1 nuclear translocation ii) to determine the effect of AIPL1 on NUB1-mediated proteasomal degradation and downstream targets of NUB1 and iii) to determine whether these mechanisms are involved in the processing of PDE and farnesylated proteins by AIPL1, potentially establishing a relational link between the various pathways thus far implicated in AIPL1 LCA. Through these investigations we will gain a better understanding of the molecular mechanisms of AIPL1 LCA, which may identify novel targets for therapeutic intervention.

Amount: £216,710
Funder: The Wellcome Trust
Recipient: University College London

Cellular and molecular mechanisms that regulate EAAT4 - a neuronal glutamate transporter. 20 Oct 2005

Extracellular glutamate levels must be tightly regulated in order to prevent neurotoxicity but maintain normal neurotransmission and neurodevelopment. EAAT4 is the glutamate transporter that is predominantly expressed in the Purkinje cell neurons of the cerebellum. There are two aspects of its expression pattern that are critical for modulating glutamate levels. First, EAAT4 is concentrated at extrasynaptic sites enabling the amount of glutamate that escapes synapses to be tightly regulated. This is important for maintaining synapse specificity and accurate information processing within densely packed terminals. Secondly, a large number of functional transporter molecules are required at the cell surface for rapid clearance. The turnover time of transport is too slow for multiple cycles to account for the efficientuptake process.We have identified the first proteins (GTRAPs) that interact with the intracellular COOH-terminus of EAAT4 and positively modulate its cellsurface expression and uptake activity. We propose to study genetically modified mice lacking the GTRAP-b-spectrin gene in order to investigate the role of this protein in EAAT4 localisation/activity, glutamatergic neurotransmission, and Purkinje cell development and survival. We also proposeto elucidate what cellular mechanisms are involved in the membrane traffickingof EAAT4 by examining the role of endocytosis, protein phosphorylation and GTRAP binding in the regulation of cell surface expression. These studies may offer new insights into therapeutic avenues for neurological diseases initiated by or propagated by glutamate-mediated excitotoxicity

Amount: £194,504
Funder: The Wellcome Trust
Recipient: University of Edinburgh

The UCL Fish Facility. 20 Oct 2005

Zebrafish is well established as a leading model organism for studying the genetic basis of vertebrate development and is fast becoming an excellent model for human diseases, for studying nervous system function in vivo, for cell biological, pharmacological and physiological studies and for analysis of gene and genome evolution. The zebrafish research community at UCL is one of the largest and most productive teams of researchers in the field. Zebrafish research at UCL entirely depends upon the UCL Fish Facility, a resource that houses several hundred genetically distinct lines of fish in 2000 tanks spread between two independent systems. However, the success of the research groups at UCL coupled with the increased availability of transgenic and mutant lines of zebrafish means that the current Facilities no longer meet the demands of the user community. Furthermore, the older and larger of the two existing systems is at the point of collapse and urgently needs replacement to avoid potentially catastrophic loss of resources. This application requests funds to replace the existing old facility and to expand the resource through construction of a third system. This project will underpin and allow expansion of research both at UCL and in the wider international community

Amount: £246,385
Funder: The Wellcome Trust
Recipient: University College London

Molecular mechanisms of successful axon pathfinding during CNS regeneration in the visual system of adult zebrafish 20 Oct 2005

Adult zebrafish, in contrast to mammals, are capable of regenerating CNS tracts. Thus, regeneration of the optic projection in zebrafish can be used to study the factors required for axon regrowth such as those that determine correct pathfinding and retinotopic mapping on the tectum during axonal regeneration. We will analyse (re-)expression of axon guidance molecules and their receptors on retinal ganglion cells (RGCs) known to play a role in axon pathfinding during development, such as ephrins/eph, semaphorins/neuropilins, slits/robos, neogenin/RGM by in situ hybridisation. By comparing expression profiles on DNA micro-arrays of different retinal sectors during regeneration we will analyse (re-)expression of other, possibly unknown receptors for topographic cues. We will test the function of these systems using anti-sense "morpholino" oligonucleotide assisted knock down in the developing and adult retina. Anterograde tracing will reveal pathfinding and mapping errors. Additionally, we will analyse adult regeneration in mutants of RGC axon pathfinding, focussing on the astray/robo2 mutant, which displays pathfinding errors of RGC axons during development. These analyses should provide insight into the mechanisms that need to be (re-)activated to achieve target specific growth of axons during development and regeneration in the adult CNS.

Amount: £284,179
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Investigation of the regulation of adipose ADMA during weight change. 07 Nov 2005

Signals from adipose tissue may underlie the relationship between obesity and metabolic diseases through their effects on insulin sensitivity and endothelial function. Asymmetric dimethylarginine (ADMA) is a novel risk factor for cardiovascular disease that inhibits nitric oxide bioavailability and causes endothelial dysfunction. ADMA is primarily cleared by catabolism through the activity of dimethylarginine dimethylaminohydrolase (DDAH). We found that adipose tissue expresses DDAH to high levels and generates significant amounts of ADMA, and the release is modifiable by changes in weight and insulin sensitizers. We propose to investigate the ADMA/DDAH pathway in adipose tissue of DDAH-1 +/- mice, and their wild-type littermates,to explore its relationship to the development of endothelial dysfunction in diet-induced obesity and to assess the reversibility of these changes by weight loss. Adipose tissue distribution and detailed quantification of changes in energy expenditure will be determined, as well as organ cultures toevaluate adipose ADMA secretion. Understanding the effects of the dynamic changes in weight on the adipose tissue DDAH/ADMA pathway and its regulation will increase our understanding of this novel product of this organ, explain the close link between body fat and endothelial dysfunction and provide a valuable basis for designing strategies in the treatment of obesity-associatedpathologies.

Amount: £236,395
Funder: The Wellcome Trust
Recipient: University College London

Regulation of lung fibroblast and epithelial cell apoptosis by cyclooxygenase-2 and prostaglandin E2 and their role in the pathogenesis of pulmonary fibrosis. 06 Dec 2005

Pulmonary fibrosis represents the end stage of a heterogeneous group of conditions with poor prognosis and no effective treatment. Recent studies suggest increased epithelial cell (EC) apoptosis and fibroblast resistance to apoptosis contributes to the pathogenesis of fibrosis but the mechanisms are incompletely understood. However, the host laboratory has shown that patients with idiopathic pulmonary fibrosis (IPF) have a decreased capacity to synthesise cyclooxygenase (COX)-2 and prostaglandin E2 (PGE2). COX-2/PGE2 induce fibroblast apoptosis and protect epithelial cells from apoptosis but their role in regulating apoptosis in fibrotic lung is unknown. I therefore hypothesise that the decreased capacity to induce COX-2/PGE2 in patients with IPF contributes to pathogenesis by increasing EC apoptosis and decreasing fibroblast apoptosis. To address this hypothesis I will determine whether COX-2/PGE2 deficiency contributes to human fibrotic lung fibroblast resistanceto apoptosis and induction of EC apoptosis in vitro. I will also examine the effect of COX-2 deficiency on EC and fibroblast apoptosis in an animal model

Amount: £242,197
Funder: The Wellcome Trust
Recipient: University College London

Identification and characterisation of Wnt target genes in the developing cerebral cortex. 20 Oct 2005

All higher mental and cognitive functions unique to humans depend on the neocortex. In order to fulfill these functions the cortex requires an enormousvariety of neurons. The general aim of my research is to contribute to our understanding of the patterning mechanisms which lead to the generation of these different cortical neurons during embryonic development.I started to address this problem by analyzing cortical development in the extra-toes mousemutant which lacks the Gli3 zinc finger transcription factor. In the Gli3 mutant cortex, the expression of several Wnt genes is severely altered and apical/basal cell polarity, an important determinant of stem cell characteristics, is lost in cortical progenitor cells. By combining transgenicand knock-out approaches with tissue and cell culture experiments, I want to identify and characterize genes which are regulated by Wnt molecules and whichmediate their functions. From these analyses, I expect to gain important insights into an important but poorly understood aspect of Wnt gene function in the developing cortex.

Amount: £570,959
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Synaptic plasticity in hippocampal interneurons: cellular mechanisms. 20 Oct 2005

We have recently found that NMDA receptor-dependent long-term potentiation (LTP) occurs in about half of GABAergic feed-forward inhibitory interneurons in stratum radiatum of the hippocampus. This is only detected if interneurons are recorded in perforated-patch mode, and is not seen if whole-cell pipettes are used, possibly explaining why the phenomenon has not previously been reported. LTP in aspiny interneurons has extensive repercussions for the interaction between memory encoding and information processing in the corticalmicrocircuitry. However, the focus of this application is the underlying cellular mechanisms. Are postsynaptic action potentials required for LTP induction? Can LTP-competent interneurons be identified electrophysiologicallyor anatomically? Can interneurons switch from LTP-incompetence to LTP-competence? What is the role of tyrosine phosphorylation of NMDA receptors? What is the induction cascade downstream of NMDA receptors? How do sub-cellular Ca2+ microdomains relate to pathway-specific LTP in aspiny cells?Do interneurons exhibit NMDA receptor-dependent long-term depression (LTD)? What are the roles of NR2A- and NR2B-containing NMDA receptors, Ca2+/calmodulin kinases, and calcineurin in LTP (and LTD) in interneurons?

Amount: £240,722
Funder: The Wellcome Trust
Recipient: University College London

Isolation and functional analysis of the oral metagenome. 25 Oct 2005

An estimated 800 bacterial species live in the oral cavity of Homo sapiens. The interaction between the commensal microbiota and its human host results in the commonest bacterial diseases of man; dental caries and periodontal diseases. A major bar to studying the orgal microbiota, whichis probably the easiest such microbial community to analyse, is the fact that 50% or more of the bacteria are uncultivable. One method of analysis which overcomes the need for culture and can enable the whole assemblage of oral microorganisms to be studied is metagenomics. We plan to construct a representative metagenomic library of the human oral microbiota and in this preliminary study analyse it for two groups of genes important for the maintenance of oral biofilms and the evolution of virulence and antibiotic resistance. Specifically, this library will be screened to identify genes encoding adhesins important in biofilm formation and for genes encoding systems involved in horizontal gene transfer. Results obtained will help in developing novel anti-plaque strategies and for understanding the ability of oral bacteria to act as reservoirs for antibiotic resistance genes and to spread these resistance genes among themselves and beyond the oral environment.

Amount: £491,528
Funder: The Wellcome Trust
Recipient: University College London

The mechanism of long-lasting activity-dependent neuroprotection. 20 Oct 2005

Several factors regulate neuronal survival during development and maturity. One important mechanism involves activity-dependent signalling through synaptic NMDA receptors (NMDARs), though the mechanism is poorly understood. We recently showed that synaptic NMDAR-dependent neuroprotection comprises twodistinct phases: 1.Acute protection triggered by continuous activity, mediatedby the PI3K-Akt pathway. 2.A novel long-lasting or 'late-phase' of neuroprotection that extends long after activity has ceased (>60 hrs), which is dependent on transcription mediated by the cAMP response element (CRE) binding protein (CREB) family of transcription factors. As neurons are not continuously active in vivo, the latter mechanism is likely to be important for activity-dependent pro-survival signals to have sustained effects during electrically quiet periods.The project aim is to define which activity-dependent changes in gene expression are responsible for promoting the long-lasting phase of activity-dependent neuroprotection.Specifically:1.Toinvestigate the cellular events underlying neuronal apoptosis which are prevented by an episode of synaptic NMDAR activity2.To use gene microarray expression analysis and bioinformatics to identify candidate CRE-regulated pro-survival genes that are induced by synaptic NMDAR activity.3.To ascertain the role of candidate CRE-regulated genes in synaptic NMDAR-dependent neuroprotection by knock-down and over-expression studies.4.To characterise the transcriptional regulation of the identified neuroprotective genes.

Amount: £265,087
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Understanding how mammalian genomes are packaged in complex chromatin structures. 13 Dec 2005

Studying chromatin is essential to understanding fundamental cellular processes that act on DNA, such as transcription, replication and repair and how it affects many human diseases. Although we have a clear understanding of the structure of the nucleosome we know very little about higher levels of chromatin folding or how it is regulated. The chromatin architecture of mammalian genomes is heterogeneous and I have previously shown that the gene-rich regions of the human genome have a more open higher-order chromatin conformation than gene-poor regions. Constitutive heterochromatin is molecularly distinct from euchromatin. I have shown that both human and mouse satellite-containing centromeric heterochromatin has a compact higher-order chromatin structure. In this proposal I aim to identify factors responsible for regulating the conformation of the chromatin fibre in heterochromatin and examine their mechanism of action. Using a biophysical assay I will determine whether histone and DNA modifications have the capacity to alter the conformation of the chromatin fibre. Using a further development of this technique to purify centromeric heterochromatin, I will examine whether the higher-order 30nm chromatin fibre has a structural RNA component that can modulate its conformation, and will identify new protein components of the chromatin fibre.

Amount: £512,274
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Integration and plasticity of sensory-evoked synaptic input in single cerebellar interneurones in vivo 13 Dec 2005

Inhibitory microcircuits play a key role in regulating excitability in neuronal networks throughout the brain. However, little is known about the extent to which interneurone circuits are modifiable by sensory experience and the mechanisms involved in such modifications. This project will investigate the plasticity of inhibitory connections in the molecular layer of the cerebellar cortex in vivo by combining two recently developed techniques - in vivo patch-clamp recording and 2-photon imaging - in order to identify the locus of plasticity driven by sensory input in these cerebellar inhibitory circuits. First, whole-cell patch-clamp recordings will be made from Purkinje cells in vivo in order to determine if patterns of sensory stimulation (e.g. whisker deflections) can trigger long-term modification of inhibitory synaptic input to these neurones. Second, we will fill interneurones and Purkinje cells with fluorescent calcium dyes and image dendritic calcium signals in vivo in order to determine if activity-dependent changes are triggered by particular patterns of dendritic calcium signaling. Finally, the experiments will be complemented by compartmental modeling of interneurones and Purkinje cells based on our experimental data. These combined approaches will provide important new insights into how interneurone networks encode changes in sensory experience.

Amount: £245,105
Funder: The Wellcome Trust
Recipient: University College London

Brain signatures of auditory information processing in the Degenerative Dementias. 06 Dec 2005

This programme will investigate pathophysiological mechanisms of disordered information processing in dementia using the paradigm of complex sound. It will integrate complementary fMRI, structural MRI, and behavioural (psychoacoustic) measures in clinically, radiologically and genetically-defined populations with the most common cortical degenerative dementias, Alzheimer's disease and frontotemporal lobar degeneration, and in age-matched healthy controls. Mechanisms of elementary auditory pattern analysis will be probed using fMRI, and brain activation profiles will be correlated cross-sectionally and serially with psychoacoustic and other behavioural measures of complex sound processing and with structural MRI. By comparing structural with functional imaging data, and imaging data with behaviour, it will be possible to assess these complementary techniques in relation to one another and in combination. The correlation of complementary disease measures will determine how pathophysiology maps onto structural damage, whether regional brain dysfunction predicts the rate and distribution

Amount: £717,782
Funder: The Wellcome Trust
Recipient: University College London

The role of the human cathelicidin LL-37 as an immunomodulator in infectious lung disease. 13 Dec 2005

Cationic host defence peptides (CHDP) are key components of innate defences, recently proposed as potent immunomodulators. LL-37 is a CHDP produced by neutrophils and epithelial cells, and upregulated during infection and inflammation. I have discovered that LL-37 promotes epithelial cell apoptosis,but inhibits neutrophil apoptosis. The differential effects of LL-37 and the underlying mechanisms will be characterised and contrasted in vitro, examining: a) priming of beneficial airway epithelial cell apoptosis through altered Bcl2 family gene expression, as a defence against infection, and b) inhibition of neutrophil apoptosis through activation of MAPK and NFkB pathways, promoting bacterial killing. I propose that these effects of LL-37 enhance innate host defence in acute infectious lung disease, but contribute to disease pathogenesis in chronic exposure, such as occurs in cystic fibrosislung disease. The in vivo contribution of these LL-37-mediated effects to the clearance of pulmonary Pseudomonas aeruginosa infection in murine models will be defined, and the significance of chronic LL-37 exposure to cystic fibrosis lung disease pathogenesis will be determined. A clear understanding of these immunomodulatory effects of LL-37 in vitro and in vivo is required to establish physiological significance and enable appropriately targeted development of synthetic derivatives as therapeutics for antibiotic-resistant infections.

Amount: £581,392
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Genome-scale ordered RNA structure (GORS) and persistence of RNA viruses: investigation of role of GORS in virus replication and interaction with innate cell defence pathways. 25 Oct 2005

The ability of many RNA viruses to persist in their hosts is essential for their survival and ongoing transmission, although mechanistically the phenomenon generally remains poorly understood. Through new developments in bioinformatic analysis, we have discovered that naturally persistent and non-persistent viruses differ fundamentally in their genome configurations, with highly evolutionarily conserved, extensive RNA secondary structure in persistent viruses that may play roles in promoting intracellular stability and/or interaction with and evasion of intracellular defence mechanisms. We propose to investigate the physicochemical nature of genome-scale ordered RNA structure (GORS), its role in virus replication, and interactions with and resistance to a range of innate cell defence pathways, including interferon (IFN)-ß induction, antiviral effects of IFN-stimulated genes, and Dicer-associated recognition and effector pathways. The physicochemical studies of GORS will use transcripts from a variety of viruses with structured and unstructured genomes, while the replication studies will exploit newly developed methods to culture hepatitis C virus (HCV) in vitro. HCV is an appropriate model for investigation of GORS because its persistence is well documented, extensively investigated and clinically important. These investigations will therefore have both direct medical relevance, and provide fundamental insights into the role of GORS in the evolution of RNA viruses.

Amount: £111,719
Funder: The Wellcome Trust
Recipient: University of Edinburgh