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Recipients:
University of Oxford

Results

Structural studies of the Sulphonylurea receptor subunit of the ATP-sensitive potassium channel by electron crystallography and molecular modelling. 12 Jun 2006

Structural studies of the Sulphonylurea receptor subunit of the ATP-sensitive potassium channel by electron crystallography and molecular modelling To understand the relationship between KATP channel structure and function, for example how mutations cause neonatal diabetes and where nucleotides and drugs bind, we need structural information of the individual subunit proteins and the way these subunits interact within the KATP channel complex. This project aims to provide that information in two ways: by molecular modelling and simulation of the SUR1 subunits and their interaction with Kir6.2, and by determining the structure of SUR1 in two-dimensional crystals by electron crystallography. Determining structures of large eukaryotic membrane proteins to even near-atomic resolution is notoriously difficult. However, our current studies indicate that the electron crystallography approach is feasible and should result in a SUR1 structure at sub-10Å or better resolution within three years. Consequently, this proposal is structured into three parts which can be addressed independently but have obvious beneficial synergies. We expect that the proposed combination of different threads such as (i) cryo-electron microscopy, (ii) models based on existing ABC transporter structures, using established and novel modelling techniques, and (iii) a structural reinterpretation of existing functional data will lead to a better understanding of SUR1 and KATP channel structure over the course of this PhD project. Part 1: Two-dimensional crystallisation of purified SUR1 and SUR2 protein and method development in the image processing of micrographs of two-dimensional crystals. Part 2: Homology modelling and molecular dynamics simulations of SUR and the KATP channel. Part 3: Developing systematic methods for the interpretation of medium resolution structural data of membrane proteins.

Amount: £138,215
Funder: The Wellcome Trust
Recipient: University of Oxford

Stimulus-timing-dependent plasticity in the auditory cortex. 14 Dec 2005

Stimulus-timing-dependent plasticity in ferret auditory cortex Adult cortical circuits possess considerable plasticity, which can be induced by modifying their inputs. In the visual system, repetitive pairing of stimuli of different orientations or at different spatial locations leads to changes in the receptive field properties of cortical neurons and in human perception, the nature of which depends on the temporal order and interval between the pairs of stimuli. The aim of this project is to determine whether stimulus-timing-dependent plasticity (STDP) is also present in auditory cortex. We will investigate whether the sensitivity of ferret cortical neurons to the location or pitch of a stimulus can be altered by asynchronous auditory conditioning, and whether the degree of plasticity varies from one cortical area to another and therefore with the role of neurons in processing the stimulus attribute in question. Another aim is to study the effects of pairing visual and auditory stimuli on the properties of auditory and multi-sensory neurons in this region of cortex, in order to determine whether STDP extends across different sensory modalities. Finally, we will use a similar paradigm to examine the role of multi-sensory experience in mediating training-induced plasticity of auditory localisation in adult ferrets.

Amount: £31,267
Funder: The Wellcome Trust
Recipient: University of Oxford

The Endurance of the Carrier Narrative: 'Patient Zero', Gaetan Dugas, and the Assignment of Blame in Epidemics. 14 Jun 2006

The proposed research intends to establish the origins of the 'patient zero' concept, account for the means of its rapid cultural diffusion, and locate it within a wider historical framework. The project has four key goals. First, it aims to reconstruct the events culminating in the early 1980s epidemiological cluster study that first posited the significance of a 'patient zero'. Second, the extent to which key players, including public health officials, Randy Shilts, the news media, and the entertainment industry, were each responsible for the promotion of the 'patient zero' character will be determined. Third, efforts will be made to reconstruct Gaetan Dugas's experience as a patient, from archival research and interviews with his acquaintances, his doctors, and the public health officials who met with him. Finally, the project aims to demonstrate the cyclical nature of the 'healthy carrier' narrative underlying the 'patient zero' concept. In this regard, the project will consider the treatment, by both the media and public health officials, of Gaetan Dugas in relation to that of 'Typhoid' Mary Mallon. Newly released testimonies from the Krever Inquiry into the contamination of the Canadian blood industry will also be examined as a more recent recurrence of the narrative.

Amount: £79,234
Funder: The Wellcome Trust
Recipient: University of Oxford

The social value of research: concept and practice in Kenya. 08 Jun 2006

A systematic review of the bioethics, social science, regulatory and other relevant literature will describe and analyse the use of the concepts of 'benefit sharing', 'social value' and the 'moral obligations of researchers' in developing country research. In the light of this analysis, using Kenya as a case study, the perceptions and beliefs of key informants (researchers, policy-makers and research governance bodies) will be explored using interviews and other qualitative research techniques. A specific focus of the interviews and subsequent analysis will be the exploration of informants' views about the allocation of responsibility for ensuring that the benefits of research are shared appropriately. This qualitative research will be complemented by an analysis of current practices concerning benefit sharing in Kenya. The research will lead to a report including: an investigation of the role of the concept of 'social value' in the ethics of research in developing countries using Kenya as a case study; analysis of empirical evidence about current benefit-sharing practice and the views of key stakeholders about best practice; a number of recommendations for good practice, and a practical 'social value template' for use by those involved in research in developing countries: funders, policy-makers, researchers and local ethics committees.

Amount: £146,576
Funder: The Wellcome Trust
Recipient: University of Oxford

Malaria burden and control at national, regional and global scales. 22 Jun 2006

The work in this application will provide the most complete understanding of the spatial distributions of malaria risk at national, continental and global scales since the 1960's. The approach will allow for a transparent, evidence-driven estimation of the public health burden posed by the malaria parasite and its diversity in space and time. The epidemiological platform will provide the means to articulate needs and model the impact of changing demographics, climate, poverty and intervention between 2005 and 2030. Effective control, however, will be predicated on a number of operational constraints which must be defined and understood to ensure that patients and communities most in need have access to interventions that work. How well interventions are delivered at national scales is the subject of a complementary programme of research: providing the link between the theoretical impacts of disease control and the likely operational efficiency of interventions when delivered as part of national policies in Africa.

Amount: £3,416,292
Funder: The Wellcome Trust
Recipient: University of Oxford

Transdiagnostic cognitive behaviour therapy for eating disorders: efficacy and mechanisms of action. 22 Jun 2006

Clinical eating disorders such as anorexia nervosa and bulimia nervosa are a cause of substantial physical and psychosocial morbidity. They typically begin in adolescence and often run a chronic course. They are difficult to treat and they impose a significant burden on health services. This application is for funds to continue a long-term, Trust-funded, programme of research on these disorders and their treatment. One major outcome of this research has been the development of the leading evidence-based treatment for eating disorders (cognitive behaviour therapy for bulimia nervosa), a treatment strongly endorsed by NICE and other national clinical practice guidelines. Recently we have developed an "enhanced" theory-driven form of this treatment (CBT-E) that is designed to be suitable for the full range of eating disorders seen in clinical practice, rather than just cases of bulimia nervosa. Our data suggest that CBT-E is a potent treatment for the majority of these patients. We now propose to study: 1) whether CBT-E operates through mechanisms that are specific to it; 2) whether CBT-E is clinically superior to the leading potential alternative treatment; 3) how CBT-E is likely to work; 4) the utility of CBT-E in treating those patients who are severely underweight.

Amount: £3,974,171
Funder: The Wellcome Trust
Recipient: University of Oxford

The placenta, oxidative stress and the maternal inflammatory response in pre-eclampsia. 03 May 2006

This program develops our long-standing research into the pathophysiology of the specific pregnancy disorder, pre-eclampsia. We have proposed that the maternal syndrome arises from a dysfunctional systemic inflammatory response, involving the entire inflammatory network, including endothelium. There are three stages: the response of the specific placental cell, trophoblast, and its mitochondria to the oxidative stress that is a fundamental problem in pre-eclampsia; release into the maternal circulation of trophoblast-derived microparticles and other factors, which signal to maternal endothelium and circulating inflammatory cells; and the triggering of maternal inflammatory responses. We will investigate mechanisms involved in all stages, relating to:i) the importance of lipid rafts and caveolin-1 to syncytiotrophoblast mitochondrial integrity and resistance to oxidative stress; ii) the contribution of apoptosis and necrosis to syncytiotrophoblast microparticle release, both physiological and pathological; iii) the importance of microparticle shedding as a signal to maternal endothelial and immune cells and iv) the potential role of NKT cells in determining the systemic inflammatory responses to processed microparticulate syncytiotrophoblast antigens in normal and pre-eclamptic pregnancies. We seek a more complete understanding of the placental causes of complexities of end-stage pre-eclampsia. The ultimate aim is to facilitate the development of scientifically targeted therapies.

Amount: £1,110,722
Funder: The Wellcome Trust
Recipient: University of Oxford

Oral History of Diabetes in the 20th Centure - Experiences of Patient Care. 14 Jun 2006

Last year we completed an oral history of experiences of patients diagnosed between 1927 and 1997, which is accessible worldwide at www.diabetes-stories.com. We now wish to enlarge this historical record by interviewing those who cared for patients. The initial goal is to interview 20-25 relatives/carers of patients and 20-25 health professionals, whose memories cover the second half of the 20th century. Selection would come through existing contacts and recommendations from medical staff, patients, and Diabetes UK. We would choose interviewees from a range of geographical, social and racial backgrounds. The next goal is to make complete recordings and transcripts of the interviews accessible on a website and readily usable for research. Indexed summaries would provide instant links to the recording or transcript of a chosen section of an interview; we would create an interactive database and word and phrase search tools. We would also list themes that we've identified, with links to relevant interview sections. The website would include written descriptions of each interviewee, edited audio extracts, and photos of people, documents and equipment. The preparation of the database, transcripts, indexed summaries, interviewee descriptions, and photos; the audio editing, and the selection of themes would represent a large proportion of the work proposed.

Amount: £93,542
Funder: The Wellcome Trust
Recipient: University of Oxford

Generation and characterisation of human monoclonal antibodies to highly pathogenic H5N1 viruses. 24 Apr 2006

New prophylactic and therapeutic strategies to combat human infections with highly pathogenic H5N1 influenza A viruses are urgently needed. This project will use immortalised memory B cells from Vietnamese adults who have recovered from infections with highly pathogenic H5N1 avian influenza A viruses as a basis for the production of human monoclonal antibodies (hMabs) specific to the H5 haemagglutinin (HA) antigen. Immortalised B cell clones that secrete hMabs specific for the H5 HA antigen will be identified by ELISA and in vitro virus neutralisation assays. The primary goal of this project is to identify broadly-reactive H5 HA-specific hMabs that prevent or modulate the course of established H5N1 influenza infection in mice. The genetic loci encoding hMabs with desirable in vitro and in vivo properties will be amplified, cloned and transfected into cell lines suitable for the large-scale production and purification of hMab.

Amount: £385,435
Funder: The Wellcome Trust
Recipient: University of Oxford

An asymmetric and imprinted chromosome segregation mechanism organizes the bacterial nucleoid. 27 Jun 2006

Chromosome organization, replication and transmission to daughter cells underlie genome integrity and the life process. New microscopic methods have revolutionized understanding of chromosome dynamics in bacteria, and have revealed an unprecedented choreography of gene and macromolecular component position in time and in space. In recent work from the applicant s laboratory, an unexpected asymmetry in the chromosome segregation process has been revealed by studying the positioning and segregatio n of 20 different genetic loci in pairwise combinations; markers duplicate in the central region of the cell, where the replication machinery is located, with one sister segregating towards a cell pole and its sister remaining closes to midcell. This generates a translation symmetry [L-R; L?R ] organization of sister chromosomes. Underlying this asymmetric segregation is an imprinting process that directs the asymmetry in the same direction through generations. The purpose of this proposal is to provide RA1A funding for an ex-Wellcome Prize Student whose pioneering D.Phil work led to the demonstration of asymmetric segregation. By using a combination of genetics and biochemistry, in combination with microscopy, this work will reveal the molecular mechanisms responsible for chromosome organization and asymmetric imprinted segregation

Amount: £228,129
Funder: The Wellcome Trust
Recipient: University of Oxford

Role of KATP-channels in the control of glucagon secretion from human and rodent pancreatic islets. 11 Jul 2006

The control of glucagon secretion from the a-cells of the pancreatic islets ispoorly understood. Both paracrine (due to substances released from neighbouring cells) as well as intrinsic processes (i.e. within the a-cell itself) have been proposed to be of importance. Here we shall apply a combination of biochemical measurements of glucagon release, biophysical experiments (patch-clamp and capacitance measurements) and confocal [Ca2+]i-imaging to rodent and human pancreatic islets. We shall: 1) test the hypothesis that the intrinsic regulation of glucagon secretion depends on closure of a-cell KATP-channels; 2) establish the ion channel complement of the a-cell, which determines the electrical as well as secretory responses to the membrane depolarization resulting from closure of the KATP-channels; 3) assess the importance of the intrinsic mechanism(s) vs. paracrine processes inthe control of glucagon secretion by experimental interference with critical signalling pathways (e.g. insulin, somatostatin, Zn2+, GABA); and 4) investigate the relative roles of KATP-channels and the cAMP effector proteinsPKA and cAMP-GEFII in the modulation of glucagon secretion by adrenaline and GLP-1; both agonists acts by increasing cAMP and yet they have opposite effects (stimulation by adrenaline and inhibition by GLP-1) on glucagon secretion.

Amount: £196,104
Funder: The Wellcome Trust
Recipient: University of Oxford

Structural studies of the paxillin interaction network and its role in focal adhesion dynamics and signalling. 27 Apr 2006

We propose to extend our recent structural studies (Arold et al., 2002; Hoellerer et al., 2003) to generate a dynamic picture of the interactions of the focal adhesion (FA) proteins FAK, ILK and actopaxin with the adaptor protein paxillin. We will define the role these interactions play in recruitment and activation of proteins to FAs as well as their eventual exclusion during FA disassembly. This picture will be developed at resolutionsthat extend from the atomic to the cellular level. Atomic details will be provided by NMR and X-ray crystallographic imaging of individual functional domains in complex with different binding partners. Molecular interactions will be characterised by studying binding events by NMR, isothermal titration calorimetry and surface plasmon resonance, using different fragments of FAK, ILK, actopaxin, paxillin, and GRB2. In particular, we will define which interactions are mutually permissive or mutually exclusive, how they are affected by phosphorylation, and we will seek to relate this information to the dynamic process of FA turnover. Models of molecular interactions developedthrough these studies will be tested in a cellular context by expression of suitable constructs in cultured cells, followed by fluorescent microscopy and cell adhesion and migration studies.

Amount: £200,690
Funder: The Wellcome Trust
Recipient: University of Oxford

Staphylococcus aureus invasion of host cells: the role of multiple fibronectin-binding sites, integrin-clustering and caveolae in invasion. 24 Apr 2006

Staphylococcus aureus is a major human pathogen. With strains emerging worldwide that are resistant to all antibiotics, it is imperative that novel strategies are developed to combat infections. The ability of any pathogen to attach to its host is critical to a successful infectious cycle. S. aureus is well equipped for this, expressing several proteins that allow it to attach to and invade host cells. The fibronectin binding-protein A (FnBPA) is one of S. aureus' major adhesins that also facilitates invasion of host cells. This study will determine the molecular interactions that occur between FnBPA and host cells to facilitate invasion by this pathogen. Key Goals: (1) Determine the role of multiple binding sites within the FnBPA protein. (2) Detect whether integrin clustering occurs after the bacteria and host cells interact. (3) Observe whether these integrin clusters migrate towards caveolae on the host cell surface. (4) Determine whether invasion is dependent upon the presence of caveolae on the host cell. Our hypotheses will be tested from both the bacterial and host cell perspective, using molecular and cellular biological techniques with a view to identifying novel strategies for the prevention and treatment of invasive diseases caused by this pathogen.

Amount: £151,213
Funder: The Wellcome Trust
Recipient: University of Oxford

New assessment procedures for surgical treatments for presbyopia. 30 Aug 2006

Accommodation is the process by which images of objects at different distancesare brought into focus by a change in power of the crystalline lens. Accommodation amplitude declines with age leading to the condition of presbyopia, in which by the fifth decade of life accommodation becomes minimal. Various experimental surgical procedures to treat presbyopia have been recently proposed. Although these procedures all aim to increase the amplitude of accommodation in presbyopes, they seek to achieve this by a variety of means. This research investigates the relative effectiveness of these competing potential treatments. It also seeks to develop procedures to assist in the optimisation of any techniques that may be shown to be effective. Much of the research will be based on the use of finite element modelling. Recent work by the applicants highlights shortcomings in current data on lens stiffness. New lens stiffness data will therefore be collected. The literature abounds with poorly supported and contentious claims on the basis of which members of the public are undergoing ocular surgery. This project will provide a more secure basis on which to assess proposed presbyopia treatments. While there is considerable commercial interest in this area, our aim is to develop impartial assessment procedures; independent funding is therefore essential.

Amount: £92,427
Funder: The Wellcome Trust
Recipient: University of Oxford

Testicular function in mice lacking sertoli cell androgen receptors and FSH receptors. 07 Nov 2005

Testicular differentiation, development and adult function are critically dependent on the Sertoli cells. These cells line the seminiferous tubules and regulate and support germ cell proliferation and differentiation. While it is known that Sertoli cells and spermatogenesis are regulated by follicle stimulating hormone (FSH) and androgen, the relative contribution of each hormone to Sertoli cell activity has remained largely unknown. The recent introduction of relevant mouse models, particularly the FSH-receptor-null (FSHRKO) mouse and the Sertoli cell specific androgen receptor-null (SCARKO) mouse, have provided the potential to dissect out the hormonal mechanisms which regulate Sertoli cell function. We propose to develop mice lacking androgen-receptors on the Sertoli cell AND FSH-receptors or circulating gonadotrophins. This will allow us to determine the extent of Sertoli cell dependence on hormonal stimulation and will show the overall effects that hormones have on Sertoli cell function. Sertoli cell development, and function will be measured in these animals using morphometric techniques and

Amount: £265,649
Funder: The Wellcome Trust
Recipient: University of Oxford

A contribution to the refurbishment of laboratory space at the Sir William Dunn School of Pathology for Prof Robertson to facilitate her move from the WT Centre for Human Genetics. 20 Sep 2006

We are studying the complex cellular interactions underlying early mammalian development, and in particular the signals provided by members of the TGFß superfamily of secreted growth factors. We have previously shown that nodal activity is required for primitive streak formation and anterior patterning during gastrulation, and at later stages for establishment of the L/R body axis. We also described an essential function contributed by the Smad2 protein, the intracellular effector downstream of TGFß/activin receptors. The proposed experiments studies further dissect nodal contribution(s) during morphogenesis of the mouse organiser and establishment of the L/R body axis. We will use gene targeting techniques to selectively delete enhancer sequences controlling asymmetric and node specific nodal expression domains respectively. Using a novel in vivo cell marking system we plan to describe mesodermal subpopulations derived from the node and its progenitors. We will also test the role of the Smad2 pathway during node morphogenesis. Overall the proposed experiments should provide a clearer understanding of TGFß signalling pathways during mouse development.

Amount: £200,000
Funder: The Wellcome Trust
Recipient: University of Oxford

Corticostriatal control over hippocampal and amygdala-dependent appetitive learning and memory systems. 13 Dec 2005

There is growing evidence that multiple, interactive learning and memory systems provide the basis of behaviour, and that disruptions or imbalances within these systems result in the manifestation of abnormal behaviour. Considerable effort is currently being directed at characterising the key neural structures comprising these systems, and this project will investigate the neural and neurochemical basis of the competitive interaction between hippocampal and amygdala-dependent learning and memory processes in rodents, using a systems and multidisciplinary approach. I hypothesise that this interaction occurs in regions of the corticostriatal system that receive converging inputs from the HPC and amygdala, and is modulated by dopaminergic and glutamatergic systems. The first set of experiments will validate the causal roles of the ventral and dorsal HPC in appetitive conditioning and establish the functional connectivity of specific limbic-accumbens pathways using selective permanent or temporary lesions and electrophysiological recordings. The neural loci of interactions between HPC and BLA-mediated information processing will then be investigated using reversible inactivationand in vivo voltammetry targeting the prelimbic-infralimbic cortical regions, orbitofrontal cortex, and rostral pole of the NAc. Finally, the neurochemical mechanism of the competition will be established using intra-cerebral infusions of neuropharmacological agents manipulating the dopaminergic and glutamatergic systems.

Amount: £465,427
Funder: The Wellcome Trust
Recipient: University of Oxford

Intestinal homeostasis: identification of the factors that influence the balance between regulatory and effector cells in the intestine and how alterations in these can lead to chronic intestinal inflammation. 24 Apr 2006

Using mouse models we have shown that colitis can develop as a consequence of excessive innate or T cell dependent responses and that these can be controlled by immune suppressive regulatory T cells (TR). Our recent studies suggest compartmentalization of the pathological response with IL-23 driving local intestinal inflammation and IL-12 mediating the systemic response. We will further characterize the cellular and molecular pathways of IL-23 driven intestinal inflammation, including IL-17 production, to identify their role in innate and T cell dependent colitis. Foxp3 and IL-10 indicator mice will be used to analyse the distribution of bacteria-induced and naturally arising TR cells in vivo as they respond to inflammation and determine their functional properties in distinct anatomical compartments. CD103+ mucosal DC's plays a key role in TR function and will determine how this DC subset influences the balance between effector and TR responses. We have also newly identified the G-protein coupled receptor Gpr 83 as a potential marker for TR cells and using Gpr83-/- mice we will assess its functional role. The results of these studies will facilitate the development of novel therapeutics for chronic inflammatory diseases via the manipulation of TR cells and tissue specific inflammatory pathways.

Amount: £2,082,531
Funder: The Wellcome Trust
Recipient: University of Oxford

Cellular immune responses in children with Plasmodium falciparum infection. 23 Mar 2006

he diversity of Plasmodium falciparum isolates is an important determinant of the heterogeneity in clinical malaria. Many targets of the humoral immune response are polymorphic or undergo antigenic variation. Clinical immunity maybe the result of cumulative acquisition of a diverse antibody repertoire. Antibody responses to a variety of malarial antigens are short-lived and detectable only during asymptomatic infection. However, the cellular mechanisms determining the nature of antibody responses in P. falciparum infection are not understood. One family of variant proteins, the P. falciparum erythrocyte membrane protein-1 (PfEMP-1) mediates adhesion of bloodstage parasites to host cells. Cytoadhesion is associated with (i) pathology, (ii) immune selection, and (iii) immune deviation. I have shown that cytoadhesion of parasites to CD36 modulates dendritic cell function in vitro and systemic cytokine responses in vivo. I now propose to determine the relationship between the phenotype of parasite isolates and the immune responses to PfEMP-1 and how this relationship evolves with exposure. I will define:(i) Whether there are differences in cellular immune responses to PfEMP-1 dependent on the adhesion phenotype of the parasite isolate.(ii) The cellular mechanisms underlying the evolution of unique and cross-reactive antibody responses to PfEMP-1 during the natural history of infection.

Amount: £1,291,901
Funder: The Wellcome Trust
Recipient: University of Oxford