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Results

Characterising patterns and determinants of smoking initiation in adolescence. 14 Oct 2008

Smoking is one of the leading causes of poor health, illness and premature death. However, despite campaigns to encourage children and young adults not to start smoking, many continue to do so. We will investigate patterns of smoking experimentation in adolescence and early adulthood, in order to identify risk periods when experimenting with cigarette smoking is associated with increased likelihood of progression to regular use. This will allow us to better target public health campaigns and gui de the formulation of policy. We will also investigate environmental and genetic risk factors for smoking initiation. This will initially focus on parental smoking as an environmental influence (in particular maternal smoking during pregnancy, where there is evidence from animal models that nicotine exposure modifies sensitivity to nicotine), and variation in nicotinic acetylcholine receptor sub-unit genes. Single nucleotide polymorphisms in the latter have recently been strongly associated w ith nicotine dependence and other smoking phenotypes, but not investigated comprehensively in smoking initiation. Importantly, this study will also provide a rich resource for the future study of factors which influence cigarette smoking, and the consequences of smoking on other outcomes. There is only one opportunity to add this value in the phenotype-rich large ALSPAC cohort.

Amount: £357,564
Funder: The Wellcome Trust
Recipient: University of Bristol

Early Life determinants of Blood pressure patterns in young Adults (ELBA Study). 14 Oct 2008

Adolescents with high blood pressure (BP) are at increased risk of hypertension and cardiovascular disease (CVD) as adults. The early life factors responsible for increased BP in youth are not well understood, partly because maternal characteristics and early childhood growth patterns have not been properly characterised, and partly because brachial BP overestimates central blood pressure, does not encompass variations in 24 hour BP or BP responses to stressors. We propose to measure brachial an d central BP, and dynamic BP responses in the whole ALSPAC birth cohort at age 17 (n=8000), and undertake more detailed measurements in a 2500 subsample, including 24 hour central and brachial BP monitoring, wave reflection, arterial stiffness, carotid intima-media thickness, and left ventricular mass. We will relate detailed early life growth trajectories, fat distribution and maternal determinants to these measures of BP, and in turn relate measures of BP to the subclinical CVD outcomes of ca rotid intima media thickness, arterial stiffness (pulse wave velocity) and left ventricular mass. This study represents a unique opportunity to assess the importance of early life exposures from birth into adolescence on blood pressure and will provide novel insights into the mechanisms of the association between growth, obesity and blood pressure.

Amount: £532,069
Funder: The Wellcome Trust
Recipient: Imperial College London

Validating choline metabolism as a drug target in the fight against T.brucei 02 Oct 2008

In this proposal we will use multi-disciplinary approaches to investigate choline phospholipid biosynthesis and metabolism in Trypanosoma brucei as a source of potential chemotherapeutic targets. Emphasis will be on understanding choline metabolic pathways, so that we can genetically and chemically validate them as drug targets. This project aims to answer three key questions; 1) T.brucei are auxotrophic for choline, so, how do they obtain choline? 2) Are T.brucei vulnerable to inhibit ion of de novo phosphatidylcholine synthesis? 3) Is catabolism of choline containing species essential to the parasite? Thus our key goals are to: genetically validate the choline branch of the Kennedy pathway (phosphatidylcholine de novo synthesis) as a drug target. understand the uptake and usage of choline containing species by bloodstream T.brucei. develop high-throughput assays for enzymes involved in choline metabolism. obtain kinetic, specificity and structu ral information about the enzymes involved in choline metabolism, that will allow the construction of structure-activity relationships to facilitate the design of more potent parasite-specific inhibitors. ultimately allowing development of potent inhibitors with activity against live trypanosomes compliant with Lipinski s rules, thus suitable for future development as novel anti-trypanosomal drugs.

Amount: £185,040
Funder: The Wellcome Trust
Recipient: University of St Andrews

Functional analysis of malarial microneme proteins essential to ookinete invasion. 02 Oct 2008

The malarial parasite must repeatedly invade host tissues to complete its life cycle. Proteins secreted from the micronemes are essential for invasion. Microneme proteins are considered prime targets for both drug and vaccine attack. We have recently completed a proteomic analysis of the Plasmodium berghei ookinete micronemes. Here we exploit the data generated to analyse the functions of 3 partially defined, and 19 novel hypothetical-class secreted proteins. Gene deletion and fluorescent tagged mutant parasites will be generated and characterised using our widely published methodologies. Key Goal 1: Proteins critical to host invasion will be mapped to established developmental checkpoints i.e. motility, host adherence, penetration/traversal of host cells. Key Goal 2: The three micronemal proteins known to be essential to ookinete development (CTRP, PB1102 and POSH) will be examined using gene mutation methodologies to determine the structure/function relationships of the prote ins, again using established methodologies. This work has the potential to inform future drug and vaccine development.

Amount: £266,380
Funder: The Wellcome Trust
Recipient: Imperial College London

Does AMP Kinase signalling contribute to skeletal health?. 15 Oct 2008

New studies have established a hormonal link between bone remodelling, food intake, and energy metabolism. We recently identified a neuroendocrine activation of AMP-activated kinase (AMPK) in bone cells. AMPK is a sensor and regulator of energy balance in the cell, but also at the whole body level where it integrates nutritional and hormonal signals in the central nervous system and peripheral tissues. We hypothesise that AMPK signalling stimulates bone formation and inhibits bone resorption and that AMPK activity in bone cells is regulated by the same hormones and neuromediators that control energy homeostasis, providing one molecular link between bone mass and energy metabolism. Our aims are to identify the direct metabolic activators of AMPK in bone cells, to determine whether AMPK activity is involved in bone cell differentiation and function, and to establish which are the specific transcriptional targets regulated by AMPK in bone cells. As antidiabetic drugs (metformin and thiazo lidinediones) can modulate AMPK and thiazolidinediones have deleterious effects on bone mass, we will also examine whether AMPK signalling mediates the skeletal effects of these drugs. A better understanding of the mechanisms linking osteoporosis to other metabolic disorders is likely to lead to new therapies for those diseases.

Amount: £240,076
Funder: The Wellcome Trust
Recipient: Royal Veterinary College

The architecture and assembly of fibrillin microfibrils, key components of elastic fibres. 10 Nov 2008

In this application we will investigate the architecture and assembly of elastic fibre microfibrils, targeting key fragments of fibrillin involved in microfibril assembly. Specifically we aim to i) Use NMR to identify the individual three-dimensional structure and dynamic properties of an N-terminal fragment (Nterm-EGF3) which contains the C-terminal interaction site. In parallel a homology model of cbEGF41-43 will be built based on the known structures of fibrillin-1 cbEGF domains and NMR wil l be used to confirm the predicted rod-like structural arrangement of the construct by the identification of conserved interdomain packing interactions ii) Identify the minimal interacting N- and C-terminal complex by fine mapping of Nterm-EGF3 and cbEGF41-43, determine its stability by surface plasmon resonance (SPR) and precisely define the interacting surfaces by NMR shift mapping and/or crystallography iii) Identify the dynamic properties and pairwise interactions of the first hybrid domain (hyb1) and adjacent domains EGF3 and cbEGF1 iv) Use cellular models of matrix assembly combined with structure-informed mutagenesis to test the importance of putative interface residues for N- and C-terminal complex formation .

Amount: £232,865
Funder: The Wellcome Trust
Recipient: University of Oxford

Drosophila as a model system to dissect the molecular mechanisms of Motor Neuron Disease pathogenesis. 08 Oct 2008

One powerful tool to analyse disease mechanisms is the development of transgenic animal models. hVAPB is the causative gene of a clinically diverse group of Motor Neuron Diseases (MNDs) including Amyotrophic Lateral Sclerosis (ALS), atypical ALS and spinal muscular atrophy. We generated a model for VAP-induced MNDs in Drosophila. Transgenic expression of the mutant protein in the larval neurons causes cell death, locomotion defects and aggregate deposition while a rough and smaller eye phenotyp e is induced by driving the expression of the same protein in the eye. We propose to undertake a genome-wide screen for genetic modifiers that modulate VAP-induced toxicity in the adult eye and, subsequently, validate the modifying activity of these interactors in tissues that are more characteristically affected in MNDs such as brain and motor systems. Recently, it was reported that VAPB could function as a molecular link between Fronto-Temporal Dementia (FTD) and ALS, two diseases with overlap ping clinical features but different aetiology. We intend to carry out a genetic approach aimed at highlighting differences and similarities in the patho-mechanisms underlying FTD and ALS. Taken together, the proposed research should lead to new insights into the pathogenesis of MNDs and provide new therapeutic targets for these disorders.

Amount: £309,092
Funder: The Wellcome Trust
Recipient: University of Edinburgh

Proteases in egress of the malaria parasite from its host red blood cell. 02 Feb 2009

Approximately 40% of the world s population is at risk from malaria, and with the increasing prevalence of drug resistance, the need for novel, effective drugs against this pathogen is increasingly urgent. The most virulent form of malaria is caused by waves of replication of the unicellular parasite Plasmodium falciparum within an intraerythrocytic parasitophorous vacuole (PV). At 48-hour intervals, rupture of the infected erythrocyte releases merozoites (a process called egress) which invade f resh erythrocytes to repeat the cycle. Egress is governed by the release of an essential parasite serine protease called SUB1 from maturing merozoites into the PV space. SUB1 initiates a cascade which involves the proteolytic processing of a papain-like enzyme family called SERA. At least two members of this family, SERA5 and SERA6, are essential for parasite viability. SERA5, and likely the other SERAs, is then further processed by another, as yet unidentified protease (which we refer to as the P50C protease). The purpose of this project is to investigate the role of the SERA proteins in parasite egress; verification of the enzymatic activity of the SERAs and identification of their substrates and of the P50C protease will provide new targets for the development of antimalarial drugs.

Amount: £177,006
Funder: The Wellcome Trust
Recipient: Medical Research Council

The dynamics of meningococcal carriage in Africa and the impact of vaccination. 14 Oct 2008

The goals of this project are (a) identification of carriers of serogroup A meningococci in countries of the African meningitis belt (b) characterisation of the dynamics of carriage within households and how this is influenced by vaccination (c) investigation of the relationship between carriage of potentially pathogenic meningococci and of non-pathogenic Neisseria before and after vaccination. Cross-sectional carriage surveys will be carried out in seven countries including subjects of all ages and urban and rural populations. Carriers of serogroup A meningococci identified during these surveys will be studied in detail. A nested case control study will identify risk factors for carriage. Household contacts of carriers will be swabbed at monthly intervals for a period of 6 months to identify the pattern of transmission within households, acquisition rate and duration of carriage. Measurement of baseline bactericidal antibody concentrations will allow correlates of protection ag ainst carriage to be determined. These studies will be repeated in three countries after vaccination. In countries where vaccination is not introduced, longitudinal surveys will be conducted. To determine the relationship between carriage of potentially pathogenic meningococci and non-pathogenic Neisseria, neisserial isolates obtained before and after introduction of vaccination will be characteristed by multilocus sequence typing (MLST).

Amount: £2,254,166
Funder: The Wellcome Trust
Recipient: London School of Hygiene & Tropical M...

The role of Sox2/SOX2 in hypothalamo-pituitary development. 08 Oct 2008

The overall aim of this project is to understand better the role of the transcription factor SOX2 in normal hypothalamo-pituitary development and in the pathogenesis of hypopituitarism in humans. Recently, we have identified a critical role for the transcription factor SOX2 in normal hypothalamo-pituitary development in both mice and humans; however, the molecular mechanism by which SOX2 dictates hypothalamo-pituitary development, namely its target genes and partner proteins, remains unknown. Th e main aims of the proposed research are: 1. To evaluate the ability of SOX2 to directly regulate specific genes known to be involved in forebrain and hypothalamo-pituitary development, and to identify the positions of these genes in the genetic hierarchy leading to normal pituitary development. 2. Identification of novel SOX2 target genes likely to be important in hypothalamo-pituitary development. 3. To investigate suitable co-operative partner factors for SOX2 in the developing pitu itary and their co-expression in human embryos. 4. Selection of candidates for mutation analysis of novel SOX2 target genes in patients with hypopituitarism and associated defects.

Amount: £359,039
Funder: The Wellcome Trust
Recipient: University College London

2D to 3: the visual representation of space in moving observers. 08 Oct 2008

As we move through the world, we acquire visual information that allows us to build up a stable representation of the scene. The aim of this project is to challenge current models of this process and inform the development of new theoretical accounts. Our high fidelity virtual reality laboratory, which relies on a close collaboration with engineering colleagues, provides a unique opportunity to test hypotheses about spatial representation in moving observers using controlled psychophysical techn iques. The current 'textbook' model of human spatial representation is Cartesian, in which there is a 1:1 mapping between physical space and its internal representation. We will test the following predictions of this model: (i) transitivity of depth judgements; (ii) independence of visual space distortions across tasks; (iii) covariance between size and distance judgements when the reliability of one cue is varied; (iv) consistency in the visual direction of objects with observer movement. We will also collaborate with colleagues in Robotics at Oxford to test alternative, non-Cartesian, view-based approaches to `homing'. A long term goal is to develop view-based models of peri-personal space and to test these in the same way that we propose here for the Cartesian approach.

Amount: £147,281
Funder: The Wellcome Trust
Recipient: University of Oxford

2D to 3: the visual representation of space in moving observers. 08 Oct 2008

As we move through the world, we acquire visual information that allows us to build up a stable representation of the scene. The aim of this project is to challenge current models of this process and inform the development of new theoretical accounts. Our high fidelity virtual reality laboratory, which relies on a close collaboration with engineering colleagues, provides a unique opportunity to test hypotheses about spatial representation in moving observers using controlled psychophysical techn iques. The current 'textbook' model of human spatial representation is Cartesian, in which there is a 1:1 mapping between physical space and its internal representation. We will test the following predictions of this model: (i) transitivity of depth judgements; (ii) independence of visual space distortions across tasks; (iii) covariance between size and distance judgements when the reliability of one cue is varied; (iv) consistency in the visual direction of objects with observer movement. We will also collaborate with colleagues in Robotics at Oxford to test alternative, non-Cartesian, view-based approaches to `homing'. A long term goal is to develop view-based models of peri-personal space and to test these in the same way that we propose here for the Cartesian approach.

Amount: £150,347
Funder: The Wellcome Trust
Recipient: University of Reading

Endoglin regulates angiogenesis: an investigation of cellular and molecular mechanisms. 10 Nov 2008

Development and maintenance of an optimally functioning vasculature are essential for health. Abnormal vessel responses can result in a range of vascular problems including haemorrhage, vessel dilatation or aneurysm, which may be associated with increased morbidity and mortality, depending on the affected organ. The aim of this project is to understand the role of the essential endothelial receptor endoglin during development of the vasculature. Pathological mutations of the endoglin gene in the familial vascular disorder Hereditary Haemorrhagic Telangiectasia lead to the local formation of arteriovenous malformations and haemorrhagic, dilated and tortuous blood vessels (telangiectases) that often enlarge or become more numerous with age. The molecular mechanisms underlying these events are poorly understood, largely because of a lack of robust animal models. We have recently derived an inducible endoglin knockout mouse which, for the first time, develops arteriovenous malformations in a reproducible manner. We will use this unique model to investigate the underlying cellular and molecular mechanisms responsible for abnormal vascular remodelling. Following this, we aim to investigate repair of these vascular abnormalities. Increased understanding of the central role of endoglin in angiogenesis has wider implications for current therapies to regulate angiogenesis and vascular repair in an extensive range of pathologies.

Amount: £105,970
Funder: The Wellcome Trust
Recipient: University College London

Endoglin regulates angiogenesis: an investigation of cellular and molecular mechanisms. 10 Nov 2008

Development and maintenance of an optimally functioning vasculature are essential for health. Abnormal vessel responses can result in a range of vascular problems including haemorrhage, vessel dilatation or aneurysm, which may be associated with increased morbidity and mortality, depending on the affected organ. The aim of this project is to understand the role of the essential endothelial receptor endoglin during development of the vasculature. Pathological mutations of the endoglin gene in the familial vascular disorder Hereditary Haemorrhagic Telangiectasia lead to the local formation of arteriovenous malformations and haemorrhagic, dilated and tortuous blood vessels (telangiectases) that often enlarge or become more numerous with age. The molecular mechanisms underlying these events are poorly understood, largely because of a lack of robust animal models. We have recently derived an inducible endoglin knockout mouse which, for the first time, develops arteriovenous malformations in a reproducible manner. We will use this unique model to investigate the underlying cellular and molecular mechanisms responsible for abnormal vascular remodelling. Following this, we aim to investigate repair of these vascular abnormalities. Increased understanding of the central role of endoglin in angiogenesis has wider implications for current therapies to regulate angiogenesis and vascular repair in an extensive range of pathologies.

Amount: £282,679
Funder: The Wellcome Trust
Recipient: Newcastle University

Role and mechanism of immunomodulation by Influenza virus and its components in the predisposition to bacterial disease during Influenza infection. 02 Oct 2008

There is overwhelming evidence to suggest that influenza infection predisposes individuals to, often more fatal, bacterial pneumonia however, the mechanisms that trigger susceptibility to bacterial disease during influenza infection are poorly understood. The increasing likelihood that highly pathogenic avian influenza viruses will cause the next worldwide pandemic underscores the need to understand the multiple mechanisms underlying the interaction between influenza virus and bacterial pathogen s.. We have demonstrated a novel pathway of immunosuppression associated with influenza haemagglutinin (HA) based on down regulation of LPS-induced bioactive IL12p70 production in vivo in a mouse model and in vitro by murine bone marrow derived dendritic cells (BMDCs). We have further evidence that live influenza infection also down regulates LPS induced IL-12p70 expression in human dendritic cells. IL-12p70 is a key cytokine which affords protection against bacterial infections which have been associated with complications of influenza infection such as streptococcus pneumonia. This study proposes to investigate the role of this immunomodulation by influenza virus and its component HA in the predisposition to pneumococcal infection in vivo and to investigate the molecular mechanisms underlying transcriptional changes in BMDCs in response to HA

Amount: £224,960
Funder: The Wellcome Trust
Recipient: Dublin City University

Plant cysteine proteinases as new antihelminthics to treat sheep GI nematode infections. 02 Oct 2008

We recently undertook a pilot study on efficacy of papaya latex in treatment of a sheep infected with Haemonchus contortus and Trichostrongylus colubriformis. Following oral administration the burden of H. contortus and T. colubriformis was 41% and 12% less than in an untreated animal. In a third infected animal administration of the same dose into the abomasum gave 87% reduction in H. contortus but 0% reduction in T. colubriformis. We consider these results achieved under non-optimised conditio ns sufficiently encouraging to merit further study. Using the same parasites and oral administration of the active fraction from papaya latex and pineapple juice we will confirm or deny efficacy by producing dose-response curves for the effect of these plant extracts on worm burden. Doses will be quantified in terms of moles of active enzyme. Read-outs will be faecal egg counts and worm burdens, with microscopy to analyse the conditions of the worms before and after treatment. To test the hypoth esis that a neutral pH environment in the abomasum will increase efficacy we will choose a sub-optimal dose from the above experiment and co-administer Cimetidine. A separate animal will be cannulaterd to allow the abomasal contents to be sampled for pH and enzyme activity.

Amount: £9,707
Funder: The Wellcome Trust
Recipient: University of Nottingham

Plant cysteine proteinases as new anthelmintics to treat sheep GI nematode infections. 02 Oct 2008

We recently undertook a pilot study on efficacy of papaya latex in treatment of a sheep infected with Haemonchus contortus and Trichostrongylus colubriformis. Following oral administration the burden of H. contortus and T. colubriformis was 41% and 12% less than in an untreated animal. In a third infected animal administration of the same dose into the abomasum gave 87% reduction in H. contortus but 0% reduction in T. colubriformis. We consider these results achieved under non-optimised conditio ns sufficiently encouraging to merit further study. Using the same parasites and oral administration of the active fraction from papaya latex and pineapple juice we will confirm or deny efficacy by producing dose-response curves for the effect of these plant extracts on worm burden. Doses will be quantified in terms of moles of active enzyme. Read-outs will be faecal egg counts and worm burdens, with microscopy to analyse the conditions of the worms before and after treatment. To test the hypoth esis that a neutral pH environment in the abomasum will increase efficacy we will choose a sub-optimal dose from the above experiment and co-administer Cimetidine. A separate animal will be cannulaterd to allow the abomasal contents to be sampled for pH and enzyme activity.

Amount: £31,597
Funder: The Wellcome Trust
Recipient: University of Sheffield

Ca2+ stores and hyperactivation of human sperm. 15 Oct 2008

The nature, location and regulation of Ca2+-release channels in the store situated at the neck/midpiece of human sperm will be established by a combination of immunolocalisation, radioligand binding and experimental/pharmacological manipulation of cells in which this store has been labelled with magfluo-4. High speed, high-sensitivity fluorescent imaging will be used to monitor Ca2+ mobilisation, Ca2+ signal spread, store mobilisation and flagellar activity in loosely-tethered cells stimulated by ryanodine receptor agonists and inducers of hyperactivation, including 4-aminopyridine (an extremely effective agonist previously characterised in this laboratory). We will then extend the imaging work to investigate signal propagation between the sperm head/midpiece and flagellum using localised uncaging of Ca2+ and Ca2+-buffers. In particular we will investigate the response of the neck/midpiece Ca2+ store to activation of CatSpers (sperm-specific, plasma membrane Ca2+ channels) in the f lagellum and the effects on flagellar [Ca2+]i of store mobilisation, thus elucidating the interaction between these two primary regulators of hyperactivation. To investigate the clinical significance of our findings we will screen sperm donated by patients with motility-related sub-fertility for responsiveness to (i) progesterone, (ii) 4-aminopyridine and (iii) elevation of pHi (to activate CatSpers) and we will assess functional characteristics of the sperm neck/midpiece store

Amount: £240,312
Funder: The Wellcome Trust
Recipient: University of Birmingham

Ca2+ stores and hyperactivation of human sperm 15 Oct 2008

The nature, location and regulation of Ca2+-release channels in the store situated at the neck/midpiece of human sperm will be established by a combination of immunolocalisation, radioligand binding and experimental/pharmacological manipulation of cells in which this store has been labelled with magfluo-4. High speed, high-sensitivity fluorescent imaging will be used to monitor Ca2+ mobilisation, Ca2+ signal spread, store mobilisation and flagellar activity in looselytethered cells stimulated by ryanodine receptor agonists and inducers of hyperactivation, including 4-aminopyridine (an extremely effective agonist previously characterised in this laboratory). We will then extend the imaging work to investigate signal propagation between the sperm head/midpiece and flagellum using localised uncaging of Ca2+ and Ca2+-buffers. In particular we will investigate the response of the neck/midpiece Ca2+ store to activation of CatSpers (sperm-specific, plasma membrane Ca2+ channels) in the flagellum and the effects on flagellar [Ca2+]i of store mobilisation, thus elucidating the interaction between these two primary regulators of hyperactivation. To investigate the clinical significance of our findings we will screen sperm donated by patients with motility-related sub-fertility for responsiveness to (i) progesterone, (ii) 4-aminopyridine and (iii) elevation of pHi (to activate CatSpers) and we will assess functional characteristics of the sperm neck/midpiece store

Amount: £198,117
Funder: The Wellcome Trust
Recipient: University of Dundee

See it, grab it: Control of automatic sensorimotor behaviour in health and disease. 08 Oct 2008

Our goal is to understand how automatic processes are involved in the flexible, volitional control of behaviour. We will integrate different lines of research concerning automatic and unconscious activation and inhibition of motor plans, which together may challenge the traditional view that volitional and automatic behaviours are mediated separately. We will investigate: The roles of medial frontal and parietal brain regions in the activation of, competition between, and inhibition of a ction plans elicited by visual stimuli in the world around us. The inability of patients to inhibit stimulus-driven responses following focal damage to these regions, or in corticobasal degeneration. The relationship between the activation, conflict and inhibition mechanisms engaged by different sensorimotor paradigms (masked priming; flankers; object affordance). A key strength of our proposal is the principled combination of experimental domains. Careful behavioural studies will deter mine performance correlates of activation, conflict and inhibition mechanisms and how they interact. A selected population of lesion patients will allow us to test hypotheses concerning the cortical substrates of these mechanisms, and the outcomes of interfering with them. Imaging will reveal the spatial distribution of implicated areas, and also the dynamics of activation within these cortical networks.

Amount: £426,191
Funder: The Wellcome Trust
Recipient: Cardiff University