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Results

Identifying novel sensory molecules and mechanisms in nematodes and mammals. 01 Apr 2014

Despite many years of study, the molecular mechanisms underlying several humansenses, in particular hearing, touch, and sour and salt taste, remain poorly understood. Each of these processes relies on ionotropic receptors that are directly gated by the sensory stimulus; however, the mechanisms underlying this gating, and in many cases even the identities of the the relevant receptor molecules, remain unknown. Recently, work from our lab and others has implicated members of the TMC family of putative ion channels as sensory receptors for taste and hearing[1,2]. In the planned research, we will characterize the in vivo roles and functional properties of worm and mammalianTMCs and determine how they respond to sensory stimuli. Since mammalian sensory receptors often retain functionality when heterologously expressed across phyla[2,3], we will use the genetic tractability of C. elegans to dissect functional domains of mouse and worm TMCs in an in vivo context. In addition, since known families of ionotropic sensory receptors are largely conserved in the worm[4], we expect that novel receptors with conserved roles in mammals can identified by worm genetics. We will therefore screen for novel ionotropic sensory receptors by highthroughput phenotyping of C. elegans mutants. Specific aims include: 1. Characterize the functional properties of mammalian and worm TMC proteins by heterologous expression in C. elegans neurons. 2. Investigate the relationship between TMC protein structure and function through analysis of chimeras and mutant proteins. 3. Using the information from heterologous expression studies, study the in vivo functions of mouse TMCs in knockout animals. 4. Identify novel sensory receptors by high-throughput phenotyping of C. elegans knockout strains.

Amount: £1,449,590
Funder: The Wellcome Trust
Recipient: Medical Research Council

Understanding cellular organisation: from archaea to eukaryotes 05 Jul 2016

We know surprisingly little about the basic logic, topology or origins of eukaryotic cell architecture even though such an understanding is fundamental to most biomedical research. Until recently, the proteins responsible for shaping eukaryotic cells (including Actin/Tubulin/coatamers/ESCRTIII) were thought to be unique to eukaryotes. This changed with the discovery of close homologues in TACK/Loki-family archaea. Despite the important part played by these proteins during eukaryogenesis, we know little about their functions in the context of archaea. To determine how these cytoskeletal systems with origins in archaea contributed to the emergence of internal compartments that define eukaryotes, our team will use metagenomic sampling and phylogenomics to trace their evolutionary history, and a combination of approaches, including live super-resolution microscopy and electron tomography to carry out a comparative analysis of their ultrastructure, dynamics and function in both archaea and eukaryotes. Ultimately, we expect this evolutionary cell biological analysis to make a start towards an understanding of archaeal cell biology, to reveal the likely path of eukaryogenesis, and to reveal underlying principles of eukaryotic cell biology that so far have eluded us. In doing so, we expect this fundamental research to have a signficant impact in the future on human health and disease.

Amount: £285,278
Funder: The Wellcome Trust
Recipient: Medical Research Council
Amount: £4,346,588
Funder: The Wellcome Trust
Recipient: Medical Research Council

Reduction of Early mortaLITY in HIV-infected African adults and children starting antiretroviral therapy: REALITY trial. 16 May 2011

The principalresearch question is how best to reduce excess early mortality in African HIV-infected adults andchildren initiating ART. Reasons for high early mortality are multi-factorial, including high rates ofco-infections (TB, bacterial infections, fungal/protozoal infections, parasites), immunereconstitution inflammatory syndrome (IRIS), malnutrition and advanced HIV infection. Severalinterventions might therefore reduce early mortality in HIV-infected patients startingART with low CD4, and could form part of a highly effective integrated care "bundle".

Amount: £793,577
Funder: The Wellcome Trust
Recipient: Medical Research Council

Biomedical Vacation Scholarship 14 Jun 2010

Not available

Amount: £1,520
Funder: The Wellcome Trust
Recipient: Medical Research Council

Genetic investigation of life course phenotypes of mental health and illness in the 1946 British birth cohort. 02 Jul 2009

Using repeated measures collected between ages 13 and 53 years in the British 1946 birth cohort we will test associations between hypothesis-driven candidate genes and novel, empirically derived life-course phenotypes of depression and anxiety, cognition and personality. Our new phenotypes are longitudinal latent classes and latent quantitative traits derived from innovative psychometric approaches that we have piloted (Colman et al, 2007). Goal 1 confirms and 2 extends the phenotypes from m ental health to personality (neuroticism) and cognition ( g ). Goal 3 involves conducting single and multi-marker genetic association studies exploring the impact of sets of genes related to brain development, neurotransmission, cognitive ageing, and endocrine function on these summary measures of life-course risk for health and psychiatric symptoms, personality and cognition. Our overarching hypothesis is that these higher-fidelity, longitudinal measures will represent more valid targets for genetic research than conventional cross-sectional, binary diagnoses. Goal 4 considers the impact of three specified effect modifiers (G x E interaction). These include an early environmental adverse event (childhood separation), pubertal stage (in early teenage years) and a protective factor, educational/occupational attainment. This research will serve as a platform for thematically and methodologically linked collaborative work in other British cohorts, and other relevant samples.

Amount: £79,356
Funder: The Wellcome Trust
Recipient: Medical Research Council

Support for refining animal usage, evolution of the Centre's website, dissemination of advances in the field and twelve new projects. 29 Aug 2008

"Physiologically based pharmacokinetic (PBPK) modelling has been proposed as having great potential for the reduction and replacement of animals in experimentation. PBPK modelling is a powerful means of simulating the factors that determine tissue dose within an organism. The ability to correlate tissue dose with a response e.g., a health effect, has led to the increased use of PBPK models in chemical risk assessment (RA). They are ideal tools for integrating disparate in vitro and in vivo mechanistic, pharmacokinetic, toxicological and chemical specific information. Consequently, the greater demands of PBPK models for more varied input parameters have led to them being described as 'data hungry' and 'resource intensive'. In order to address the latter and facilitate the more widespread use of PBPK modelling in chemical risk assessment, the Health and Safety Laboratory has developed and merged a model equation generator (MEGEN) and PBPK parameter database, which permit the construction of models in minutes rather than days. The user is engaged in a dialogue relating to the details of the physiology of the system to be modelled, and the biochemistry and physicochemistry of the compound of interest. Model parameters are retrieved from an electronic database, which is interrogated during use of MEGEN. On the basis of this information, a model is produced in the form of an XML document, which provides a format for generic storage of models. The XML model can be exported and transformed to a preferred commercial visualisation script. The ability to integrate in vitro data into PBPK models enhances the value, and facilitates the interpretation of many in vitro techniques proposed as alternatives to the use of animals in toxicological research. It is envisaged that MEGEN will play a major role in shifting the emphasis from the perceived requirement for considerable expertise in mathematics and computer programming to biology. This shift should encourage an increased take-up and use of PBPK modelling in chemical RA and facilitate the inclusion of validated in vitro alternatives in the risk assessment process. Therefore, the greater availability of such a PBPK modelling capability could potentially also lead to a marked reduction in the use of animals."

Amount: £671,000
Funder: The Wellcome Trust
Recipient: Medical Research Council

Pitch perception by cochlear implant users 12 Oct 2006

Cochlear implants (CIs) allow previously-deaf patients to understand speech in quiet, but are very poor at encoding pitch. This results in poor speech understanding in noise, and in reduced enjoyment of music. A major limitation is that most CI users cannot derive pitch from changes in electric pulse rate above about 300 pps, whereas normal-hearing (NH) listeners exploit temporal cues up to much higher rates. We will use both psychophysical techniques and a measure of auditory-nerve activity, the electrically evoked compound action potential (ECAP), to investigate this upper-rate limitation. We (i) Examine whether the alternating-amplitude pattern, previously observed in the ECAP to high-rate pulse trains, is responsible for the limitation. We will study manipulations that should reduce the alternation and compare the effect on the ECAP with that on pitch tasks, (ii) Study instances where pitch varies non-monotonically with rate, again using a combination of behavioural and ECAP measures, (iii) investigate whether the high-rate limitation can be overcome by concurrent stimulation of multiple electrodes. Finally, we investigate the match between the place and rate of stimulation that, it has been suggested, is important for good pitch perception.

Amount: £146,417
Funder: The Wellcome Trust
Recipient: Medical Research Council

Life course and trans-generational influences on cardiovascular disease and cancer 05 Dec 2006

CVD and cancer are major causes of death and morbidity in developed countries; they are assuming increasing importance in non-industrialised societies. Risk factors measured in middle- and older-age do not fully explain socioeconomic or geographical differentials in these chronic diseases, so implicating processes occurring earlier in life, and even between generations, in the aetiology of CVD and cancer. A small number of recent studies have identified some potential pre-adult risk indices for later CVD and cancer. I plan to expand this evidence base by examining the role of new and emerging physiological, behavioural, socioeconomic and psychological risk factors (and their cross-generation transmission) in later disease risk. To do so I will utilise data from a series of studies from low and high income countries. During the tenure of the fellowship, in collaboration with colleagues, I will produce manuscripts for publications in high-impact, peer-reviewed journals; present my work at international meetings; supervise/teach post-graduate students; and seek funding for further data collection in selected studies. This body of work may be used in interventions in childhood and young adults aimed at reducing the burden of CVD and cancer in later life.

Amount: £574,957
Funder: The Wellcome Trust
Recipient: Medical Research Council

How do pattern defects cause apoptosis in developing tissues?. 30 May 2007

Tissue homeostasis depends on the appropriate integration of cell proliferation, cell differentiation and apoptosis. The apoptosis program is activated to remove superfluous, mis-specified, or genetically damaged cells. I plan to investigate the mechanisms that activate apoptosis in cells that are mis-specified during development. To address this question, I will first determine the spatial pattern of cell death in Drosophila embryos in response to the lack or excess of Wingless signalling. I wi ll also look at the behaviour of these cells under conditions that prevent them from undergoing apoptosis. In parallel, I will use existing databases and microarray analysis to search for genes that could mediate the response to mis-specification. One possibility is that cell surface molecules will be involved, allowing cells to display and compare their state of specification within a field. I expect such genes as well as genes encoding components of the signal transduction machinery to come ou t of my search At the end of my fellowship I will initiate the functional analysis of these genes.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: Medical Research Council

Structural and functional analysis of interactions involving the nuclear transport machinery that generate nuclear RNA and protein export and orchestrate mitotic spindle assembly. 01 Nov 2006

My overall goal is to understand how nuclear transport factors interact with their cargoes and other components of the transport machinery to (i) export macromolecules from the nucleus during interphase and (ii) orchestrate spindleassembly during mitosis. These aims share a common focus on nuclear transportfactors and their interaction with different partners, and build on my previous work that established the structural basis for key steps in the nuclear protein import cycle. Molecular recognition by transport factors is fundamental to the nuclear export of proteins, mRNA, pre-microRNA, and tRNA, and is also crucial in mitotic spindle organization. My primary goal is to usethe interdisciplinary approach I developed for studying nuclear protein import, in which structural, biochemical, molecular and cellular methods will be used in concert to investigate the key complexes involved in each process and establish interaction interfaces. This information will then be used to define how each function is generated by a precisely orchestrated series of interactions, employing structure-based engineered mutants that alter specificinteractions. These mutants will be used to establish the spatial and temporalpattern of interactions that generate function and so enable these important cellular processes to be understood at the molecular level.

Amount: £535,853
Funder: The Wellcome Trust
Recipient: Medical Research Council

Evaluation of the efficacy of hydroxychloroquine in decreasing immune activation and viral replication in asymptomatic HIV-infected patients . 15 May 2007

The proposal is to conduct a randomised, double-blind, placebo-controlled clinical trial of hydroxychloroquine for the treatment of early stage HIV infection. A total of 90 asymptomatic, antiretroviral na ve HIV-infected patients with CD4 T-cell counts greater than 400/ L and with no major contraindications to treatment will be recruited from major HIV treatment centres in or around London. Patients will be randomised to receive hydroxychloroquine 400mg/day or matching placebo to be taken once d aily by mouth for 48 weeks, and will be followed at regular (1 to 3 monthly) intervals for assessment of efficacy and safety. Efficacy parameters include measurement of T-cell activation, proliferation and apoptosis, viral load and absolute CD4 T-cell counts. Safety assessments include standard clinical and laboratory toxicity monitoring as well as rigorous observation for evidence of retinopathy. The primary endpoint is the change in CD8 T-cell activation at week 48 compared to baseline, and th e main secondary endpoints are change in viral load and CD4 T-cell count at week 48 compared to baseline (analysis will compare change in hydroxychloroquine and placebo groups). The study has 90% power to detect a 25% reduction in CD8 T-cell activation and a 0.4log reduction in viral load in the hydroxychloroquine group.

Amount: £246,685
Funder: The Wellcome Trust
Recipient: Medical Research Council

Connecting defective replication initiation to inherited human diseases: Biochemical and genetic analysis of the RecQL4 helicase. 01 Nov 2006

We have found that the RecQL4 protein, mutated in human diseases characterizedby chromosome fragility, developmental malformations and premature aging, plays an unexpected role in the initiation of DNA replication (Sangrithi et al. (2005) Cell 121, 887). RecQL4 contains an N-terminal domain homologous to yeast Sld2, and a RecQ-domain, but lacks other features conserved in RecQ helicases. Our first key goal is to determine how RecQL4 promotes assembly of the replication machinery at origins. We find that the Sld2-like domain is phosphorylated by cyclin/CDK activity, and interacts with Cut5/TopBP1, and will investigate the functional effects of phosphorylation on RecQL4 activity and function. In an ongoing collaboration with Shamoo's lab in Houston, a structural analysis of RecQL4 domains is underway, with encouraging preliminary progress. We will perform structure-based analyses of RecQL4 function using this platform. Our second key goal is to develop a vertebrate genetic system to study the functional effects of disease-associated RecQL4 mutations on replication-associated processes like chromatid cohesion that maintain chromosomal integrity. The system will also facilitate genetic analysis of thebiological pathways dependent on RecQL4 activity. Our work should provide insight into the fundamental mechanisms controlling replication initiation, and into how their dysregulation triggers human genetic diseases.

Amount: £164,396
Funder: The Wellcome Trust
Recipient: Medical Research Council

Graded hedgehog signalling in the neural tube: mathematical modelling of a developmental multistate switch. 01 Nov 2006

Morphogens are graded positional cues that control cell fate specification in many developing tissues. The activity of Sonic Hedgehog (Shh) in the spinal cord represents an example where progress has been made in understanding morphogen activity. In response to graded Shh signaling, distinct neuronal subtypes emerge in a precise spatial order from progenitor cells arrayed along the dorsoventral axis of the spinal cord. Cross-repressive interactions between responding genes appear to ensure the g eneration of discrete changes in gene expression. Thus, graded Shh signalling controls a multiway differentiation switch composed of concentration-dependent gene-regulation and a network of interactions between responding genes. Here we propose to analyse this process using a combination of mathematical and developmental biology. The mechanisms by which a gradient of Shh signalling is formed, refined and interpreted are not well understood. We will construct a mathematical model which describes the formation and interpretation of the Shh gradient. In vitro and in vivo experiments in embryos will be used as the foundation of the model and to test key predictions. The resulting model will be used to analyse how graded Shh effects a multiway switch and to identify critical features of the mechanism that confer precise and reliable patterning.

Amount: £173,324
Funder: The Wellcome Trust
Recipient: Medical Research Council

Methods for Stabilisation and Crystallisation of Unstable Eukaryotic Membrane Proteins. 28 Apr 2009

Determination of membrane protein structure requires crystallisation of purified protein. The main problem in obtaining crystals of many important eukaryotic or human membrane proteins such as G-protein-coupled receptors (GPCRs) or ion channels is their poor stability after detergent solubilisation, which is essential for purification and crystallisation. Recent work by the Tate group at LMB, following earlier work by Bowie, showed it is possible to increase greatly the stability of membrane pro teins by limited mutagenesis while retaining key functions, termed conformational thermostabilisation. We propose to develop further the technology involved by tackling three particularly challenging eukaryotic membrane protein structures, each posing new problems that require extensions of the existing very promising results. The structures are (a) the agonist-bound beta1-adrenergic receptor, an unstable conformation that binds ligands weakly (b) the antagonist state of human muscarinic M1 acet ylcholine receptor in which the third cytoplasmic loop is very large, and (c) the human voltage-dependent sodium channel, NaV1.7, which is a very large molecule with multiple functional conformations. Development of more rapid assays for binding of weaker ligands to lower levels of expressed protein will allow the method of conformational stabilisation to be extended so that it can be used on many more membrane proteins..

Amount: £391,707
Funder: The Wellcome Trust
Recipient: Medical Research Council

Workshop on new antiretroviral therapy (ART) trials in Africa to be held in Entebbe, Uganda on 29-30 March 2007. 30 Jan 2007

Workshop on new anti-retroviral therapy (ART) trials in Africa Prioritising the main questions about ART treatment strategies now facing Africa needs to be undertaken by professionals at sites treating adults, children and families with HIV infection on the ground in Africa, in particular centres who have already been involved in addressing research questions around current first-line ART. Partnerships between such groups and those from the North in order to build on expertise learnt from managing patients, as well as expertise in the design and execution of large multicentre clinical trials is needed to identify knowledge gaps and opportunities and to drive the agenda forward. A number of questions need answers from large randomised controlled trials. These can be broadly divided into: The timing of ART decisions When to start When to switch from first-line to second-line ART Strategies to maximise long-term efficacy and minimise toxicity. Approaches for both first and second-line ART include cycling drugs and drugs regimens, induction-maintenance approaches, simplification of treatment to improve adherence, and intermittent therapy. Monitoring patients prior to and on ART - with which tests and how frequently Management of patients failing second-line therapy Use of adjunctive therapies with ART - such as immunomodulants, nutritional supplements and drugs for prevention of opportunistic infections.

Amount: £15,000
Funder: The Wellcome Trust
Recipient: Medical Research Council

An examination of the origin and mechanism of formation of the parasitophorous vacuole membrane in erthrocytic stages of the malaria parasite Plasmodium falciparum. 09 Dec 2013

What is the originof the parasitophorous vacuole membrane(PVM) that is producedwhen the malaria parasite, Plasmodium falciparum, invades its host erythrocyte, andwhatare the contributions of host and parasite components, particularly those of the malarialrhoptry organellesininvagination of the erythrocyte membrane and subsequent establishment of thePVM?Thisis a long standing unresolved, question that has not received much attention recentlybut that is a fundamental aspectof Plasmodium biology. Newly developed genetic and imaging technologieswillbe applied that will allow new insight into this question.

Amount: £80,000
Funder: The Wellcome Trust
Recipient: Medical Research Council

Investigation of the PTB-dependent RNA operon that regulates cytoskeletal organisation and cell migration. 14 Jun 2010

Messenger RNAs are subject to post-transcriptional control by a number distinct of mechanisms. Expression of the corresponding proteins can be regulated by changes in the rate of the mRNA degradation, and by transport of the mRNA to a specific cellular location. Cytoplasmic post-transcriptional control is tightly regulated by defined groups of mRNA binding proteins and it has been suggested that specific RNA-operons , comprised of RNA motifs and their cognate RNA binding proteins, ensure co-r egulated synthesis of proteins with common functions. To define the PTB-operon we have carried out polysome profiling following a reduction in PTB expression in conjunction with RNA co-immuno-precipitation using a PTB specific antibody to identify the mRNAs that bind to PTB and/or are dependent upon this protein for efficient translation. Approximately 25% of the mRNAs identified by these screens have a role in cytoskeletal organisation/cell migration. Our data suggest that PTB controls both the translation and the localisation of these mRNAs. The overall aims of this project are to identify the RNA elements and the proteins (in addition to PTB) that comprise the PTB operon and are involved in the post-transcriptional regulation of mRNAs that have a role in cytoskeletal organisation and cell migration.

Amount: £338,371
Funder: The Wellcome Trust
Recipient: Medical Research Council