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Results

VALUE IN PEOPLE AWARD. 30 Aug 2006

Not available

Amount: £300,000
Funder: The Wellcome Trust
Recipient: Imperial College London

Characterisation of immune mechanisms underlying the natural history of tuberculosis infection. 05 Jun 2006

Tuberculosis (TB) is an enormous and increasing public health burden. Basic and translational research have potential to help control this epidemic, particularly in two key areas: improved diagnosis and an improved vaccine. Recent genomic advances have identified the RD1 genomic segment which is present in M. tuberculosis but absent from BCG.RD1 gene products thus present the opportunity to develop more specific tests for diagnosing MTB infection. Using a highly sensitive, yet rapid, ex vivo interferon-? (IFN-?) enzyme-linked immunospot (ELISPOT) assay, I enumerated T cells specific for ESAT-6, the first RD1 gene product to be identified, in TB patients, contacts and controls. These proof-of-principle studies have shown that this rapid T cell-based assay detects active and latent MTB infection with high sensitivity and specificity, and has the potential to improve tuberculosis control. I now propose to rigorously validate the assay (and incorporate a second RD1 gene product, CFP10) in the relevant target populations where it could be of major benefit. I will validate its clinical utility for the rapid diagnosis of active TB in a low prevalence population and for the diagnosis of TB meningitis in a high prevalence population. I will also apply this assay to investigate the basic parameters and pathways of MTB transmission and the natural history of TB in distinct epidemiologic settings, including populations with a high prevalence of both TB and HIV. Rational development and clinical evaluation of new TB vaccines requires an understanding of correlates of protective immunity. The host response largely determines the outcome of MTB infection, with long-term immunological control of latent bacilli being the best clinical outcome. My cross-sectional studies of TB patients and contacts suggest that ESAT-6 specific T cells may correlate with clinically-defined protective immunity. I am to follow through this observation with longitudinal studies of T cells specific for ESAT-6 (and other RD1 gene products) in recently exposed healthy contacts, using multiple techniques of ex vivo analysis. I will also study the kinetics of these MTB-specific T cell populations in HIV-positive individuals with latent MTB infection during anti-retroviral therapy, to see if they correlate with immune reconstitution. Simultaneously, I will investigate the effects of these CD4 and CD8 T cells on intracellular MTB in vitro. These studies will shed light on the phenotype, function and antigen-specificity of T cells associated with immunological control of MTB in vivo, and should thus assist the development and evaluation of new TB vaccines.

Amount: £1,464,220
Funder: The Wellcome Trust
Recipient: Imperial College London

The PE and PPE proteins of Mycobacterium tuberculosis and Mycobacterium bovis: exploring their potential as variable antigens. 13 Dec 2005

The PE and PPE proteins of Mycobacterium tuberculosis and Mycobacterium bovis are encoded by large, multigene families which account for approximately 10% of the genome. Although the function of these proteins remains unclear, they are widely speculated to represent a source of antigenic variation, and thus a means for these pathogens to evade host immune defences. The overall aim of the proposed study is to determine whether the PE/PPE proteins do indeed represent variable antigens. Specifically, I will test the hypothesis that the pattern of PE/PPE expression changes during the course of infection and that this in turn modulates the host immune response. After characterising PE/PPE expression profiles in vitro, I will use two experimental models: infection of mice with M. tuberculosis, and infection of cattle with the closely-related M. bovis to examine in vivo expression and T cell recognition. These models are well-established in the sponsoring and collaborating laboratories and there is evidence in both systems that the bacterial phenotype and the immune repertoire change over the course of infection. In parallel with this in vivo approach, I will investigate the control of PE and PPE expression by identification and characterization of relevant transcriptional regulators in M. tuberculosis.

Amount: £490,127
Funder: The Wellcome Trust
Recipient: Imperial College London

A facility for the analysis of the intrinsic and extrinsic regulation of Plasmodium falciparum development in mosquitoes, and the evaluation of pre-erythrocytic, and transmission-blocking. 09 Feb 2006

Ongoing studies on rodent malaria parasites have described the molecular basisfor, and regulation of, parasite development in Anopheles stephensi, and parasite interactions with the vector immune system. This proposal will extendthe hypotheses generated, to the important human pathogen P. falciparum in itsnatural vector A. gambiae. In addition the project will provide critical materials, sporozoites and assays, for the development of pre-erythrocytic, and transmission-blocking vaccines respectively. The project will: i) characterize parasite phenotypes in wild-type mosquitoes challenged with mutated parasites (gametocyte signalling-Billker; ookinete-vector interaction - Sinden); ii) provide P. falciparum sporozoite-infected mosquitoes for ongoing studies on the development of pre-erythrocytic stage vaccines (Hill); iii) evaluate new transmission-blocking monoclonal antibodies, and sera from phase I trials (Carter/Saul) and iv) study the responses of RNAi immune knock-down mosquitoes (Kafatos/Christophides). Specific outcomes include the better understanding of vaccine design and application; the discovery of noveltransmission-blocking targets in the parasite and vector, and a coincidental reduction in animal experimentation. Imperial College has established a majorinitiative in parasite-vector interactions/innate immunity, and now has one ofthe few units able to transmit P. falciparum (including genetically modified (GM) lines) with confidence through both Anopheles stephensi (susceptible or GM refractory) and A. gambiae (susceptible, refractory and GM). National and international demands for this resource now exceed the capacity of current staff. We request funds to support the work described above, and to fund an additional technician to support the key needs of others (see attached letters). Collaborators not funded by The Trust will be asked to pay full costs, and the monies used to establish a rolling fund to sustain the additional technician long-term.

Amount: £293,968
Funder: The Wellcome Trust
Recipient: Imperial College London

Role of protein kinase A-dependent G-protein switching of the beta2-adrenoreceptor in depression of cardiac contraction. 07 Nov 2005

Although the b2-adrenoceptor (b2AR), like the b1AR, is known to stimulate cardiac contraction through Gs/adenylyl cyclase/cAMP, we have observed two distinct cardiodepressant actions mediated through b2ARs in isolated ventricular myocytes. Overexpression of the b2AR itself produces a constitutive depression after the initial constitutive activation of contraction, and also reveals an acute negative effect of b2AR ligands (including compounds previously classed as b2AR antagonists). The second effect (and possibly the first also) is evident in myocytes from failing, but not non-failing, human hearts. We have evidence that each of these effects is due to increased b2AR-Gi coupling, with a negative inotropic mechanism mediated through activation of the Na+/Ca2+-exchanger. Phosphorylation of the b2AR by cAMP-dependent protein kinase (PKA) has been shown to switch the b2AR from Gs- to Gi-coupling in reconstituted systems. Our hypothesis is that persistent Gs activation in the animal models and failing human heart produces this switch. Our aims are 1) to manipulate PKA to produce an increased (using PKA agonists) or decreased (by overexpressing PKA inhibitor peptide using adenovirus) activity in human and b2AR-overexpressing rat ventricular myocytes, and determine the effect on cardiodepression and b2AR phosphorylation; 2) to do the same after adenoviral transfection of a mutated b2AR lacking PKA phosphorylation sites; 3) to distinguish between Gia and Gbg as the effector.

Amount: £127,870
Funder: The Wellcome Trust
Recipient: Imperial College London

Regulation of gene expression in African Trypanosomes. 25 Oct 2005

Trypanosoma brucei is the causative agent of sleeping sickness in man and Nagana in cattle. One interesting aspect of trypanosome biology is the almost complete absence of transcriptional control, which is the major control point for regulating gene expression in most eukaryotes. Therefore it would not be surprising to identify novel mechanisms of post-transcriptional gene regulation exemplified in these organisms that are important but subtle in other eukaryotes. Understanding this fundamental aspect of trypanosome biology may reveal an Achilles heel in these pathogenic parasites. My genome wide survey of the 2004 completed T.brucei genome sequence suggests that the novel CCCH zinc finger family of proteins, that has been implicated in post-transcriptional regulation of gene expression via RNA binding, may be of great importance in trypanosomes. This project will define the lifecycle specific expression pattern, cellular consequences of perturbed expression, cellular localisation and mechanism of RNA binding for 4 selected T.brucei CCCH proteins. One of these will be prioritise for further dissection via more detailed processing analysis and expression profiling. This will determine the regulatory extent and cellular function(s) of these novel CCCH proteins and indicate the significance of the CCCH family of proteins in T.brucei regulated gene expression.

Amount: £222,302
Funder: The Wellcome Trust
Recipient: Imperial College London

BMP2/4 signalling in T cell development. 25 Oct 2005

The thymus, the primary site of T cell production, is seeded throughout life by blood borne lymphocyte progenitor cells from the foetal liver or adult bone marrow. This project aims to test the hypothesis that the Bone Morphogenetic Protein (BMP) 2 and 4 signalling pathway is an important regulator of haematopoiesis and thymopoiesis. The BMP family of secreted intercellular signalling molecules are powerful regulators of patterning and organogenesis of many mammalian tissues during embryonic development, but relatively little is known about the function of BMP signalling in the immune system. To avoid complications of redundancy and promiscuity between components of the signalling pathway, we will focus on the type I BMP Receptors for BMP2 and BMP4: BMPR1A and BMPR1B. We will use conditional BMPR1A knock-out mice to study the function of BMP signalling in haematopoietic stem cells and lymphocyte progenitor cells and developing thymocytes. As BMPR1B-/- are viable, we will use these animals to investigate the function of BMPR1B in lymphocyte progenitor cells and developing T cells. Key goals: (1) To define the functions of BMP2/4 signalling in thymocyte development(2) To elucidate molecular mechanisms that underlie these functions(3) To identify target genes that are transcriptionally regulated by the pathway.

Amount: £302,561
Funder: The Wellcome Trust
Recipient: Imperial College London

High resolution functional dissection of the 'B-Finger' domain of basal transcription factor TFB/TFIIB. 17 Oct 2005

The core archaeal transcriptional machinery consists of TATA-binding protein (TBP), TFB (a homolog of eukaryotic TFIIB) and RNA polymerase (RNAP). The work described in this proposal will focus on a detailed characterization of the functional properties of the archaeal basal transcription factors TFB. This factor cooperates intimately with RNA polymerase (RNAP) during promoter recruitment and transcript initiation (especially the abortive transcription stage). Based on previous work, we have developed a series of assays for testing a variety of subfunctions of TFB, which we will apply to understand the structural basis of these activities in more detail. Specifically, we will dissect by site-directed mutagenesis the function of the B-finger of TFB which is inserted into the immediate vicinity of the catalytic site of RNAP. A bioinformatics analysis of B-fingers shows a high degree of variability (especially in the electrostatic properties) across the evolutionary range which are likely to result in significant functional differences in e.g. start site selection and/or abortive transcription behaviour. Due to the structural similarities between the archaeal transcription system and the eukaryotic RNAPII machinery many of the insights that we will obtain will also be applicable to understanding gene expression mechanisms in higher organisms.

Amount: £210,911
Funder: The Wellcome Trust
Recipient: Imperial College London

Biomarkers for paediatric TB. 25 Oct 2005

There is an urgent need for new diagnostic methods for TB in children. In a pilot study, funded by the Wellcome Trust, we have found 4 serum protein biomarkers that discriminate between culture positive proven cases of paediatric TB from other infections/inflammatory conditions with a sensitivity and specificity of 92.3% and 94.3% respectively. With a view to developing a point of care (POC) test, we will identify the 4 biomarkers at the molecular level and determine whether they can be detected at sufficient sensitivity by immunological means. If so, then a POC test with great potential to save children's lives can be developed with confidence. Specifically our aims are:(1) The molecular identification of 4 serum biomarkers specific for paediatric TB that we have found in a cohort of Cape Town (South African) children.(2) Confirmation of biomarker identity by immunological and/or biochemical means.(3) Validation of biomarkers by ELISA as an initial step in developing an immunological based POC test for use in resource poor countries.

Amount: £110,094
Funder: The Wellcome Trust
Recipient: Imperial College London

A genome wide systematic deletion analysis of Plasmodium berghei protein kinases to reveal molecular mechanisms of life cycle regulation. 25 Oct 2005

The genome-wide functional analysis of protein kinases in model organisms is beginning to provide exciting new insights into the molecular regulation of basic cellular processes1-3. In malaria parasites we are beginning to appreciate the functions of protein kinases as key regulators of the life cycle. Gene knock-out parasites in Plasmodium berghei have recently shown essential, stage-specific functions for unusual protein kinases in cell cycle progression, motility and host vector interactions4,5[and our unpublished data]. We now propose to combine the in silico analysis of the complete complement of protein kinases in P. falciparum6 with recent advances in gene knock-out technology in P. berghei to carry out a systematic deletion analysis of the approximately 70 protein kinase-like genes we identified in P. berghei. Deletion mutants generated in the asexual erythrocytic phase of the parasites' life cycle will be transmitted to Anopheles stephensi mosquitoes and their phenotypes analysed to map kinase functions throughout the life cycle. We expect to gain important new insights into molecular mechanisms of parasite transmission and life cycle progression by identifying pathways regulating poorly understood processes, such as the switch to sexual development, cell cycle events during sexual differentiation and sporogony, which may serve a model for schizogony. The project will also generate a list of protein kinases with likely essential functions in schizogony. Recognising that protein kinases are now major targets for the development of selective inhibitors7, these will be important candidates for evaluation as drug targets.

Amount: £362,851
Funder: The Wellcome Trust
Recipient: Imperial College London

Role of insulin-like growth factors in preantral follicle development and function in normal and polycystic ovaries. 23 Feb 2006

Polycystic ovary syndrome (PCOS) has profound implications for both reproductive and metabolic health but many aspects of its aetiology and pathogenesis remain poorly understood. Anovulation in PCOS is characterised byarrested antral follicle development but we have recently demonstrated abnormalities in the very earliest stages of preantral follicle development. Our preliminary data indicate that (1) key components of the intraovarian IGF system are expressed in human preantral follicles, that (2) IGF-I effects bothgrowth and survival or early preantral follicles in culture and that (3) thereare differences between normal and polycystic ovaries in expression and actionof IGFs. The specific aims of this project are: (1) to study the expression ofIGFs, their receptors and binding proteins in human preantral follicles; (2) to study the action of IGFs on recruitment, growth, survival and differentiation of human preantral follicles, using cultures of ovarian cortical tissue; (3) to compare expression and action of IGFs in preantral follicles from normal and polycystic ovaries. In complementary studies (4) we

Amount: £184,663
Funder: The Wellcome Trust
Recipient: Imperial College London

Expression and function of indoleamine 2,3-dioxygenase (IDO) following corneal transplantation. 09 Feb 2006

This research is aimed at understanding the role of indoleamine 2,3-dioxygenas to what extent IDO expression has a role in the rejection of corneal allograft the factors that control IDO expression in corneal allograft rejection· whether over-expression of IDO in corneal allografts can prevent rejection· if over-expression of IDO in dendritic cells (DCs) will induce regulatory T-c if administration of IDO expressing DC can prevent graft rejection, and to com

Amount: £201,302
Funder: The Wellcome Trust
Recipient: Imperial College London

The role of the dorsal auditory pathway in the rehabilitation of aphasic stroke. 27 Feb 2006

The project will investigate the neural basis of behavioural rehabilitation ofspeech processing in aphasic stroke. Based on previous functional imaging evidence, I hypothesise that recovery of function within the dorsal auditory pathway, a posterior temporal-parietal-frontal cortical network engaged in both speech comprehension and output, is critical for the successful rehabilitation of aphasic stroke. This longitudinal study will use functional magnetic resonance imaging (fMRI) to investigate changes in cortical activation and cortico-cortical connectivity within the dorsal auditory pathway in chronic left temporo-parietal aphasic stroke patients, in response to an intensive short-duration rehabilitation program designed to improve speech comprehension and repetition. The same techniques will be used to investigate functional plasticity within the dorsal auditory pathway of normalsubjects, in a simulated rehabilitation program involving learning to understand acoustically distorted speech. Functional MRI will be supplemented with diffusion tensor imaging (DTI) of dorsal pathway white matter tracts.

Amount: £375,765
Funder: The Wellcome Trust
Recipient: Imperial College London

Mapping expression QTLs for obesity in humans and mice. 27 Apr 2006

Obesity is a complex genetic disorder resulting from the interaction of genes and environmental factors. It is now possible to identify expression quantitative trait loci (eQTL), i.e. areas of the genome that are genetically linked to the expression level of a particular transcript, using microarrays. By carrying out genome scans in full pedigrees of humans and microarray analysis of expression in subcutaneous fat tissue eQTLs that co-localise with peaks of linkage for obesity traits will be identified. This strategy will allow not only the identification of genes involved in obesity susceptibility or in obesity-associated QTLs but also of trans-eQTLs that are likely to shed new light on pathways and networks of genes involved in obesity. Association analysis of the candidate genes will then be used to identify causative variants for obesity in different human populations. Comparison of the data with our other collaborator's data, i.e. Prof Nick Wareham, Dr Panos Deloukas and Dr Ines Barroso at the Sanger Institute, Cambridge and Prof Daniel Pomp atthe University of Chapel Hill in North Carolina will significantly improve theanalysis of our dataset. Preliminary functional analysis will provide insightsinto the normal physiological role of the identified gene products.

Amount: £586,581
Funder: The Wellcome Trust
Recipient: Imperial College London

Unravelling the TccP and Nck actin remodelling pathways of attaching and effacing E coli (AEEC). 24 Apr 2006

Enteropathogenic (EPEC) and enterohaemorrhagic E. coli (EHEC) are human pathogens that translocate the Tir protein into the plasma membrane of the host cell. Through interaction with the outer membrane adhesion molecule intimin Tir connects the extracellular bacterium to the host cell actin cytoskeleton. Intimin-Tir interaction focuses Tir and triggers actin polymerisation at the site of bacterial adhesion. While both converge on N-WASP, Tir-mediated actin accretion by EPECE2348/69 requires Tir tyrosine (TirY474) phosphorylation and the host adaptor Nck, whereas TirEHECO157 is not phosphorylated and utilises TccP, a bacterial effector that binds, albeit indirectly, Tir and activates N-WASP. While screening for tccP among a large collection of EPEC and non-O157 EHEC we found that many strains carry tccP and a TirY474 equivalent. Preliminary results showed that the TccP/TirY474 strains simultaneously utilise the Nck and TccP pathways during infection, defining a new class of versatile and potentially more virulent diarrhoeagenic E. coli. The main goals of this project are to characterise the signalling pathways used by the TccP/TirY474 strains, to determine their role, synergy or redundancy during infection and colonisation using in vitro and in vivo models and to find the host cell adaptor protein(s) that links TccP to Tir.

Amount: £198,436
Funder: The Wellcome Trust
Recipient: Imperial College London

Investigation of a factor in synovial fluid which suppresses inflammatory signalling in cartilage. 03 Apr 2006

The mechanism of activation of cJun-N-terminal Kinase (JNK) in articular cartilage in response to mechanical injury is unknown. Removal, or dilution ofsynovial fluid has been shown to activate JNK in cartilage. Initial characterisation of the suppressive activity in synovial fluid suggests that it may be due to a protein, between 5 and 50 kDa in size, which is not presentin plasma. This project aims to characterise this factor further, purify it from synovial fluid (using techniques such as ion exchange chromatography and electrophoresis) and identify it by mass spectrometry. A bioassay of ATF-2 suppressive activity will be used to indicate the presence, or absence, of thesuppressive factor. The role of the factor in cartilage and other tissues, particularly in the response to sharp injury will be explored. Antibodies to the factor will be generated and used for western blotting and immunohistochemistry. The factor's role in the regulation of other signalling pathways in articular cartilage will also be investigated, by phospho-western blotting of cartilage lysates. The nature of a suppressor of JNK in synovial

Amount: £174,420
Funder: The Wellcome Trust
Recipient: Imperial College London

Investigation of the role of Neuromedin S, a newly identified powerful regulator of food intake. 12 Jul 2006

Neuromedin S (NMS) is a newly identified powerful regulator of food intake. I will define the role of NMS in the control of appetite and the development of obesity. My key research goals are to: Determine the distribution of NMS and its response to changes in energy intake. Investigate the effects of CNS injection of NMS on food intake. Investigate the effects of NMS on known hypothalamic regulators of appetite. Examine the effects of NMS on long-term weight regulation using adeno-associated virus mediated gene transfer. These experiments will help to determine the importance of NMS in the hypothalamic regulation of food intake.

Amount: £236,661
Funder: The Wellcome Trust
Recipient: Imperial College London

Is the anaerobic quadriceps muscle phenotype in COPD mediated by reduced muscle concentrations of Peroxisome Proliferator-Activated Receptors a and d? 12 Jul 2006

Background Quadriceps weakness is a disabling feature of Chronic Obstructive Pulmonary Disease (COPD). It results from loss of aerobic muscle fibres. In vivo work suggests that this is mediated by reduced Peroxisome Proliferator-Activated (PPAR) a and d activity.Goals To investigate whether 1) reduced quadriceps PPARa and d concentrations correlate with an anaerobic muscle phenotype in patients with severe COPD 2) clinical interventions reverse the anaerobic phenotype and concurrently upregulate PPARa and d.Approach Study 1 75 patients with severe COPD and 30 controls undergo assessment of quadriceps function and a muscle biopsy to determine PPARa and dconcentrations and proportion of aerobic muscle fibres. Study 2 30 patients from Study 1 are randomised to cardiopulmonary training (pulmonary rehabilitation) or a control group. Study 3 30 patients from Study 1 are randomly assigned to isolated leg training with repetitive magnetic femoral nerve stimulation (rMS). Study 2 and 3 subjects are treated for 8 weeks beforebeing re-studied as in Study 1.Significance Identifying pathways underlying quadriceps abnormalities in COPD will facilitate development of treatments. RMS, if effective, could have clinical applications. This work may benefit patients with heart failure who have a similar quadriceps phenotype to those with COPD.

Amount: £191,722
Funder: The Wellcome Trust
Recipient: Imperial College London

Functional genomic analysis of Anopheles gambiae innate immunity and interaction with the malaria parasite. 26 Apr 2006

Anopheline mosquitoes are obligatory vectors of human and other mammalian malaria parasites of the genus Plasmodoum. This research programme will capitalize on the newly available genome sequence of Anopheles gambiae, the major human malaria vector in Africa, and on postgenomic tools (many developed in our laboratory) to understand the mosquito innate immune system and its interactions with the rodent and human parasites (P. berghei and P. falciparum). Our recent work has established that innate immunity is a major determinant of the mosquito's vectorial capacity: Anopheles immune reactions account for substantial parasite losses during invasion of the mosquito midgut, but often allow immune escape and parasite transmission. We aim to elucidate key immune reactions, including parasite lysis and melanisation, at the molecular and cellular level. We wish to reveal the molecular module underlying each major immune reaction, to dissect its effector or regulatory functional networks and their molecular components (genes/proteins), and ultimately to understand the operation of each module as a whole. This work will contribute significantly to the emerging comparative understanding of innate immune mechanisms and may open future possibilities for controlling malaria transmission in the vector.

Amount: £93,750
Funder: The Wellcome Trust
Recipient: Imperial College London