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Results

Mind over Matter: Exploring brain donation and its role in biomedical science - extension 20 May 2011

Recent scandals surrounding the unconsented retention of bodily parts have heightened public anxiety about the collection of human tissue for use in bio-medical research. This has resulted in a marked decline in willingness to donate bodily organs and tissues for such purposes. This award would fund a groundbreaking multimedia installation that highlights the contribution that Britain's oldest prospective brain donors (now aged in their 90s) are set to make to the 21st century technoscientific project of finding cures for debilitating diseases such as Alzheimer's and Parkinson's. Photographic portraits of the donors (unprecedented in the history of such research) will be supplemented by audio recordings of their personal philosophies on life, death, disease and donation. Interactive touch screens will provide scans of their brains and information on the ways in which these, and the brains themselves, will be employed after their deaths. The exhibition will illustrate the vitally important role that brain donation plays in the analysis and cure of neurological disease and celebrate their role in this important project. Audience members will be encouraged to reflect on their own attitudes towards the practice of bodily donation and to record their thoughts and feelings on the subject. The aim of the project is to begin to rehabilitate the practice of bodily donation in the public imagination. The exhibition will be mounted at the Science Museum or ICA and will be accompanied by a catalogue and a website providing an on-going interactive platform for exploration of the project by the public.

Amount: £29,685
Funder: The Wellcome Trust
Recipient: Queen Mary University of London

Medical and Literary Language in the Late Fourteenth Century. 19 Oct 2010

This research has two goals: to demonstrate how literary texts used medical discourse as a rich source of imagery and narrative techniques in the late fourteenth-century and to explore how and why medical writers used literary devices to make sense of illness. I am interested generally in the question of how English literature invented itself by channelling other registers e.g. historical writing and practical discourses. Exploring seemingly generically diverse texts side by side will, I h ope, demonstrate how these kinds of writing acted upon each other as English literature emerged in force. I will also explore how medical writers especially Arderne used literary devices. Why do writers seek to understand illness through story-telling and through metaphor? I recently discovered that Arderne treated Thomas Usk and this has led me to think more about links between doctors and writers (Arderne advises doctors to be like clerks ) and between their texts (Arderne may have us ed the Gawain-poet s illuminator; the countess of Devon bequeathed romances and medical tracts together). Key texts include Arderne s writings, the Livre de seyntz medicine, penitential manuals, and poetry by Chaucer and the Gawain-poet; both genre theory and disability studies are important frameworks for this research.

Amount: £13,191
Funder: The Wellcome Trust
Recipient: University of Oxford

Francois Rabelais: Medical Humanist. 11 Nov 2010

The project will lead to a monograph: Fran ois Rabelais: Medical Humanist. The primary texts for consideration are Pantagruel, Gargantua, Le Tiers Livre, Le Quart Livre, Le Cinquiesme Livre, despite the latter s contested authorship, and correspondence such as Rabelais s letters from Italy. The first section of the book will analyse the presentation of various medical fields in these texts. Account will be taken of the extent to which Rabelais reflects Renaissance thought and what deliberate mis representation he introduces. Evidence will be taken from Classical, Arabic and Renaissance medical sources to support the analysis and from more modern theories of the body such as those proposed by Bakhtin, Kristeva, Laqueur, Foucault and Merleau-Ponty. The second part of the project will address health promotion via pharmacology, humour and literature as therapy. In the dedicatory epistle to the Quart Livre Rabelais explicitly states how the writer administers to the sick reader in the same w ay that a doctor attends a patient, and how the creation of art fosters health. Theories of humour, studies of doctor-patient relationships and of the therapeutic value of the arts will underpin an investigation of how Rabelais uses his works to encourage physical and mental wellbeing in his readers.

Amount: £43,756
Funder: The Wellcome Trust
Recipient: Swansea University

PTTG, PBF AND p53 IN HEAD AND NECK CANCER 11 Apr 2011

There has been a steady increase in the incidence of human papilloma virus (HPV) related oropharyngeal cancer in many Western countries, with a doubling of incidence over the last 10 years. HPV-oropharyngeal cancer occurs in younger patients than HPV negative disease, and is less commonly related to smoking. Unlike HPV-negative disease, the biology of HPV-positive oropharyngeal cancer is characterised by p53 degradation, retinoblastoma RB pathway inactivation, and p16 upregulation. Multiple studies have now reportedthat the proto-oncogene PTTG is over-expressed in head and neck cancer, with PTTG over-expression generally predicting higher pathological stage, more extensive lymph node metastasis and reduced survival. Together with its binding partner PBF, PTTG interacts with p53 and alters its functionality. We hypothesise therefore that the interacting proteins PTTG and PBF, which are over-expressed in head and neck cancer and bind p53, are critical to the aetiology of HNC. Our key goals therefore will be to determine the relationship between PBF, PTTG and p53 expression in human oropharyngeal tumours; to assess how p53 might regulate PBF in vitro; to dissect the contributions of PBF and PTTG to p53 ubiquitination and half-life; to examine the down-stream functional implications of altered PBF and PTTG expression in terms of apoptosis and genetic instability; and to challenge key observations of the project in primary cells from PBF and PTTG knock-out mice.

Amount: £147,343
Funder: The Wellcome Trust
Recipient: University of Birmingham

Wellcome Trust Joint Basic and Clinical PhD Programme at the University of Birmingham: 'Regulation of germinal centre derived plasma cell differentiation'. 14 Dec 2010

The role of IL-22 for plasma cell output from germinal centre. (a) Aims: Germinal centres (GC) are the sites where high affinity antibody and B cell memory develop. The signals directing differentiation of GC B cells are not clear. We have recently identified IL22 as a factor influencing plasma cell differentiation from GCs. IL22 deficient mice produce larger clusters of GC associated plasmablasts upon immunization. The project will define the mechanism, by which IL22 regulates GC B cell differentiation, and will investigate whether IL22 has other effects on B cell differentiation. Understanding a role of IL22 for GC B cell differentiation may lead to ways to manipulate antibody responses to vaccines, pathogens, or autoantigens.

Amount: £47,585
Funder: The Wellcome Trust
Recipient: University of Birmingham

Molecular and Cellular Biology 31 Aug 2011

The methyl cap is a structure added to mRNA, which mediates processing and translation initiation. Synthesis of the methyl cap is catalysed by two enzymes: CE and RNMT. We are investigating the pathways that regulate these enzymes and methyl cap synthesis by characterising CE and RNMT interacting proteins and post-translational modifications. My host lab discovered that synthesis of the methyl cap is regulated by c-Myc oncogene in mammary epithelial cells. Using mass spectrometry, I identified phosphorylated residues on the cap methyltransferase, some of which are c-Myc-dependent in mammary epithelial cells. In order to determine whether these phosphorylation events are functionally significant, mammary epithelial cell lines will be created in which the modified amino acids are mutated to alanine, to prevent their phosphorylation, and the effect on RNMT expression, activity and localisation will be assessed. If these assays suggest that the phosphorylation events are functionally significant, we will raise antibodies against the phosphorylated residues, and use a panel of inhibitors to dissect the kinase and signalling pathway responsible. Simultaneously, methyl cap formation will be studied for the first time in mouse embryonic stem (ES) cells, investigating the role of cap methylation in self-renewal and cell differentiation.

Amount: £146,952
Funder: The Wellcome Trust
Recipient: University of Dundee

Role of mitochondrial protein O-GlcNAcylation in neurons. 31 Aug 2011

Modification of proteins with O-linked N-Acetylglucosamine modification (O-GlcNAcylation) is a reversible post-translational modification that is driven by two enzymes: O-GlcNAc transferase (OGT) and O-GlcNAc hexosaminidase (OGA). The former exists in three splicing isoforms. One of those, mOGT, contains a mitochondrial localisation sequence, but the biological role of protein O-GlcNAcylation in mitochondria is not understood. More recently, mitochondrial dysfunction has been implicated in the pathogenesis of neurodegenerative disorders, in particular Parkinson's and Alzheimer's diseases. In my PhD project I aim to elucidate the role of O-GlcNAc in mitochondria, in particular its role in neuronal function and neurodegeneration. This proposed study will probe the links between energy metabolism in mitochondria, metabolic disorders and neuropathologies. Specifically, the main objectives of my PhD project are: 1. Study the function and localisation of the mitochondrial OGT isoform, 2. Determine the mitochondrial O-GlcNAc proteome, 3. Provide mechanistic biology of regulation of of mitochondrial protein function by O-GlcNAc,4. Probe the link between O-GlcNAc and the development of neurodegeneration.

Amount: £146,952
Funder: The Wellcome Trust
Recipient: University of Dundee

Spatial and temporal patterns of gene flow in Plasmodium falciparum can informprophylaxis administration strategy and vaccine design 31 Aug 2011

Spatial and temporal patterns of gene flow in Plasmodium falciparum and other infectious diseases

Amount: £156,774
Funder: The Wellcome Trust
Recipient: University of Oxford

Role of non-muscle myosin II in Caenorhabditis elegans stem-like seam cell asymmetric division 31 Aug 2011

Caenorhabditis elegans (C. elegans) stem cell-like seam cells undergo both symmetric and asymmetric divisions during larval development, thus providing a powerful system to study cell proliferation versus differentiation. The aim of my proposed research is to study how C. elegans seam cell asymmetric divisions are regulated. We have obtained preliminary data in which nmy- 2 was knocked down by RNAi, suggesting that a non-muscle myosin II-dependent mechanism may be responsible for ensuring proper seam cell asymmetric divisions. I will focus on the role of nmy-2 in this process, mainly by high-resolution microscopy and video lineage analyses of cell divisions in both RNAi-treated worms and mutant worms. Our early evidencesuggests that nmy-2 plays an important role in regulating seam cell asymmetric divisions.

Amount: £156,774
Funder: The Wellcome Trust
Recipient: University of Oxford

Molecular mechanisms of Repulsive Guidance Molecule (RGM) action 31 Aug 2011

Repulsive Guidance molecules (RGMs), a family of membrane-anchored glycoproteins, are involved in two key signalling pathways: the Neogenin (NEO1) [1] and bone morphogenetic protein (BMP) [2] pathways. RGMs control and fine-tune a wide range of functions from neural development [3] to leukocyte migration [4], and are implicated in several severe diseases, for example juvenile hemochromatosis [5,6] and cancer [7]. The aim of this research project is to fully characterise the actions of RGMs at the membrane interface with both of these pathways. This will involve biophysical and cell-based measurements to build on a crystal structure of RGM bound to BMP (obtained in my first rotation project) to understand how RGMacts as an activator in this pathway. It will also involve crystallisation of complexes involving proteins from both pathways to study how the two pathways are connected. I will also work towards crystallising the full-length type I membrane protein BMP-receptors to gain insight into how the signal is transmitted across the membrane. This will be supported by functional studies using fluorescence techniques, biophysical and cellular analyses.

Amount: £156,774
Funder: The Wellcome Trust
Recipient: University of Oxford

Understanding the mechanism of cohesion establishment 31 Aug 2011

The cohesin ring topologically entraps sister chromatids to ensure timely and error-free chromosome segregation during cell division. In interphase, cohesin is continually loaded onto and removed from the DNA by kollerin and releasin complexes, respectively. Acetylation of the ring is crucial for cohesion establishment this modification is believed to overpower the antiestablishment activity of releasin. In many systems outside of yeast, another essential protein sororin is also required for releasin neutralisation. One of the minor aims of this project is to conduct a small-scale screen to determine whether or not sororin exists in Saccharomyces cerevisiae. The primary goal of this project is to investigate the anti-establishment activity of releasin. One of the key aims is to determine whether releasin has the ability to physicallyremove cohesin from both DNA strands. The bulk of this project will involve reconstituting releasin activity in vitro by building on an existing physical assay for cohesion. Ultimately, this project aims to establish the minimal requirements for the anti-establishment activity of releasin.

Amount: £156,774
Funder: The Wellcome Trust
Recipient: University of Oxford

Properties of GABAergic inhibition in the prefrontal cortex. 12 Jul 2011

The molecular mechanisms underpinning GABA receptor mediated synaptic and tonic inhibition in the prefrontal cortex (PFC) will be investigated. Dysfunction of the PFC is implicated together with GABA neurotransmission in numerous neurodevelopmental disorders. The main objective of this project is to analyse the basic mechanisms involved in inhibitory transmission in the PFCand understand how these can be modulated by dopaminergic and serotoninergic pathway activation and by neurosteroids. We will target PV-positive GABAergic interneurons and their target pyramidal neurons in layer II/III of the PFC. Inhibitory transmission will be studied using acute and organotypic brain slice preparations as well as dissociated neuronal cell cultures. The underlying mechanisms will be explored using biochemical, chemical, electrophysiological, imaging (single particle tracking), pharmacological and molecular approaches involving mutated GABA receptors and photo-active receptor ligands. Our understanding of inhibition in the PFC will be used in conjunction with mouse models to try and corroborate their significance with

Amount: £157,778
Funder: The Wellcome Trust
Recipient: University College London

Infection, Immunology and Translational Medicine-'Towards the development of auniversal influenza vaccine:Investigation of heterosubtypic humoral and cellular immune responses to influenza induced by vaccincation with viral 12 Jul 2011

Seasonal influenza epidemics and pandemics are associated with a non-trivial mortality, morbidity and carry a heavy socioeconomic burden. Vaccination is still the primary strategy for the prevention and control of influenza despite the limitations of currently licensed vaccines and their requirement of periodic reformulation and annual revaccination of at-risk individuals. A first generation T-cell inducing influenza vaccine developed at the Jenner Institute has demonstrated partial efficacy in a human trial. However, there is further workto be done in terms of targeting other conserved antigenic sites that can efficaciously provide heterosubtypic B cell immunity between multiple strains of influenza. We hypothesise that by targeting both arms of the adaptive immune system through rational vaccine design this could provide the highest level of protection against seasonal and pandemic flu. I will assess this by (i) designing new viral vector vaccines that targetcellular and humoral immunity, (ii) testing appropriate regimens in preclinical studies, (iii) measuring induced immunity to influenza antigens and (iv) delineating the mechanisms of B cell memory induction. As we are interested in assessing the use of these candidate vaccines in combination with or as a booster to seasonal influenza vaccination I will investigate a best in class' regimen including our novel vaccine.

Amount: £156,774
Funder: The Wellcome Trust
Recipient: University of Oxford

Infection, Immunology and Translational Medicine - 'Establishment of a transgenic zebrafish model to study the innate immune response to melanoma' 12 Jul 2011

Although immune mechanisms, such as cytokines produced by immune cells in response to the tumour environment, may provide protection against cancer by elimination of transformed cells, they may also aid tumour development by immunosuppressive mechanisms. Epigenetic mechanisms that alter chromatin landscape, enabling the unwrapping of transcriptional programs play important roles in all cellular processes including immune response mechanisms and carcinogenesis. It remains difficult to assess the overall effect of innate immunity during early tumourigenesis since direct in vivo models for evaluating the effects ofthese phenomena on initial tumour growth are missing. We propose to develop a melanoma model in zebrafish to study the initial host immune response to melanoma with particular focus on epigenetic changes. Key Goals 3.1 Establish a zebrafish model system to study the innate immune response to melanoma. 3.2 Characterise the interaction of neutrophils and macrophages with oncogenicmelanocytes as compared to normal melanocytes in vivo. 3.3 Carry out a genome-wide analysis of macrophages and neutrophils' response to melanoma compared to control melanocytes. i. Identify differentially expressed genes by comparing transcriptomes of innate immune cells ii. Identify changes at the epigenomic level in innate immune cells that may be resulting in differential cytokine expression 3.4 Investigate findings in melanoma patients.

Amount: £156,774
Funder: The Wellcome Trust
Recipient: University of Oxford

Investigation of the mechanisms used by Vaccinia virus protein C6 to modulate the host immune response and contribute to virus virulence. 12 Jul 2011

This project aims to understand the mechanisms used by Vaccinia virus (VACV) protein C6 to modulate the host immune response. Specifically, how C6 inhibits type I interferon (IFN)- induced gene expression, the function of the interaction between C6 and the cellular protein SMARCc1, and the contribution of different C6 interactions to virulence in vivo. The subset of IFN-induced genes whose expression is altered by C6 will firstlybe determined. Key events in the signalling pathway required for the IFN-dependent induction of gene expression will be analysed in the presence of C6 to determine where inhibition by C6 occurs. SMARCc1 is a component of the mammalian SWI/SNF complex involved in chromatin

Amount: £155,810
Funder: The Wellcome Trust
Recipient: University of Cambridge

Characterisation of the Type Three Secretion System Effector NleG 31 Aug 2011

Enterohaemorrhagic (EHEC) and enteropathogenic (EPEC) Escherichia coli, which share an infection strategy with the mouse-specific pathogen Citrobacter rodentium, colonise the human intestine is conferred by a Type III secretion system that translocates bacterial 'effector' proteins into enterocytes, wherethey subvert cellular pathways and central organelles. The focus of this project is the NleG effectors, which mimic the structure andfunction of eukaryotic RING finger/U-box ubiquitin E3 ligases. While EHEC contains 9 NleG orthologs, EPEC strain E2348/69 and C. rodentium contain one and three homologs respectively. The targets and role in virulence of the NleGs remain unknown. During Bevin's rotation we found that EHEC NleG targets the nucleus, resulting in diminished staining intensity of histone H3, while NleG7 is found diffused in the cytosol. The goals of this project are to: 1. Determine the intracellular trafficking of the NleGs 2. Identify the NleGs' substrate proteins and the role of the NleGs' in cell signalling 3. Determine the impact of the NleGs on nuclear and cytosolic proteins' ubiquitylation and turnover 4. Determine the role of NleGs during infection using in vivo models

Amount: £156,706
Funder: The Wellcome Trust
Recipient: Imperial College London

Molecular and Cellular Basis of Infection. 31 Aug 2011

EBNA3C is a viral protein expressed in human B cells that have been transformed into lymphoblastoid cell lines (LCL) by infection with Epstein-Barr virus. EBNA3C is encoded by one of three related genes (EBNA3A, EBNA3B and EBNA3C), the products of which function as transcription factors regulating host cell genes. A recent exon microarray experiment in our lab identified a small number of B cell genes whose expression is very substantially altered (up to 60-fold changes were seen) by 'switching on' a conditional EBNA3C encoded by recombinant EBV in LCLs. Several of these genes (eg COBLL1, ADAM28 and ADAMDEC1) are repressed by EBNA3C and at least one gene(AICDA) is activated by EBNA3C. We have found that COBLL1 expression is repressed just as dramatically and with similar kinetics shortly after the infection of primary B cells by EBV - indicating that the conditional EBNA3C cell system is likely to be an accurate model for the processes involved in repression during normal infection of primary B cells. . The aim of this project is to use these genes as model targets of EBNA3C and determine the molecular mechanisms underpinning the epigenetic regulation of transcription associated with this large nuclear viral protein.

Amount: £156,706
Funder: The Wellcome Trust
Recipient: Imperial College London

Regulation of miRNA biogenesis involved in neuronal differentiation 12 Jul 2011

Many cellular functions depend on tightly regulated expression of various proteins. Canonical control of the protein expression is associated with transcriptional regulation. However, only recently the small non-coding RNAs called microRNAs (miRNAs) were identified as post-transcriptional regulators of gene expression. In a typical manner miRNAs originate similarly to the coding RNAs and are processed in a multi-step maturation process. It has been shown that miRNAs are very important for proper functioning of all human tissues. Interestingly the human nervous system contains over 70% of all miRNAs. However, despite the important role of miRNAs, little is known about the mechanisms regulating their biogenesis. The current project is going to identify unknown factors involved in the regulation of selected miRNAs that have been shown to play important roles during neuronal development. RNA chromatography coupled with quantitative proteomics will be used to identify the putative regulators. These factors will be validated using RNA-immunopreciptiation followed by qRT-PCR assays and their functional

Amount: £147,915
Funder: The Wellcome Trust
Recipient: University of Edinburgh