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Recipients:
University of Cambridge
Award Year:
2011

Results

Enhancement: Interactions between the circadian clock and virus infection 06 Oct 2011

Daily (circadian) rhythms form a fundamental part of our existence, necessarily so because of our 24h solar environment. We know that the clock consists of an autoregulatory negative feedback loop involving various core clock genes. I seek to understand how the molecular clock affects neural processes to coordinate our rhythmic physiology and behaviour. Until now, addressing this question was not possible. With the recent advent of high-throughput tools to interrogate transcriptional contr ol, global gene expression and the proteome, it is now possible to tackle this problem in a molecular context. Expression of circadian genes starts with binding of transcription factors to DNA, then transcription of those genes into mRNA, and finally translation of this mRNA to protein. Each stage of this process will be interrogated, but in reverse order, starting with DiGE/iTRAQ to assay the proteome, expression microarrays (e.g. Affymetrix/Illumina) to look at transcript levels, and finall y ChIP-chip to address transcription factor binding to promoter regions of circadian genes. The interrelationships between DNA-mRNA-protein dynamics will be modelled using systems biology tools and bioinformatics to identify novel control points. A subset of the novel proteins will be functionally characterised to define novel circadian elements and/or targets for future therapeutic benefit.

Amount: £197,142
Funder: The Wellcome Trust
Recipient: University of Cambridge

Establishing a healthy growth trajectory from birth: The baby milk trial. 07 Nov 2011

The prevalence of childhood obesity has increased rapidly over the past two decades. Excess weight in childhood tracks into adult life and causes problems both in the short term and in the long term. National surveys show that more than one in five children are already overweight (13%) or obese (10%) when they start school. Hence any efforts to prevent obesity must start early. The Foresight Report and the Healthy Weight Healthy Lives strategy have highlighted the importance of preventing childhood obesity by focussing on the early years. However, to date there is little evidence on which to develop effective preventive strategies. Infancy is a period of rapid growth and weight gain and obesity prevention during this period may be effective. Nutrition and growth during infancy may also have long term effects by altering eating behaviours and risks of obesity and obesity-related disorders in later life. UK Infant Feeding Surveys show that at birth one in three (35%) of babies receive formula-milk and this number increases to almost all babies (92%) at 6 months of age. Hence, in addition to promoting breastfeeding, it important to optimise the growth of formula-milk fed babies. Our previous research shows that parents who give their babies formula-milk as part of their everyday diet need more information and support. Researchers at the Centre for Diet and Activity Research (CEDAR) and MRC Epidemiology Unit in Cambridge have been working with mothers and healthcare professionals to develop a feeding programme which aims to avoid excess weight gain in formula-milk fed babies. The programme we have developed aims to support parents who feed their babies formula-milk to achieve a healthy pattern of growth and weight gain. The infant feeding programme will be tested in a randomised controlled trial involving 700 mothers and their babies. Half the mothers will be given advice and support to follow the new feeding programme. The other half will be given routine advice about formula-milk feeding and weaning. The growth of babies in the two groups will be compared. This comparison is important to test whether our new feeding programme is effective in preventing excess weight gain and subsequent obesity. The results of the study will help to inform infant feeding guidelines and will also help us understand the links between infant feeding, behaviour, appetite and growth.

Amount: £145,606
Funder: The Wellcome Trust
Recipient: University of Cambridge

High speed super-resolution imaging with the OMX microscope. 09 Mar 2011

The imaging of fluorescent proteins in living cells has proved a powerful approach in cell biology, but many processes cannot be visualised because of the limited sensitivity and resolution of current microscopes. We seek funding for an OMX imaging system that overcomes these limitations. The OMX has a simplified light path that makes it much more sensitive than standard microscopes, and is configured to image three wavelengths simultaneously. These increase the speed of time-lapse imaging by an order of magnitude, allowing the detection of faint, fast-moving fluorescent objects that are otherwise invisible. The greater sensitivity also allows the use of lower levels of illumination, which reduces photo-toxicity and photo-bleaching for long-term time-lapse imaging of light-sensitive samples. Another major innovation is the use of structured illumination to break the diffraction limit, doubling resolution to 110nM. The OMX can perform super-resolution imaging deep inside cells at several frames/second (unlike other super-resolution microscopes), and can therefore reveal dynamic features of subcellular structure at a new scale. This microscope will be a shared resource for all cell biologists in Cambridge, and will be used to investigate topics such as mRNA trafficking, neuronal polarity, the spindle checkpoint and DNA damage foci.

Amount: £784,137
Funder: The Wellcome Trust
Recipient: University of Cambridge

Normative neurophysiology. 10 May 2011

Not available

Amount: £989,211
Funder: The Wellcome Trust
Recipient: University of Cambridge

Master's studentship 12 Jul 2011

Not available

Amount: £21,566
Funder: The Wellcome Trust
Recipient: University of Cambridge

Naked Neuroscience: a spine-tingling interactive, educational multimedia initiative 05 May 2011

Working alongside research-active neuroscientists and educators, we envisage the creation of a multimedia, neuroscience-focused, audience-interactive touring stage show aimed at schools and the general public and comprising a series of linked experiments and demonstrations designed to illustrate the workings of the nervous system. This initiative, which will be curriculum-relevant and targeted at ages 12 and up, will be supported by a suite of freely-accessible online multimedia content including illustrated webpages, worksheets and interactive experiments for users to try at home, as well as video sequences and a monthly 60 minute neuroscience podcast. The podcast will be conversational, news-led and feature updates on recent discoveries in the neuroscience arena as well as interviews with leading researchers internationally. Moreover, it will be produced and presented by researchers themselves, providing valuable training in traditional and new media broadcast techniques. To maximise the overall reach of the project, the resulting content will also form part of the weekly output of the Naked Scientists BBC radio show, podcast and website. These are existing awardwinning public engagement initiatives that reach a large (multi-million scale) and diverse listenership from a range of ages and backgrounds, including audiences judged to be hard to reach. Together, these initiatives will enable us to take neuroscience-focused content to millions of people, including, most critically, young people whose interest in science we are seeking to nurture. At the same time, the direct involvement of scientists of all levels, including PhD students and undergraduates, means that we have an opportunity to help these researchers to develop their own skills in public engagement while simultaneously ensuring that the resulting project content remains scientifically robust and relevant.

Amount: £120,576
Funder: The Wellcome Trust
Recipient: University of Cambridge

Interdisciplinary Training Programme for Clinicians in Translational Medicine and Therapeutics at the University of Cambridge: Support for the 2011 MPhil Appointments. 20 Sep 2011

We propose an innovative training scheme for Translational Medicine and Therapeutics (TMAT) which builds on the exceptional conjunction on the Cambridge campus of leading scientists and clinical specialists, with an industrial research environment embraced both by international pharmaceutical and local biotech companies. Much of this is found under the same roof, the Addenbrookes Centre for Clinical Investigation (ACCI), with a track record of integrated training: academic with industrial, clinical with scientific, pharmacology & therapeutics with patient-based specialties. The novel TMAT programme will attract the brightest candidates at several levels of seniority, ranging from MB PhD students to clinical lecturers, some wishing translational skills in their chosen specialty, others not yet differentiated who may become future leaders and teachers of TMAT. Each trainee will have a customised programme. Part of this will be a bespoke, modular MSc modelled on the well-known small-group lectures and supervisions of the Cambridge final year undergraduate courses. However the centrepiece for most candidates will be a PhD including formal teaching in a wide range of translational and pharmacological skills, and a project which takes proof-of-concept studies in cell or animal systems forward to proof-of-concept studies in humans. We have assembled an outstanding faculty of PhD supervisors spanning a wide choice of skills and experience in basic and clinical science. All trainees will have the opportunity for hands-on exposure to the design and conduct of experimental medicine studies investigating the therapeutic potential of new drugs, in collaboration with our industrial partner, GlaxoSmithKline (GSK). Our product will be a new generation of clinician scientists with 360-degree vision of the complex landscape of modern therapeutic medicine, who can rise to the challenges and opportunities of 21st century drug development.

Amount: £19,563
Funder: The Wellcome Trust
Recipient: University of Cambridge

Translational Medicine and Therapeutics Programme at the University of Cambridge: 'The apelin-ACE-2 axis in cardiopulmonary disease'. 31 Aug 2011

The objective of the project is to test the hypothesis that apelin signalling is altered in PAH and that apelin may be a new mediator and potential new drug target for this condition. Basic and translational research into the pharmacological actions of apelin has been hampered by a lack of selective agonists and antagonists. Two novel molecules have recently been discovered by the group: MM07 an agonist and MM54, a competitive antagonist at the apelin receptor (APJ). This project will focus on identifying the cellular expression of apelin and APJ and measuring APJ densities and pharmacological characteristics in lung and right ventricle from patients with PAH to determine changes in the apelin/APJ system in this disease. Parallel studies will be carried out in heart and lung of the monocrotaline-treated rat to discover if this model reflects the changes in the apelin system in human tissues. I will determine the effects of MM07 and MM54 on progression of PAH in this animal model to identify whether pathway stimulation or blockade improve outcome. In collaboration with Dr I Wilkinson, I plan to perform forearm plethysmography in healthy subjects. If successful, it would be possible, subject to ethics approval, to perform limited studies in PAH patients.

Amount: £268,427
Funder: The Wellcome Trust
Recipient: University of Cambridge

6 month extension - Wellcome Trust Centre for Stem Cell Research 12 Jul 2011

The new Institute for Stem Cell Biology in Cambridge will be an international centre of excellence in fundamental stem cell research. The Institute will focus on definition of the genetic and biochemical mechanisms that control stem cell fate, providing foundations for applications in disease modelling, drug discovery and regenerative medicine. This proposal is for provision of core resources for embryonic stem cell manipulation and transgenesis. A central resource of skilled personnel will maximise research productivity and continuity, promote cooperation and synergy, and accelerate technological innovation. Timely and efficient production of customised gene-modified stem cells and mice is essential underpinning. Specialised expertise will support advanced genetic engineering of mouse and human stem cells, and operation of robotic platforms to develop screening methodologies for isolating genetic, protein and chemical regulators. A dedicated PdD programme in stem cell biology will capitalise on the opportunity for high level research training provided by the intellectual environment and core facilities in the Institute. A Strategic Award will immediately establish the Institute for Stem Cell Biology amongst the best-resourced and most attractive environments for stem cell research world-wide, providing a magnet for recruitment, and a much-needed focus for UK and European stem cell biology.

Amount: £505,062
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cambridge Stem Cell Institute Four year PhD studentship supplements 17 Jan 2011

The new Institute for Stem Cell Biology in Cambridge will be an international centre of excellence in fundamental stem cell research. The Institute will focus on definition of the genetic and biochemical mechanisms that control stem cell fate, providing foundations for applications in disease modelling, drug discovery and regenerative medicine. This proposal is for provision of core resources for embryonic stem cell manipulation and transgenesis. A central resource of skilled personnel will maximise research productivity and continuity, promote cooperation and synergy, and accelerate technological innovation. Timely and efficient production of customised gene-modified stem cells and mice is essential underpinning. Specialised expertise will support advanced genetic engineering of mouse and human stem cells, and operation of robotic platforms to develop screening methodologies for isolating genetic, protein and chemical regulators. A dedicated PdD programme in stem cell biology will capitalise on the opportunity for high level research training provided by the intellectual environment and core facilities in the Institute. A Strategic Award will immediately establish the Institute for Stem Cell Biology amongst the best-resourced and most attractive environments for stem cell research world-wide, providing a magnet for recruitment, and a much-needed focus for UK and European stem cell biology.

Amount: £53,456
Funder: The Wellcome Trust
Recipient: University of Cambridge

Characterisation of 18NaF as a novel marker for vascular calcification, and development of new treatment strategies for soft tissue minralization 12 Jul 2011

Arterial calcification is a process that involves calcium deposition in vessel walls. Mineralization is often found in human atherosclerosis, and a recent report suggests that coronary artery calcium scoring serves as a superior predictor of cardiovascular events. 18F-NaF has been proposed as a reliable marker of vascular calcification. However, it is currently unclear which molecular mechanism are detected using this molecule, which biological processes are involved, and how this informs on plaque rupture risk. To address these issues, we have proposed three aims: Aim 1 is to evaluate the ability of 18F-NaF to quantify calcification in human ex vivo plaque; Aim 2 is to study animal models that can recapitulate the process of calcification using PET imaging for the assessment of calcification and Aim 3 isto examine whether animal models provide a mechanism to test the ability of drugs to alter the calcification process. Together the fulfilment of these aims will allow us to assess 18F-NaF as a novel marker for vascular calicifcation and cardiovascular risk, and test pharmacological treatments with this model. These findings could have important implications to decrease mortality worldwide.

Amount: £155,834
Funder: The Wellcome Trust
Recipient: University of Cambridge

Developmental programmingof insulin resistance and obesity in offspring of diet induced obese mothers. 21 Feb 2011

To investigate the mechanisms involved in the developmental programming of obesity and insulin resistance in peripheral and central tissues of offspring of obese mothers using a mouse model of maternal diet-induced obesity.

Amount: £52,518
Funder: The Wellcome Trust
Recipient: University of Cambridge

The reprogramming of sperm compared to somatic celi nuclei. 17 Jan 2011

The sperm cell has a highly specialised developmental programme and gene expression profile. However, in order to allow embryo-specific gene expression, the paternal genome has to undergo reprogramming. Reprogramming is also crucial for a proper embryonic development during another process -somatic cell nuclear transfer (SCNT). Normally, a cell once differentiated, cannot de-differentiate. However, it has been shown that it is possible to de-differentiate a cell experimentally. When somatic cell nuclei of Xenopus laevis were transferred into enucleated eggs, healthy embryos were generated. However, in contrast to fertilization, SCNT seems to be significantly less efficient in embryo generation [1]. But can mechanisms of reprogramming after fertilisation be directly compared with those that follow SCNT? Probably not, as both processes occur differently. In order to investigate the comparative efficiency of fertilisation events and SCNT in offspring generation, I would treat the sperm in the same way as the somatic cell is treated in the SCNT procedure and examine the developmental capacity of such embryos. If the results prove that the sperm is indeed more efficient than a somatic cell nucleus in producing normal embryos, I would investigate what is so special about the sperm making it so efficient. This would lead to an identification of sperm-specific factors responsible for the efficiency of the reprogramming after fertilization. Ultimately, further characterisation of these factors and mechanisms of their action should shed light on similarities/differences between reprogramming after fertilization and SCNT. It would be a major contribution to understand what controls the ability, especially of nuclei from differentiated cells, to lead to normal embryo development.

Amount: £29,661
Funder: The Wellcome Trust
Recipient: University of Cambridge

Allergen like molecules in Schistosoma haematobium: roles in human immunity and acute disease. 31 Aug 2011

This project will be the first systematic study of 1111tigenic proteins from Schistosoma haematobium, a major helminth pathogen of man. lgE-mediated immune mechanisms are central to immunity to parasitic worm infections and allergy. Recombinant forms of S. haematobium Tegumental Allergen-Like (ShTAL) proteins will be used to characterise patterns of anti-ShTAL lgE responses and IgE-mediated effector functions in human cohorts living in S. haematobium endemic areas of Mali, and in travellers returned to UK with recently acquired infections. These data will be analysed in relation to human susceptibilitY and immunity to infection, the regulation of human IgE and lgE-mediated effector mechanisms, and acute and chronic schistosomiasis morbidity. Specific aims: To identify tegumental allergen-like (TAL) proteins in S. haematobium using adult worm and egg EST databases. To create expression profiles of S. haematobium TALs (ShTALs). To express and purify recombinant ShTAL proteins. To establish patterns of antibody isotype responses to these ShT ALs in human sera collections from studies in aS. haematobium high transmission area of Mali. To test the ability of individual ShTALs to trigger human lgE-dependent immune effector mechanisms. To analyse anti-ShTAL antibody isotype responses in relation to age, sex, intensity of infection and the effects of chemotherapy. To analyse antibody isotype responses to the ShTALs (and circulating cytokine levels) in relation to human immunity, reinfection and urogenital morbidity. To analyse anti-ShTAL IgE and IgG subclass antibody responses and passive and active histamine release, in travellers returned to UK with S. haematobium infection.

Amount: £5,150
Funder: The Wellcome Trust
Recipient: University of Cambridge

Wolbachia as a defence against RNA viruses in insects. 07 Mar 2011

The bacterial endosymbiont Wolbachia protects insects against viral infections. The aim of this project is to understand this new form of antiviral protection, using Drosophila as a model system. Our results will be relevant for attempts to use Wolbachia to control viral diseases of humans and animals that are transmitted by insect vectors. To understand the causes of this antiviral resistance, we will first determine which stage of the viral replication cycle Wolbachia affects (entry into ce lls, replication, translation or exit). In Drosophila, we will screen for host genes and pathways that are required for the antiviral effects of Wolbachia and examine whether the antiviral protection relies upon the insect immune system or other host pathways. From the bacterium s perspective, we will identify Wolbachia genes up-regulated upon host viral infection and test these for their antiviral effects. Additionally, we will use next-generation sequencing to identify genes associated with n aturally occurring variation in the antiviral properties of Wolbachia. Finally, to see if interventions using Wolbachia will be sustainable, we will test whether viruses can evolve to overcome the antiviral effects of Wolbachia and identify the mutations that underlie these changes.

Amount: £548,004
Funder: The Wellcome Trust
Recipient: University of Cambridge

Does the potential for proteins to be allergenic depend on structural homologies with IgE targets on metazoan parasites? 07 Mar 2011

IgE is found only in mammals, and is presumed to have evolved to combat metazoan endo- and ecto-parasites (helminths and arthropods). Recently, a closer molecular relationship between major allergens and metazoan products has become apparent. We have tabulated the known allergens and found that 8 of the 10 most abundant allergen protein superfamilies are represented in metazoan parasite genomes, although in only 3 cases have metazoan proteins been experimentally verified as IgE targets. We prop ose to study 5 metazoan gene families containing homologues of known allergens, to establish if these are indeed targets of IgE in natural and experimental infections. To fully validate the hypothesis that all allergens contain structural homology to metazoan antigens, we will also analyze the 2 gene families for which homologues with recognizable sequence homology have yet to be found in metazoan parasites. These will be subject to surface structural feature analysis, which will enable us to se arch metazoan genome databases for structural homologues which will then be tested for IgE reactivity. The technique will then be extended to provide a searchable database of the metazoan parasite surface features which can be searched to predict allergenic epitopes in food and environmental organisms.

Amount: £180,679
Funder: The Wellcome Trust
Recipient: University of Cambridge

The structural dynamics of modular polyketide synthases. 09 Mar 2011

Many natural products of clinical importance are made by type I polyketide synthases (PKSs), multienzyme systems that comprise modules of covalently linked catalytic domains. The key players in each module are acyl carrier protein (ACP) domains, which serve as attachment points for the growing substrate chain. The details of ACP-mediated delivery of substrate to each active site are central to understanding how new polyketide chains are assembled. Using NMR spectroscopy, we recently discovered t hat the interaction between an ACP from the erythromycin type I PKS and its downstream thioesterase (TE) works in an unexpected way: chain transfer occurs in the absence of a protein-protein interface, with contact limited to the acyl terminus of the substrate. We now aim to build on that success by determining how ACPs communicate with every other type of enzyme domain in the erythromycin-producing DEBS PKS, the paradigm type I modular system. We will then extend our study to the PKS in Mycobac terium ulcerans that synthesizes mycolactone, the causative agent of the disfiguring tropical disease Buruli ulcer.

Amount: £287,265
Funder: The Wellcome Trust
Recipient: University of Cambridge

Transcription & post-transcriptional processing in the Plasmodium chloroplast 09 Mar 2011

It is now recognized that Plasmodium has photosynthetic ancestry, being closely related to dinoflagellate algae. It has a remnant chloroplast, including a 35kbp genome, expression of which is essential for Plasmodium viability. The chloroplast is recognised as a target for new antimalarials. Very little is known about transcription and post-transcriptional processing in the Plasmodium chloroplast, although by analogy with other chloroplasts they are expected to be important determinants of gene expression. Although the Plasmodium chloroplast genome encodes some of the subunits of a bacterial-type RNA polymerase, we have identified a nuclear gene for a phage-type RNA polymerase, which algorithms predict is chloroplast targeted (probably in addition to the mitochondrion, and similar to what may be the case for dinoflagellates). Using our experience of chloroplast molecular biology, we have also identified putative genes for other important proteins, including a sigma factor for the bacte rial-type polymerase, an RNA processing enzyme and two RNA binding proteins. All of these are predicted in silico located in the Plasmodium chloroplast, with varying degrees of confidence. We wish to confirm the chloroplast location of these five proteins, and test their function. This will provide a basis for developing a detailed understanding of Plasmodium chloroplast gene expression.

Amount: £364,457
Funder: The Wellcome Trust
Recipient: University of Cambridge