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Results

Environmental enrichment and recovery following anterior thalamic lesions. 15 Feb 2010

The research has two parallel aims. The first is to study the rescue of memory loss after brain injury using lesions of the anterior thalamic nucleus in rats to model ?diencephalic amnesia?. In particular, the research will determine the functional impact of environmental enrichment on recovery and examine potential mechanisms for the beneficial effects that have so far been described. The second aim is to identify clinical cases with amnesia and damage to diencephalic structures and determine the potential for rehabilitation procedures based on the enrichment programme with rodents.

Amount: £35,320
Funder: The Wellcome Trust
Recipient: Cardiff University

Clinical PhD Programme at Imperial College London: 'Gene and variant discovery of inherited cardiac conditions'. 31 Aug 2010

Heart failure is a major cause of morbidity and mortality in humans. A substantial proportion of dilated heart failure results from idiopathic dilated cardiomyopathy (IDC) which is characterised by left ventricular dilatation and systolic dysfunction after known causes have been excluded. IDC may be familial in up to 50% of cases and over 40 causative genes have been identified, however a cause is found in only 20-30% of cases. The goal of my research is to increase understanding of heart failure pathogenesis using IDC as a model and to contribute to the development of more effective, specific and safer treatments. I plan to harness the power of new target enrichment technologies coupled with new high throughput sequencing technologies to investigate candidate genes and for whole exome studies that would not be feasible using conventional sequencing in large cohorts of well phenotyped patients. Direct sequencing of exomes has been shown to be an elegant and efficient way of searching for the causative gene for monogenic disorders. I will prioritise large pedigrees with severe or early onset disease for investigation as cohorts with extreme phenotypes are likely to be enriched for rare variants consequently increasing the likelihood of their discovery.

Amount: £224,864
Funder: The Wellcome Trust
Recipient: Imperial College London

Clinical PhD Programme at Imperial College London: 'Small-area ischaemic heart disease incidence and survival in England.' 31 Aug 2010

Geographical variations in mortality across England have been documented for almost a century. When broken down by medical causes, one half of the regional differentials in mortality are accounted for by ischaemic heart disease (IHD). It is however unknown what proportion of the variance in IHD mortality among small area units such as wards or local authorities is due to differences in IHD incidence vs. treatment. Incident IHD, unlike incident cancer or sexually transmitted disease, is not comprehensively recorded in England. Thus, while circulatory diseases are the single largest medical cause of death, very little is known about the differences between small areas in incidence or prognosis of IHD. This limits the evaluation of current preventive and health service interventions aimed at reducing IHD incidence and improving survival, especially in the worst-off regions. This project aims to combine three administrative datasets using a Bayesian hierarchical model, in order to develop a consistent and comparable quantification of IHD incidence at small area level in England. The outputs of the project will be estimates of small area IHD incidence and survival. The final part of the project will examine the socioeconomic and health service associations of the variations seen, and will suggest possible interventions to reduce the burden of IHD in aggregate as well as its disparities.

Amount: £233,378
Funder: The Wellcome Trust
Recipient: Imperial College London

Clinical PhD Programme at Imperial College London: 'Good and bad sparks - Identifying and targeting arrhythmogenic calcium sparks in the failing heart.' 21 Sep 2010

Half of all heart-failure deaths are due to sudden ventricular arrhythmias. One reason for such arrhythmias is the change in elemental calcium release events (calcium 'sparks') seen in heart failure which can result in arrhythmogenic calcium waves. In our rat model of heart failure (HF) we observe increased ventricular arrhythmias together with increased spark frequency and amplitude compared with age-matched controls (AMCs). In heart failure rats treated with SERCA gene therapy (HF+SERCA), in an attempt to replenish this depleted calcium pump, there exists a lower risk of ventricular arrhythmia associated with reduced spark amplitude (though not frequency). This project has four main aims: (1) Fully characterise the differences in spark populations between the AMC, HF and HF+SERCA rats using confocal microscopy of isolated cardiomyocytes and define high risk spark 'fingerprints'. (2) Establish which elements of the HF phenotype contribute to differences in spark fingerprints by manipulation of normal cardiomyocytes in ways that mimic HF cells (e.g. detubulation). (3) Antagonise elements of the HF phenotype in HF cells and assess resulting changes in spark fingerprints (e.g. PKA/CamKII inhibition). (4) Evaluate whether the benefits seen in SERCA treated rats are purely related to SERCA activity or to in-vivo remodelling of myocytes.

Amount: £265,544
Funder: The Wellcome Trust
Recipient: Imperial College London

Wellcome Trust PhD Programme for Clinicians at Imperial College London. 14 Jun 2010

Aspiration pneumonitis (AP) has significant morbidity and mortality in various clinical settings within hospital medicine. Manifestations vary from mild sub-clinical aspiration to severe acute respiratory distress syndrome, but all aspiration events predispose to pneumonia. Using a genetic approach, we found that, in the early phases of mouse AP, tumour necrosis factor-alpha (TNF) has critical and opposing effects on pulmonary oedema formation, depending on which of its two receptors it signals through. We therefore hypothesise that during the entire course of AP (a model of sterile acute lung injury), TNF receptor I (TNFR1) mediates deleterious pro-inflammatory effects, whereas TNF receptor II (TNFR2) mediates anti-inflammatory/pro-resolving effects. We aim to investigate the mechanisms by which TNFR signaling influences the progression and resolution of AP, focusing on three key lung injury paradigms: a. Alveolar oedema development and fluid clearance mechanisms. b. Intra-alveolar coagulation and resolution through fibrinolysis. c. Alveolar macrophage phenotype and function ? pro-inflammatory vs pro-resolving. The potential therapeutic impact whereby manipulation through specific inhibition of the TNFR1 and/or activation of the TNFR2 may attenuate injury in acute pulmonary syndromes is enormous.

Amount: £235,037
Funder: The Wellcome Trust
Recipient: Imperial College London

Wellcome Trust PhD Programme for Clinicians at Imperial College London: 'Impact of tumour necrosis factor receptors in the inflammation and resolution of pulmonary injury'. 21 Sep 2010

Aspiration pneumonitis (AP) has significant morbidity and mortality in various clinical settings within hospital medicine. Manifestations vary from mild sub-clinical aspiration to severe acute respiratory distress syndrome, but all aspiration events predispose to pneumonia. Using a genetic approach, we found that, in the early phases of mouse AP, tumour necrosis factor-alpha (TNF) has critical and opposing effects on pulmonary oedema formation, depending on which of its two receptors it signals through. We therefore hypothesise that during the entire course of AP (a model of sterile acute lung injury), TNF receptor I (TNFR1) mediates deleterious pro-inflammatory effects, whereas TNF receptor II (TNFR2) mediates anti-inflammatory/pro-resolving effects. We aim to investigate the mechanisms by which TNFR signaling influences the progression and resolution of AP, focusing on three key lung injury paradigms: a. Alveolar oedema development and fluid clearance mechanisms. b. Intra-alveolar coagulation and resolution through fibrinolysis. c. Alveolar macrophage phenotype and function ? pro-inflammatory vs pro-resolving. The potential therapeutic impact whereby manipulation through specific inhibition of the TNFR1 and/or activation of the TNFR2 may attenuate injury in acute pulmonary syndromes is enormous.

Amount: £49,853
Funder: The Wellcome Trust
Recipient: Imperial College London

Forward genetic analysis of T regulatory cell development and function. 15 Feb 2010

Regulatory T (TREG) cells maintain tolerance to self and control autoimmune deviation. They prevent runaway responses to pathogens and allergens and help maintain a balance with obligate microbial flora. They maintain allogeneic transplant tolerance in experimental models but also facilitate tumour escape from immune monitoring. It is because of this fundamental importance for immune function and their great potential for therapeutic modulation that TREG cells have attracted extraordinary interest. However, our understanding of their development remains incomplete. Using a forward genetic approach, N-ethyl-N-nitrosourea (ENU) germline mutagenesis, Philip Ashton-Rickardt's laboratory aim to identify all non-redundant genes required for the development of TREG cells. Given the time constraints of a 3-year fellowship, this project aims to identify 2 such genes. 1500 ENU mutant C57BL/6 mice will be subjected to a single-stage screen with the aim of identifying 2 mutants with abnormal TREG development. Transmissibility of the mutations will be confirmed and homozygous mutant strains established. Positional cloning and exon sequencing will identify the culpable mutation in the affected gene. In depth phenotypic analysis will determine how the affected gene controls the development and function of TREG cells and how they suppress allo-reactivity and autoimmunity in model systems.

Amount: £103,135
Funder: The Wellcome Trust
Recipient: Imperial College London

Wellcome Trust PhD Programme for Clinicians at Imperial College London. 20 Oct 2009

Vasoactive intestinal polypeptide (VIP) is a neurotransmitter of the secretin/glucagon family, all of whose members inhibit appetite. VIP shares strong homology with pituitary adenylate cyclase activating polypeptide (PACAP). VIP and PACAP bind with equal affinity to the VPAC1R and VPAC2R whilst PAC1R is specific for PACAP. VPAC2R and PAC1R are expressed in the hypothalamus, specifically in nuclei known to regulate appetite. Both VIP and PACAP have been shown to reduce food intake but administration of PACAP, acting via PAC1R, is associated with other behavioural abnormalities. My preliminary experiments have shown VIP powerfully reduces food intake in rodents without any effect on behaviour and that hypothalamic VPAC2R expression is reduced by a 24 hour fast. I will now investigate the physiological role of hypothalamic VIP in the regulation of food intake. To achieve this I will determine the hypothalamic site of action of VIP and the neuronal pathways involved. I will also investigate how chronic increased and decreased hypothalamic VIP expression affects energy homeostasis. This programme of work will characterise the physiological role of VIP in the regulation of food intake and its potential as a target, in the development of novel treatments for obesity.

Amount: £235,491
Funder: The Wellcome Trust
Recipient: Imperial College London

Wellcome Trust Clinical PhD Programme at Imperial College London: 'Investigation of the physiological role of hypothalamic VIP in the regulation of food intake.' 31 Aug 2010

Vasoactive intestinal polypeptide (VIP) is a neurotransmitter of the secretin/glucagon family, all of whose members inhibit appetite. VIP shares strong homology with pituitary adenylate cyclase activating polypeptide (PACAP). VIP and PACAP bind with equal affinity to the VPAC1R and VPAC2R whilst PAC1R is specific for PACAP. VPAC2R and PAC1R are expressed in the hypothalamus, specifically in nuclei known to regulate appetite. Both VIP and PACAP have been shown to reduce food intake but administration of PACAP, acting via PAC1R, is associated with other behavioural abnormalities. My preliminary experiments have shown VIP powerfully reduces food intake in rodents without any effect on behaviour and that hypothalamic VPAC2R expression is reduced by a 24 hour fast. I will now investigate the physiological role of hypothalamic VIP in the regulation of food intake. To achieve this I will determine the hypothalamic site of action of VIP and the neuronal pathways involved. I will also investigate how chronic increased and decreased hypothalamic VIP expression affects energy homeostasis. This programme of work will characterise the physiological role of VIP in the regulation of food intake and its potential as a target, in the development of novel treatments for obesity.

Amount: £49,123
Funder: The Wellcome Trust
Recipient: Imperial College London

Wellcome Trust PhD Programme for Clinicians at Imperial College London: Investigating the physiological role of hypothalamic glucose-sensing neurones in glucose homeostasis. 13 Apr 2010

Until recently it was thought that day to day blood glucose is regulated by peripheral factors, principally insulin. Recent data suggests glucose sensing in the brain is important for the regulation of whole body glucose homeostasis. These effects are thought to be mediated by a complex network of specialised glucose sensing neurones. Glucokinase is the body's glucose sensor and is expressed within these neurones. Glucose sensing neurones have been identified in the ARC and PVN of the hypothalamus. My pilot data provides evidence that overexpression of glucokinase in the ARC using recombinant adeno-associated virus (rAAV) results in increased glucose disposal during a glucose tolerance test. Despite recent advances there is little evidence linking neuronal glucose sensing directly to the in vivo day to day regulation of glucose homeostasis. To further test the hypothesis that hypothalamic glucokinase is the key neuronal regulator of glucose control I will use virally mediated gene transfer to increase or decrease glucokinase expression specifically in the ARC and PVN of the hypothalamus and determine the effect on glucose homeostasis. These studies will determine the physiological role of glucokinase in the hypothalamus and may lead to the identification of new therapeutic targets to treat diabetes.

Amount: £50,770
Funder: The Wellcome Trust
Recipient: Imperial College London

Wellcome Trust PhD Programme for Clinicians at Imperial College London. 20 Oct 2009

Aim: To understand which health-systems factors may act as barriers to the effectiveness of ACT in reducing malaria transmission. Objectives: 1) To extend a model of the impact of ACT on malaria transmission to incorporate health systems dimensions 2) To collate relevant data on health-systems to apply the model to a specific setting in Tanzania 3) To identify which health-systems constraints on ACT delivery have the greatest impact on malaria transmission and treatment demand, in order to inform estimation of the marginal costs of overcoming such bottlenecks. Methodology: 1) Review of past scale-up programmes to identify which health-systems inputs are critical to effective delivery of interventions and the consequences of system constraints. 2) Extension of a model of the impact of ACT on malaria transmission to explore the extent to which health-systems variables could reduce operational effectiveness, focusing on 4 aspects: heterogeneity in access and response to treatment, diagnostic capacity, treatment capacity and human resources. 3) Collation of relevant data from collaborating institutions in Tanzania as a case-study and incorporation of these data into a combined model to identify the relative importance of these health-systems variables in limiting ACT impact.

Amount: £245,728
Funder: The Wellcome Trust
Recipient: Imperial College London

Wellcome Trust PhD Programme for Clinicians at Imperial College London. 20 Oct 2009

Induced Pluripotent Stem Cells (iPSC) are created from adult somatic cells by ectopic expression of key 'stemness' transcription factors, avoiding the ethically problematic use of Embryonic Stem Cells (ESC). Autogenic iPSC also avoid technical problems associated with ESC, such as host immune rejection. Consequently iPSC derived Cardiomyocytes (iPSC-CM) may be more suitable for use in regenerative medicine and as in-vitro disease models. To ensure that iPSC-CM are safe and effective it is important to establish that they are capable of full differentiation and maturation. Furthermore their use as in-vitro disease models must be validated by comparison with human ESC derived Cardiomyocytes (ESC-CM), adult human cardiomyocytes and previously characterised animal heart preparations. As techniques to evaluate gene expression and cell morphology have significant limitations in determining the phenotype of both developing and adult cardiomyocytes characterisation of the electrophysiological properties of iPSC-CM is critical. The electrophysiological properties of singleand multi-cellular iPSC-CM preparations will be compared with ESC-CM, adult human heart tissue routinely removed during cardiac surgery, and well characterised animal heart preparations. Several techniques including multi-electrode arrays, patch clamping, voltage sensitive dyes and optical mapping techniques will be used.

Amount: £200,386
Funder: The Wellcome Trust
Recipient: Imperial College London

Wellcome Trust PhD Programme for Clinicians at Imperial College London: 'Characterisation of the electrophysiological properties of cardiac myocytes derived from induced pluripotent and embryonic stem cells'. 14 Jun 2010

Induced Pluripotent Stem Cells (iPSC) are created from adult somatic cells by ectopic expression of key 'stemness' transcription factors, avoiding the ethically problematic use of Embryonic Stem Cells (ESC). Autogenic iPSC also avoid technical problems associated with ESC, such as host immune rejection. Consequently iPSC derived Cardiomyocytes (iPSC-CM) may be more suitable for use in regenerative medicine and as in-vitro disease models. To ensure that iPSC-CM are safe and effective it is important to establish that they are capable of full differentiation and maturation. Furthermore their use as in-vitro disease models must be validated by comparison with human ESC derived Cardiomyocytes (ESC-CM), adult human cardiomyocytes and previously characterised animal heart preparations. As techniques to evaluate gene expression and cell morphology have significant limitations in determining the phenotype of both developing and adult cardiomyocytes characterisation of the electrophysiological properties of iPSC-CM is critical. The electrophysiological properties of singleand multi-cellular iPSC-CM preparations will be compared with ESC-CM, adult human heart tissue routinely removed during cardiac surgery, and well characterised animal heart preparations. Several techniques including multi-electrode arrays, patch clamping, voltage sensitive dyes and optical mapping techniques will be used.

Amount: £13,755
Funder: The Wellcome Trust
Recipient: Imperial College London

Identification of novel biomarkers by in vitro proton magnetic resonance spectroscopy in acute and acute-on-chronic liver failure. 03 Dec 2009

Modern metabonomic methods using magnetic resonance spectroscopy (MRS) combine high resolution spectrometers with highly sophisticated statistical techniques. They have been applied in a variety of situations, but seldom in the field of organ dysfunction in liver failure. In vitro MRS is particularly suited to determining concentrations of molecules involved in these processes (such as ammonia and amino acid trafficking in hepatic encephalopathy). This project will apply these principles to the diagnosis and prediction of outcome in cerebral and renal dysfunction in acute and acute-on-chronic liver failure. Patients will be recruited from the cohort at King's College Hospital (including control groups with confusion and critical illness, but no liver disease) and blood, urine and muscle samples taken. We will make an accurate assessment of ammonia, amino acid, phenolic compound and fatty acid metabolism using MRS and principle components analysis. The aim is to identify biomarkers to better detect these conditions, which may then be used for predicting clinical outcome (including need for transplantation) or translated into simple diagnostic tests.

Amount: £140,800
Funder: The Wellcome Trust
Recipient: Imperial College London

Poxvirus immune evasion strategies. 01 Dec 2009

This research programme will study the immune evasion strategies of vaccinia virus (VACV), the vaccine used to eradicate smallpox. The key goals are to i) identify new VACV proteins that interfere with the host response to infection, understand the mechanism of action of these proteins and what host molecules they interact with, and to evaluate the contribution these proteins make to virus virulence and immunogenicity; ii) further characterise VACV proteins that are known to interfere with the h ost response to infection and determine their structures alone and in combination with binding partners, and iii) identify and study the host molecules that sense dsDNA in the cytoplasm and to characterise VACV inhibitors of this(ese). Overall, this programme of work is designed to increase our knowledge of virus pathogenesis and the strategies viruses use to interfere with the host response to infection, to better understand the host innate response to infection, and to build more immunogenic p oxvirus based vaccines.

Amount: £3,485,047
Funder: The Wellcome Trust
Recipient: Imperial College London

Mechanism of physiological thalamocortical rhythms. 01 Jul 2010

The aim of this project is to understand the cellular, synaptic and network rules that govern thalamic physiology, and how they coalesce within cortico-thalamo-cortical modules to bring about EEG rhythms of different vigilance states. We will use a multidisciplinary approach that includes somatic single and paired recordings as well as somato-dendritic calcium imaging in vitro, intracellular recordings in vivo, and large neuronal ensemble recordings in freely moving, naturally waking-sleeping an imals. Specifically, we will determine: 1 - the cell-specificity of the firing dynamics of thalamocortical neurons and the physiology and pharmacology of intranuclear thalamic synapses; 2 - the dendritic mechanisms underlying the integration of sensory and cortical signals in thalamocortical neurons; 3 - the input-specificity, modulation by thalamic transmitters and physiological role of the tonic GABAA receptor-mediated inhibition of thalamocortical neurons; 4 - the spatio-temporal firing dynamics of simultaneously recorded large thalamic and cortical populations during two behaviourally significant EEG waves: the alpha rhythm and the slow (< 1Hz) sleep rhythm. By establishing a full mechanistic picture of thalamic computation during different behavioural states, this study will further our knowledge of subcortical sensory processing and higher frequency cortico-thalamic network rhythms, and thus help our understanding of thalamic alterations in neurological disorders.

Amount: £1,462,677
Funder: The Wellcome Trust
Recipient: Cardiff University

Modulation of host immunity by human cytomegalovirus. 08 Feb 2010

HCMV has the largest genome of any characterised human virus (236kb). All 167 putative ORFs, 14 miRNAs and additional non-coding RNAs will be available in a newly-constructed adenovirus (Ad) vector library. In addition, HCMV deletion mutants encompassing >80 ORFs have been generated. All HCMV genes will be screened in NK cell functional assays using a combination of the Ad vector library and HCMV mutants. Preliminary studies reveal that HCMV regulates expression of a subset of host cell functio ns implicated in NK cell recognition; the Ad library and HCMV mutants will be screened to identity the genes responsible. Novel reagents will be developed to expand the range of NK cell receptor:ligand interactions that can be screened. Furthermore, HCMV BAC (Bacterial Artificial Chromosome) technology will be developed to provide for conditional expression of essential immunomodulatory functions and enable experimentation in a broader range of cell types. The mechanism-of-action of novel NK cel l modulators will be determined, and ongoing studies exploring unexpected novel properties of UL18, UL40, UL135, UL141, US2 and US11 will be developed. The capacity of NK cells derived from asymptomatic carriers and patients with overt disease to control HCMV infection will be evaluated.

Amount: £1,062,032
Funder: The Wellcome Trust
Recipient: Cardiff University

Using fluorescence dilution to study Salmonella infection. 08 Jul 2010

We have developed methods based on fluorescence dilution for measuring the dynamics of intracellular Salmonella replication at the population and single cell level. We wish to exploit this to: (a) Analyse the contributions of bacterial virulence proteins to replication in macrophages and epithelial cells. (b) Analyse the influence of host receptors and resistance proteins to intracellular replication and killing of Salmonella. (c) Identify signals leading to bacterial entry into a dormant-like s tate and to determine if these bacteria can be resuscitated. (d) Study the dynamics of bacterial replication at the population and single cell level during growth in infected animals.

Amount: £407,687
Funder: The Wellcome Trust
Recipient: Imperial College London

The detection and management of ivermectin resistance in human onchocerciasis. 08 Jul 2010

Global neglected tropical disease control has intensified the use of mass drug administration against major human helminthiases, raising concerns that anthelmintic resistance may develop. Although no resistance cases have been confirmed in human onchocerciasis, molecular genetic markers of drug-induced selection are being identified in ivermectin-treated Onchocerca volvulus populations, and suboptimal host responses to treatment have been characterized. Yet, evidence of drug resistance remains i nconclusive due to scarcity of longitudinal studies, difficulties in assessing ongoing transmission and treatment coverage, and lack of studies linking host response to treatment phenotype with parasite phenotype and genotype. Genetic analysis of (already collected) parasites from Ghana and Cameroon (looking at a number of loci under selection) will be conducted and the resulting data will be used to fit mathematical models to individual host responses to treatment to link suboptimal responses w ith molecular markers for drug resistance. Mathematical models for O. volvulus, merging population dynamics and population genetics, will be refined to quantify the impact, upon ongoing control programmes, of ivermectin resistance were it confirmed, and formulate strategies to mitigate such an impact and delay its spread. Results are anticipated to be of major significance for the protection of investments already made in onchocerciasis control.

Amount: £338,756
Funder: The Wellcome Trust
Recipient: Imperial College London

The role of the EBNA3 proteins in EBV biology and disease pathogenesis. 08 Jul 2010

The focus of this programme of research is the family of EBV-encoded nuclear proteins (EBNAs 3A, 3B and 3C) expressed in the type of viral latency generally associated with EBV-driven B cell proliferation. Although the EBNA3s are vital to EBV biology, our knowledge of their functions was until recently quite limited, but they are gradually moving centre stage. Using a series of unique, engineered recombinant viruses carrying a variety of mutations in the EBNA3 locus and microarray technology, we have discovered a remarkably large number of cell genes regulated by one or more of the EBNA3 proteins. Regulation in some cases involves stable epigenetic changes to chromatin and in some involves transcriptional elongation. Furthermore it is now clear at least one of these proteins (EBNA3C) additionally targets multiple cellular proteins involved in the regulation of cell cycle checkpoints. Key aims of the study are: a) To fully characterise the molecular mechanisms underpinning EBNA3 actio n and cooperation in gene regulation. b) To clarify the roles of the EBNA3s in cell cycle deregulation. c) To explore their contribution in lymphomagenesis using a small animal model. d) To understand their contribution to human disease involving EBV.

Amount: £500,000
Funder: The Wellcome Trust
Recipient: Imperial College London