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Recipients:
University of Oxford

Results

Functional circuits in visual cortex: multi-photon imaging and computer modelling. 19 Apr 2010

It has long been known that the retina adapts to the prevailing level of lightentering the eye. It is also now clear that the visual cortex can dramaticallychange its profiles of temporal and spatial integration depending on the pattern, the movement, and the contrast of the scene. A striking example is adaptive temporal integration (ATI), which Movshon and I discovered in complexdirection selective cells of the primary visual cortex (V1): the responses of these neurons speed up as they are challenged with faster moving stimuli. Findings of this type have far-reaching implications for mapping and modellingneuronal function, particularly for understanding how the visual cortex responds during natural viewing, when the statistics of the scene change frequently from moment to moment. The key goal is to integrate computational modelling and experimental electrophysiology into a unified research group to formulate a biologically plausible model that explains ATI and other fast-acting adaptive phenomena. Major cell classes in V1 will be tested with dynamic stimuli to find the origin of ATI. The spatial and temporal selectivity of ATI and its influence on synchronous firing will be probed in V1 and in the motion area V5/MT. The resulting model will adhere to four principles: (1) modular components will represent major cell classes at several levels from the retina to the perceptually relevant responses in V5/MT, (2) arbitrary time-varying stimuli will be accepted as input, (3) responses will be given as spike trains and membrane voltages, (4) the model will be publicly available online so that it can be utilized and refined by scientists anywhere in the world.

Amount: £199,872
Funder: The Wellcome Trust
Recipient: University of Oxford

Characterisation of genetic variation regulating gene expression within the MHC class III region. 02 Jun 2010

Characterisation of genetic variation regulating gene expression within the MHC class III region This study aims to define DNA sequence variation that alters the way genes are regulated. The inability to identify regulatory DNA polymorphisms is a major roadblock to investigating the genetic basis of susceptibility to common multifactorial diseases. For variation resulting in a coding change in the translated protein, the consequences are amenable to functional prediction and testing. In contrast it is currently unclear how best to identify and analyse functionally important non-coding polymorphisms that modulate gene expression. I propose to define how allele-specific gene expression relates to sequence diversity in vivo across a 300kb region of the Major Histocompatibility Complex Class III region on chromosome 6. Until recently, it has been possible to analyse only a minority of genes for allele-specific expression due to the requirement for a transcribed marker polymorphism to distinguish between alleles. This study will be able to determine allele-specific expression among all combinations of variants at a given gene using a novel approach I have developed which quantifies the relative allelic loading of actively transcribing Pol II, the enzyme responsible for transcript synthesis. The endpoint of this research would be to resolve allelic differences in primary human cells in a disease state. However to attribute allelic differences to genetic variance on a given allele, heritability needs to be assessed. Therefore initial work will use a model system of lymphoblastoid B cell lines established from family pedigrees spanning three generations of individuals. Molecular mechanisms operating in vivo will be resolved by interrogating specific stages in the process of transcriptional regulation, epigenetic phenomena and protein-DNA binding. These molecular models of how genetic variants may modulate transcription will be tested by reporter gene analysis and by mutagenesis of large intact genomic regions transferred into cells. I will proceed to analyse candidate regulatory variants in other cellular contexts, notably primary human peripheral blood mononuclear cells.

Amount: £297,954
Funder: The Wellcome Trust
Recipient: University of Oxford

Impact of HLA class I alleles on immune control of adult and paediatric HIV infection. 27 Apr 2010

The overarching aim of the work undertaken in the applicant's research group is to better understand what are the CD8+ T cell responses mediating effective control of adult and paediatric HIV infection. In a population-based study in KwaZulu-Natal, South Africa, we showed that only Gag-specific CD8+ T cell responses are associated with low viraemia in chronic infection. Env- or Accessory/Regulatory-specific responses are associated with high viral loads. The first aim of the proposed work is therefore to determine whether Gag-specific responses are inherently more effective than non-Gag-specific responses, or whether these discordant associations with viral load are merely the consequence of chronic infection. The second aim is to determine whether HIV adaptation at an individual level is reflected by adaptation at a population level to these effective CD8+ T cell responses in Gag. The third aim is to extend studies initiated to examine whether CD8+ T cell response play an important role in control of paediatric HIV infection. Our preliminary data suggest that they do, both via the specificity of the responses generated in infancy by the child, and also via the impact maternal CD8+ T cell responses might have on the replicative capacity of transmitted virus.

Amount: £31,000
Funder: The Wellcome Trust
Recipient: University of Oxford

The regulation of B cell responses during malaria infections. 24 May 2010

The literature provides strong evidence that germinal center B cell responses, and the subsequent generation of long-lived memory B cells and high affinity plasma cells, are impaired during malarial infections. We propose to examine the context in which antigen is presented in the follicle (whole parasites or just soluble protein antigen?), and to examine the cues that lead to an unusual positioning of plasma cells in the splenic T cell zone during P. chabaudi infection. The process of selection of high affinity germinal center B cells involves competition for antigen and for T cell help. We postulate that the release of large amounts of malarial antigens during periods of high parasitemia may lead to impaired selection of germinal center B cells. We aim to generate transgenic parasites expressing duck egg lysozyme, a low affinity antigen for the transgenic Hy10 B cells line, to enable us to follow the cognate response in vivo, and assess the efficiency of affinity maturation during ma laria infections. We will infect mice with different ratios of transgenic and WT parasites, to determine whether the availability of antigen plays a part in regulating the process of selection of high affinity B cells during malaria infection.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford

The Trypanosome flagellar pocket -functions and adaptations in differentiation, pathogenicity and immune evasion. 24 May 2010

Cell body architecture of unicellular organisms influences a variety of cellular functions. The goal of this research is to understand how a specialised invagination of the trypanosome cell surface membrane called the flagellar pocket (FP) functions in differentiation, pathogenicity and immune evasion. I will investigate the stumpy form FP to determine what structures distinguish it from other lifecycle stages. I will perform a highly detailed electron tomography study on the FP, correlat e this with specific functions of the FP and then determine the effects of temperature and lifecycle progression on FP structures. This will enable me to understand how trypanosomes use their FP to perceive and respond to changes in their environment as they move between the mammalian and insect hosts. I will then combine reverse genetics with live cell imaging and molecular and cellular biology techniques to investigate specific questions relating to how some proteins are retained within th e FP whereas other proteins traffick freely to the bulk surface membrane. I will dissect the mechanism of protein retention within the FP and determine what role proteins signals, motifs and facilitator proteins play. I will also investigate the specificity of FP protein release that is observed under some conditions.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Sensorium Tests 14 Apr 2010

Taking as its starting point a real-life scientific experiment on mirror-touch synaesthesia (2005, by S.J. Blakemore, D. Bristow, G. Bird, C. Frith, and J. Ward), Sensorium Tests, a 20 minute long, 16mm experimental art film, sets out to be the first artwork to express the sensory effects of this neurological condition, experienced by perhaps one in twenty-five people, in which visually observed touch to others' bodies is perceived as a touch to the synaesthete's own body. Adopting a multidisciplinary approach in my treatment of the theme of perception, I will draw on film aesthetics, neuroscience and my rich background in artmaking to interrogate the possibility of evoking a visceral sense of 'touch' through the audio visual medium of film.

Amount: £29,996
Funder: The Wellcome Trust
Recipient: University of Oxford

"Genomic analysis of relatives of soldiers who died during the 1918-19 influenza pandemic as a means to understand history and discover mortality risk factors" to be held in Oxford 21 Sep 2010

The influenza pandemic of 2009 demonstrated our ignorance of relevant mortality risk factors. Although few died in 2009, the large mortality of 1918-19 offers potential insights into the historical and biological causes of death from influenza. Extensive by-name morbidity and mortality data were prospectively collected by the British and USA military and are now available from on-going epidemiological studies centred on the Australian Army. We propose to meet in order to review the historical and medical data and determine if genomics analyses of relatives of those known to have died during the influenza pandemic 1918-19 could inform both the historical appreciation of the greatest single human mortality event which occurred in 1918-19 as well as our current understanding of pandemic influenza and genetic risk/protection factors.

Amount: £5,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Advanced Microscopy for Chromosome and RNA Dynamics. 12 Jul 2010

We are requesting a strategic award to establish a new Wellcome Trust Centre for Chromosome and RNA dynamics that will bring together 15 leading investigators from three different Departments within the South Parks Road science campus at the University of Oxford. Our central premise is that by applying and developing advanced in vivo imaging approaches together with novel and innovative methods to track, manipulate and modify defined factors, we can achieve a new level of understanding of the me chanisms that govern the function of complex molecular machines in chromosome and RNA biology, including in the context of developing multicellular organisms. The Centre will provide the essential infrastructure for advanced imaging instrumentation, proteomics, genomics and data storage/curation as well as staff to manage facilities and analyse high volumes of data that are required to achieve our goals. It will also facilitate programs and activities through which we can build a highly interac tive and collaborative interdisciplinary environment. The Centre will significantly enhance the world leading research programmes of participating groups, and through training, mentoring and dissemination activities strengthen this key strategic area within the UK research community.

Amount: £3,878,703
Funder: The Wellcome Trust
Recipient: University of Oxford

Acceleration of the development of vaccines and diagnostics for typhoid fever using a human challenge model 23 Apr 2010

Typhoid is a serious infection which kills up to 600,000 people every year. Many children and adults are affected by the disease and it is the commonest bacterial cause of fever in children attending hospital in some parts of South Asia. It is very expensive to undertake the field studies that are needed to see if new vaccines work and this has stalled development of some new generation vaccines which might give better protection against typhoid. In this project a research team lead by Professor Andrew Pollard from Oxford University will use a model of infection in healthy volunteers to see if a new vaccine can prevent the disease. The researchers will also use the model to understand typhoid infection better and study which components of immunity are important in vaccine protection. The team will use the model to try to develop new blood or urine tests for better diagnosis of typhoid. It is hoped that these studies will improve case management and move vaccine development more quickly to eventually save lives.

Amount: £1,568,986
Funder: The Wellcome Trust
Recipient: University of Oxford

Development of a PorA/FetA meningococcal vaccine for broad protection against meningococcal disease: progression from pre-clinical studies to Phase I clinical trials in humans. 22 Jan 2010

In the UK, Neisseria meningitidis expressing the serogroup B capsule (MenB), causes 1500-2500 cases of invasive infection each year and is the leading infectious cause of death in childhood. Unfortunately, the serogroup B capsule is poorly immunogenic in humans due to its similarity with human antigens. Vaccine development has therefore focussed on subcapsular surface antigens, but has been hampered by their variability. We have found that expression of meningococcal surface proteins (including PorA and FetA), is highly structured, such that a limited repertoire of these proteins are associated with each of the hyper-invasive genotypes of meningococci. This provides the potential for prevention of MenB disease with a multivalent FetA/PorA vaccine which we have been developing since September 2007 supported by a Wellcome Trust Translation award. FetA is only expressed under iron-restricted conditions so a constitutively expressing strain has been constructed from which an outer membrane vesicle is being manufactured in Norway for a phase I study to evaluate the safety and immunogenicity of this vaccine as the proof of concept in humans. This submission for additional funding is requested to widen the scope of supporting epidemiological data, to cover an increase in costs of manufacturing, and strengthen the preclinical data that will underpin the potential utility of the vaccine.

Amount: £985,100
Funder: The Wellcome Trust
Recipient: University of Oxford

Transnational trauma: Taiwanese psychiatry and the construction of 'psychological trauma', 1945-1995 15 Feb 2010

This project aims to investigate into the historical transformation of psychiatric knowledge with reference to a psychological subject, trauma, which was transformed by a number of individuals and institutions in cross-cultural contexts. From shell-shock to PTSD, the conceptualization of trauma has undergone a 'paradigm shift' in the course of 20th Century history. However, it was primarily considered within military and Anglo-American model. In the course of history, trauma has acquired different names and features under various social and cultural circumstances. In a non-western setting, trauma developed a completely different picture from what it initially meant in western psychiatry. The fields I target are Taiwan National University psychiatric department, which contributed the main inputs in the activities of psychiatric development at the international level, and the early projects developed by the World Health Organization Mental Health Section (later renamed as Unit), World Federation for Mental Health, and other post-war health organizations.

Amount: £1,083
Funder: The Wellcome Trust
Recipient: University of Oxford

Biomedical Vacation Scholarship 14 Jun 2010

Not available

Amount: £17,280
Funder: The Wellcome Trust
Recipient: University of Oxford

Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics. 22 Feb 2010

The Wellcome Trust Centre for Human Genetics was established in 1994 to undertake research into the genetic basis of common diseases. The objective of the Centre is to gain insight into mechanisms controlling genetic susceptibility to human disease, including the localization and identification of disease genes or disease-causing variants, functional characterization of genetic variants responsible for susceptibility, understanding how they contribute to disease risk in populations and how genet ic factors contribute biologically to disease processes, and the development and application of new analytical tools. In order to achieve this objective the Centre has brought together multidisciplinary research groups collaborating on human and rodent genetics, genetic epidemiology and statistical genetics, functional analysis of disease genes, and structural biology. The Centre has a strong focus of expertise, equipment, and resources centralized in Core groups allowing all research groups to benefit and expand their research strategies. Recent years have seen major advances in human genetics, in which Centre scientists have played leading roles, and we see major opportunities and challenges ahead. This application is for the renewal of the 5-year core award to fund the Centre's Core Groups: Genomics, Bioinformatics, Molecular Cytogenetics and Microscopy, Transgenics, and IT, for the period 1.4.2011 to 31.3.2016.

Amount: £11,000,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Purchase of an "on loan" CCD X-ray detector to work with a micro-focus X-ray generator (Bruker AXS) for structural studies. 21 Jul 2009

The Applicants are an inter-Divisional team of five Principal Investigators, all of whom are involved in the determination of the 3-dimensional structures of biological macromolecules as a central focus for highly interdisciplinary research programmes. A unifying theme to the systems studied is their significant potential biomedical relevance. We seek 237,713 of a total project cost of 342,676 for the purchase of a state-of-the-art Bruker Charged Coupled Device X-ray detector (with associat ed kappa goniostat), a cryostat and a dedicated staff scientist to run our multi-user macromolecular crystallography facility. This facility provides open access to groups from the Departments of Chemistry, Pharmacology, Physiology and Pathology, in addition to 8 research groups from within the Biochemistry Department. Under an agreement with the University of Oxford, we have had the Bruker CCD detector on loan from the manufacturer for 3 years (2005-2008). This has given us the opportunity to test and thoroughly assess its capabilities. The detector has already permitted the determination of several novel macromolecular structures that would not have been possible with our previous in-house equipment. Purchase of this detector will ensure that we have the best equipment that is currently available to ensure optimal measurement of diffraction data.

Amount: £155,000
Funder: The Wellcome Trust
Recipient: University of Oxford

A psychological approach to understanding and treating bipolar disorder: investigating new cognitive mechanisms. 17 Jun 2009

Given the need to improve our understanding and treatment of bipolar disorder, this research investigates cognitive and emotional processes underlying mood instability. My previous research demonstrated that imagery has a powerful impact on emotion. I have developed a theory of mental imagery s amplification of emotion within bipolar disorder, proposing that this drives mood instability. The research will test hypotheses from this theory (and existing pilot-work), investigating whether biase s in mental imagery form part of the disorder s psychopathology. Treatment of imagery-related abnormalities will be explored. The research goals are to determine whether imagery-related abnormalities: (A) Occur in bipolar disorder and are specific to it; (B) Predict mood fluctuation; (C) Have causal significance; (D) Respond to cognitive behavioural treatment procedures? Each goal is the subject of a specific project. Project A compares imagery biases between clinical and non-clinic al groups. Project B prospectively studies patients with bipolar disorder using SMS (mobile phone) technology to track process changes over time. Project C experimentally manipulates imagery (in analogue samples) to determine whether hypothesised mechanisms have a causal role. Treatment development with patients in Project D will be informed by the experimental work. Project D includes a preliminary uncontrolled evaluation of the new cognitive behavioural treatment.

Amount: £587,035
Funder: The Wellcome Trust
Recipient: University of Oxford

CpG island binding proteins: elucidating the function of the histone demethylase KDM2 and the leukemic histone methyltransferase MLL in the zebrafish. 21 Jul 2009

The aim of this research proposal is to investigate how the ZF-CxxC domain containing KDM2 and MLL proteins contribute to CpG island function, chromatin modification, and development in the model organism the zebrafish (Dania rerio). 1) To identify zebrafish orthologues of ZF-CxxC KDM2 and MLL proteins and examine their biochemical properties. 2) To perturb the expression of KDM2 and MLL and to analyse the phenotypic consequence during development. 3) To examine mechanistically the domain function of KDM2 and MLL by targeted rescue experiments.

Amount: £152,906
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural studies of the Type III secretion system. 29 May 2009

The Type Ill Secretion System (T3SS) is a complex molecular machine that is a key virulence determinant for important Gram-negative pathogens including E. coli, Shigella, Yersinia and Salmonella species. The T3SS consists of multiple copies of 25 different proteins (totalling -7MDa), spans both bacterial membranes and drives insertion of a contiguous pore into the host-cell membrane. Virulence factors are secreted via this apparatus directly into the host cell. This proposal seeks to probe a key stage in regulation of the secretion through a T3SS by investigating the structure and interactions of the so-called gatekeeper protein SepL which, with its interacting partner SepD, is known to control the specificity of effector secretion through the apparatus from the bacterial cytoplasm.

Amount: £152,906
Funder: The Wellcome Trust
Recipient: University of Oxford

GPCR-G Protein Interactions Investigated Using Electron Microscopy and Surface Plasmon Resonance. 29 May 2009

G Protein Coupled Receptors (GPCRs} are pharmacologically important membrane receptors comprising, at over BOO proteins, the largest superfamily (1%) of the human genome. They are the first link in a chain of signal transduction events that passes messages from the exterior of the cell to the nucleus, ultimately resulting in transcription and translation of proteins in a response pathway. Initial signals occur via interactions with heterotrimeric guanine nucleotide binding proteins (G proteins} (Figure 1) [1]. G protein activation by the receptor initiates signalling via changes in the levels of intracellular messengers such as cyclic-3',5'-monophosphate (cAMP), Ca2+ or signalling lipids. Classical GPCR signalling theory suggests that the activated ligand-receptor complex is required for G protein binding [2], but more recent evidence has shown that a pre-coupled receptor-G protein complex [3; 4], and even a liganded receptor dimer-G protein complex is able to form [5]. All GPCRs have a canonical structure of seven transmembrane ?-helices. The N-terminus in extracellular, the C-terminus is intracellular, and there are three interhelical loops on either side of the membrane. The GPCR family has proved particularly intractable to most high-resolution structural techniques such as X-ray crystallography or nuclear magnetic resonance (NMR), due to the intrinsic conformal flexibility of these proteins, their relatively low expression levels and the fact that they are membrane-bound. While 30-40 % of current drugs target GPCRs [6], less than 2 % of the Protein Database (PDB) comprises membrane protein structures [7]. GPCR structures make up fewer than 30 of the known membrane protein structures, and of those, approximately two thirds are rhodopsin structures (see Table 1 in [8] and references cited therein}. Many functional and structural aspects of the receptor-G protein complex remain to be elucidated, and mechanistic information about the complex is essential for rapid, targeted drug research to proceed apace.

Amount: £152,906
Funder: The Wellcome Trust
Recipient: University of Oxford

Blood brain permeation of central nervous system therapeutic molecules and influence of P-glycoprotein. 29 May 2009

1. To characterise at the atomistic level the interaction of a series of compounds that are classified as Blood brain barrier active (BBB+) or otherwise (BBB-). 2. To elucidate which molecular features may be important in determining CNS activity in terms of bilayer permeation. 3. To examine the influence of protonation states on the free energy of permeation. 4. To investigate the influence of lipid composition, including cholesterol, on the free energy of permeation of these compounds. 5. To explore the role of cooperativity in the free energy profile of these compounds. 6. To use this data to generate more accurate knowledge-based models that capture the essential features of the model but offer massive improvements in speed. 7. To investigate which aspects of the structure of P-glycoprotein (P-gp) may be important in substrate recognition. How access to the binding pocket is likely to be influenced by initial penetration of the compounds.

Amount: £152,906
Funder: The Wellcome Trust
Recipient: University of Oxford

Analysis of T cell responses to HIV-1 infection in Kenyan infant cohorts. 08 Jun 2009

General aim: to determine immunological correlates that contribute to lack of viral suppression during vertical transmission of HIV-1 in two Kenyan infant cohorts. Specific aims 1) To determine the varying capacity of infant cytotoxic T lymphocytes (CTL) to suppress HIV-1 replication 2) To investigate the mechanism by which CD4+ T cell and dendritic cell (DC) responses contribute to the lack of viral control during primary HIV-1 infection in infants The dynamics of primary Human Immunodeficiency Virus-1 (HIV-1) infection differs markedly between adults and infants. During acute infection in adults, an initial rise in viraemia that peaks 3-4 weeks after infection is brought under control1,2. By contrast, vertically infected infants experience a greater rise in peak viraemia coupled with a reduced capacity to contain viral replication3. As a result, disease progression proceeds rapidly with mortality rates in Kenyan infant cohorts of up to 52% within 2 years of life in the absence of ART4. Several lines of evidence indicate that HIV-specific T cell responses play critical roles in the control of viral replication in adults during acute and chronic stages of infection. For instance, CD8+ T cell numbers correlate inversely with viral load during acute infection1,5 , broad HIV-specific CD4+ and CD8+ T cell responses are associated with long term control of chronic infection6,7 and specific escape mutations emerge in the viral genome as a response to the selective pressure exerted by cytotoxic T cells (CTLs)8. The role of T cell responses during infant HIV infection is less clear. CD8 T+ cell cytokine production and proliferation are reported to be compromised in infants compared to adults9,10. By contrast, congenital cytomegalovirus infection leads to virus-specific CD8+ T cell responses with the same functional phenotype as those in adults11. Such disparate outcomes suggest a fundamental flaw in the machinery used to prime and maintain effective CD8+ T cell responses during primary HIV infection in infants. The focus of the present project is to investigate the mechanisms by which the immune axis involved in priming and maintaining CD8+ T cell activity contributes to the lack of viral control during infant HIV-I infection.

Amount: £152,906
Funder: The Wellcome Trust
Recipient: University of Oxford