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Recipients:
University of Oxford
University College London

Results

Control and the therapeutic trial in 20th century Britain. 09 Mar 2006

I propose to undertake further research into the subject of my MD thesis 'Control and the therapeutic trial 1918 - 1948', awarded earlier this year, in order to publish the work as a book. My thesis offered a novel assessment of the genesis and hegemony of today's 'controlled trial' though an historical analysis of the rhetorical associations of the term 'controlled' and their exploitation, in particular, by the Medical Research Council (MRC.) My analysis has considerable implications for current medical research and evidence-based practice. Although I briefly discussed these implications in my thesis, I intend to expand this analysis, including an overview of the use of the rhetoric of the 'controlled trial' from 1948 to the end of the 20th century (outside the scope of my original thesis) and further discussion of the extent to which its rhetorical function is implicit in current research and lay discourse. This would involve analysis of medical journals and textbooks, lay newspapers and magazines covering the latter half of the twentieth century, together with further reading of secondary sources which largely fell outside my original thesis. I also intend to explore further, notions of 'control' during the earlier twentieth century.

Amount: £32,050
Funder: The Wellcome Trust
Recipient: University College London

The role of chloride regulation in epilepsy. 10 May 2006

In both human cases of epilepsy, and in animal models, seizure activity has been shown to lead to abnormal neuronal morphology and connectivity. For example, the inducement of epileptic-like activity in the rat hippocampus leads to a decrease in the density of dendritic spines within pyramidal neurons of around 20-40%. Tissue samples taken from temporal lobe epileptic patients also reveal significant atrophy of the neocortical grey matter with pyramidal cells possessing sparser dendritic trees and reduced spinie density compared to age-matched controls. Such patho-morphological changes are believed to have important consequences with regards to normal neuronal function and may lead to increased susceptibility and likelihood of future epileptic insults. The cellular processes behind these changes are poorly understood and any insights would help to elucidate the mechanisms by which epileptic states are initiated and maintained within neuronal tissue, as well as potentially providing novel therapeutic targets and approaches to treating the disorder.

Amount: £141,236
Funder: The Wellcome Trust
Recipient: University of Oxford
Amount: £141,236
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

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

Transcription termination: interconnections between transcription and pre-mRNA processing. 17 Oct 2005

All stages of gene expression from nuclear transcription to cytoplasmic translation are intimately connected. We demonstrated two decades ago that the pre-mRNA processing reaction of 3' end cleavage/polyadenylation connects to transcription elongation/ termination. Since then all mRNA processing reactions have been shown to occur co-transcriptionally, affording tight gene regulation. We will extend our understanding of these connections to an advanced stage. We aim to determine how the chromatin template influences the connection between transcription and mRNA processing. We will then concentrate on dissecting the different ways transcription termination occurs in both yeast and mammalian genes. We will also extend our understanding of how termination feeds back to reinitiation of transcription by analysis of recently discovered gene loops. Our approach of comparing the mechanism of RNA polymerase I and II transcriptional termination in yeast as well as comparing RNA polymerase II termination between yeast and mammalian cells has already generated new data (see Appendix Figure 1-5). We now plan to fully dissect the molecular mechanism and biological significance of eukaryotic transcriptional termination. As such we are investigating fundamental aspects of eukaryotic gene expression, an essential approach to interpret the significance of the human genome sequence.

Amount: £1,853,834
Funder: The Wellcome Trust
Recipient: University of Oxford

Supplement for Laos Infectious Disease Building. 30 Aug 2006

The research conducted by the Thailand-based clinical research programme has changed the treatment of both severe and uncomplicated malaria, and melioidosis. The central aim of this proposal is to develop and evaluate effective and practical means of diagnosing, treating, and, if possible, preventing the main tropical diseases responsible for significant morbidity and mortality in rural areas of Southern and Eastern Asia. These are malaria (P. falciparum, P. vivax, and severe infections), melioidosis, leptospirosis, cryptococcal meningitis, pneumococcal disease in infancy, enteric fever, rickettsial diseases, infantile beriberi, and the burgeoning problem of counterfeit anti-infective drugs. Integrated epidemiology, field based studies of pathophysiology and pharmacology, diagnostics, clinical trials, laboratory research, and innovative approaches to analysis will be combined. This will also provide a platform for regional capacity building and training. We are confident we can achieve our main objective of providing achievable and measurable methods of improving the health outcomes of these major diseases within the five year programme.

Amount: £219,771
Funder: The Wellcome Trust
Recipient: University of Oxford

An oral history of assisted medical decision making. 30 Jun 2006

Identification of 25 potential interviewees who have made significant contributions to the development of medical decision support. The obtaining of informed consent including an agreement to transfer copyright to an archive and the fulfilment of the relevant ethical and data protection obligations. Prioritisation of the potential interviewees essentially geographically for a travel plan but allowing for other factors. Recording up to 25 interviews following verbal consent and following a part-structured set of open-ended questions and allowing for deletions. Recordings are transcribed by the interviewer and a proportion by a professional transcriber. The transcriptions made by the interviewer and the professional are compared. CDROM copies are made. Transcript and CDROM are sent to interviewee for review. Supplementary interviews are made if considered essential. Copyright and consent forms are signed by interviewee. Digital transcripts are tagged for availability in different formats. Transcripts and CDROMs are delivered to the host archive. Host organisation makes the material available to researchers in accordance with terms of copyright. Use of the internet and other forms of dissemination are considered in addition to the conventional forms of archiving.

Amount: £8,030
Funder: The Wellcome Trust
Recipient: University College London

Today's Neuroscience, Tomorrow's History - A Video Archive and Outreach Project. 14 Jun 2006

This proposal is to record, transcribe, and archive video interviews with 12 scientists who have made substantial contributions to modern neuroscience. The key goals are: To deposit material in the Wellcome Library so that it is available to historians, and other analysts of and commentators on contemporary medicine and medical science. Transcripts will also be available on either the web-site of the Wellcome Library and/or that of the British Neuroscience Association (BNA). To edit each interview for professionals in the neurosciences and cognate subjects, to enhance their understanding of the historical and scientific precedents of contemporary neuroscience, and illuminate the pathways of discovery behind standard accounts. To produce shorter recordings of each interviewee to raise and address issues of public interest that arise from biomedical science, and to describe what neurosceintists have done To develop and deliver an integral public engagement programme that effectively targets the audiences for goals 2 and 3.

Amount: £96,935
Funder: The Wellcome Trust
Recipient: University College London

The Greek medical papyri from Graeco/Roman Oxyrhynchus: An edition of 60 unpublished texts from a centre of learning and scholarship in middle Egypt. 09 Mar 2006

The project which is being proposed here is truly interdisciplinary. It brings together scholars in the field of the history of medicine and papyrologists who are trained to decipher the most difficult texts. The aim of this project is to publish the Greek papyri of medical content which were excavated among many others in the town of Oxyrhynchus in Middle Egypt. While poetic and prose texts of all kinds, as well as documents, have been published in great numbers, the medical pieces have remained nearly untouched by scholars. Oxyrhynchus was a hellenized city with a high living standard; scholars from Alexandria spent their leisure time there. Studying papyri found in Oxyrhynchus enables us to have at least a glance into the holdings of the lost library at Alexandria. It is time finally to address this gap. These papyri, which range from recipes to fragments of learned treatises, some perhaps by famous names from Alexandria and elsewhere, show at which level medical care was offered and received by people living in this place in which the Greek and Egyptian cultures met. The texts will be edited, along with translation and commentary, in one or two volumes in the Oxyrhynchus Papyri series.

Amount: £37,859
Funder: The Wellcome Trust
Recipient: University College London

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

The neuroanatomical basis of frontal lobe cognitive dysfunction in frontal lobe and idiopathic generalised epilepsies. 10 May 2006

Frontal lobe epilepsy is a common form of epilepsy that is often difficult to treat successfully with antiepileptic drugs. In some medically refractory cases, surgical treatment is possible, which carries risk of cognitive and behavioural deficit.Juvenile Myoclonic Epilepsy is associated with a particular personality, behavioural and neuropsychological profile that suggests involvement of frontal lobe dysfunction. The aim of this project is to investigate the functional anatomy of cognitive dysfunction in these two common forms of epilepsy. The objective is to better understand the functionalcorrelates of frontal lobe disorders, and to explore whether the findings may assist in the consideration of surgical treatment for refractory frontal lobe epilepsy. Specifically, we will determine whether there is evidence of abnormal functional and structural connectivity of the frontal lobes and whether that predicts the cognitive and psychological deficits that may occur after surgery to the frontal lobes. The combination of cognitive fMRI, tractography and comprehensive neuropsychological assessment pre- and postoperatively represents an unique opportunity to improve understanding of the imaging correlates of neuronal circuits, and the effects of these epilepsysyndromes on cognition.

Amount: £244,430
Funder: The Wellcome Trust
Recipient: University College London

Developmental trajectories of unimodal and cross-modal attention deficits: the case of fragile X syndrome. 10 May 2006

Fragile X syndrome (FXS) is caused by the silencing of a single gene affectingmultiple aspects of cortical development. In late childhood and adulthood, FXSis associated with striking inattention and hyperactivity. Our previous work revealed attentional deficits in toddlers and infants with FXS, highlighting very early onset of difficulties. Hitherto, deficits have been investigated using visual stimuli, but clinical evidence points to difficulties in other modalities, such as audition. Critically, attentional deficits in FXS may be exacerbated by the requirement of selecting multimodal real-world stimuli. Theprimary aim of the current proposal is therefore to investigate the impact of FXS on early developmental trajectories of visual and, for the first time, auditory and crossmodal attention, combining genetics, cognitive developmentaland psychophysical methods. More specifically, we aim to test the following hypotheses: i) developmental trajectories of unimodal and crossmodal attentionin fragile X syndrome will increasingly deviate from normal over early childhood (Goal A); ii) tasks resulting in conflict across modalities will

Amount: £341,196
Funder: The Wellcome Trust
Recipient: University of Oxford

Function of the lipid transporter, PITP-beta in the early secretory pathway. 27 Apr 2006

Phosphatidylinositol transfer protein-beta (PITP-beta) is a transporter that can bind and transfer either phosphatidylinositol or phosphatidylcholine, thereby impacting upon lipid metabolism. Ablation of the gene encoding PITP-beta is embryonic-lethal indicating its essential function. We have identified PITP-beta localisation in early Golgi compartments, which suggests a role for this protein in the early secretory pathway where traffic is mediated by COP-1-coated vesicles. We want to identify potential binding partners of PITP-beta, using both affinity purification and yeast two-hybrid system, and characterise further any proteins purified. We will use siRNA to deplete PITP-beta levels and examine Golgi morphology and steady state dynamics of proteins of the COP1 pathway, in particular ARF GAP1, beta-COP, KDEL receptor and ARF1. The activity of ARF GAP1 is sensitive to membrane deformations which might be brought about by PITP-beta-mediated changes in lipid metabolism. Thus, perturba tion in lipid metabolism together with protein traffic will be analysed following depletion of PITP-beta levels. Our working hypothesis is that PITP-beta regulates local levels of diacylglycerol and/or phosphoinositides in the vesicular tubular compartments (VTC) and cis-Golgi, thereby regulating the COP-1 machinery. Using mutants deficient in binding and transfer of phosphatidylinositol, the specific function of PITP-beta in the secretory pathway will be investigated.

Amount: £193,339
Funder: The Wellcome Trust
Recipient: University College London

Structural studies of the human Notch-1 ligand-binding region. 21 Feb 2006

During development it is essential that cells are guided to their correct location within the embryo and that they differentiate into the appropriate cell type. A key short-range signal which has been highly conserved during metazoan evolution involves the Notch receptor which regulates spatial patterning, timing and outcomes of numerous cell fate decisions. A structural understanding of the Notch receptor -ligand interaction, which is currently lacking, would greatly enhance our understanding of the signalling mechanism and may lead to the design of novel agonists and antagonists of the receptor. With the current interest in cell-based therapies, manipulation of the Notch signal represents a promising strategy to produce defined cell types in vitro for therapeutic use. In this application we aim to i) crystallise and determine the individual atomic structures of the ligand binding region of human Notch-1 (hN-1) and the receptor binding portions of its ligands human Delta-like 1 and human Jagged-1 ii) identify the structural basis for the observed inhibitory effect of hN-1 EGF10 on ligand binding and the mechanism by which post-translational modification overcomes this effect iii) identify the stability of a Notch-ligand complex by SPR, and determine its atomic structure by X-ray crystallography and/or NMR shift mapping.

Amount: £184,579
Funder: The Wellcome Trust
Recipient: University of Oxford

Characterisation and functional analysis of Hesx1-interacting proteins in mouse and human. 20 Oct 2005

Hesx1 is a conserved member of the paired-like class of homeobox genes, which is expressed in the rostral region of the developing vertebrate embryo, but isabsent in non-vertebrate species. Hesx1-deficient mice show defects in the forebrain and pituitary gland, and HESX1 mutations are associated with congenital hypopituitarism and septo-optic dysplasia (SOD) in humans. Therefore, it is now established that Hesx1/HESX1 is a critical developmental gene in both mouse and humans. However, little is known about the functions ofHesx1 at a molecular level, i.e., about its regulators, target genes and interacting proteins. To gain further knowledge on the molecular basis of forebrain and pituitary development in mouse and gain insights into the mechanisms underlying congenital hypopituitarism and SOD in humans, we have recently carried out a yeast two-hybrid screen, identified five Hesx1-interacting proteins and partially characterised these interactions. Themain goal of this study is to carry out a detailed characterisation of these interactions with the primary objective of understanding better how Hesx1

Amount: £235,911
Funder: The Wellcome Trust
Recipient: University College London

Neuronal thalamic gap junctions: identity, location and role in slow EEG rhythms of (patho)physiological states 20 Oct 2005

Synchronized activity among thalamic and cortical neurones underlies the EEG expression of different behavioural state-dependent rhythms, whereas its alterations may lead to EEG paroxysms such as the spike-and-wave discharges (SWDs) of absence epilepsy. Our in vitro studies have identified a key role for gap junctions (GJs) among the glutamatergic thalamocortical (TC) neurones in the expression of synchronized, low-frequency thalamic oscillations, that define two behavioural states, i.e. the alpha rhythm and the slow (<1 Hz) sleep rhythm. In addition, connexin 36 (Cx-36)-based GJs among GABAergic nucleus reticularis thalami (NRT) neurones is known to support synchronized oscillations in this thalamic nucleus in vitro. Here we propose:1. to identify in vivo the contribution of GJs among TC neurones and among NRT cells to the expression of SWDs and of three EEG rhythms: the alpha rhythm, sleep spindles and the slow (<1 Hz) sleep rhythm;2. to identify the sites of GJ coupling in TC and NRT neurones, and the molecular identity of the Cx(s) present in TC neurones using electron microscopy, and triple labelling of dye-coupled neurones and immunocytochemistry with specific Cx antibodies.This multi-disciplinary approach from two laboratories with established expertise in their respective field will shed light into the role of thalamic GJs in EEG rhythms of fundamental importance in health and in one of the generalized epilepsies.

Amount: £170,107
Funder: The Wellcome Trust
Recipient: University College London

Isolation and functional analysis of the oral metagenome. 25 Oct 2005

An estimated 800 bacterial species live in the oral cavity of Homo sapiens. The interaction between the commensal microbiota and its human host results in the commonest bacterial diseases of man; dental caries and periodontal diseases. A major bar to studying the orgal microbiota, whichis probably the easiest such microbial community to analyse, is the fact that 50% or more of the bacteria are uncultivable. One method of analysis which overcomes the need for culture and can enable the whole assemblage of oral microorganisms to be studied is metagenomics. We plan to construct a representative metagenomic library of the human oral microbiota and in this preliminary study analyse it for two groups of genes important for the maintenance of oral biofilms and the evolution of virulence and antibiotic resistance. Specifically, this library will be screened to identify genes encoding adhesins important in biofilm formation and for genes encoding systems involved in horizontal gene transfer. Results obtained will help in developing novel anti-plaque strategies and for understanding the ability of oral bacteria to act as reservoirs for antibiotic resistance genes and to spread these resistance genes among themselves and beyond the oral environment.

Amount: £491,528
Funder: The Wellcome Trust
Recipient: University College London

Synaptic plasticity in hippocampal interneurons: cellular mechanisms. 20 Oct 2005

We have recently found that NMDA receptor-dependent long-term potentiation (LTP) occurs in about half of GABAergic feed-forward inhibitory interneurons in stratum radiatum of the hippocampus. This is only detected if interneurons are recorded in perforated-patch mode, and is not seen if whole-cell pipettes are used, possibly explaining why the phenomenon has not previously been reported. LTP in aspiny interneurons has extensive repercussions for the interaction between memory encoding and information processing in the corticalmicrocircuitry. However, the focus of this application is the underlying cellular mechanisms. Are postsynaptic action potentials required for LTP induction? Can LTP-competent interneurons be identified electrophysiologicallyor anatomically? Can interneurons switch from LTP-incompetence to LTP-competence? What is the role of tyrosine phosphorylation of NMDA receptors? What is the induction cascade downstream of NMDA receptors? How do sub-cellular Ca2+ microdomains relate to pathway-specific LTP in aspiny cells?Do interneurons exhibit NMDA receptor-dependent long-term depression (LTD)? What are the roles of NR2A- and NR2B-containing NMDA receptors, Ca2+/calmodulin kinases, and calcineurin in LTP (and LTD) in interneurons?

Amount: £240,722
Funder: The Wellcome Trust
Recipient: University College London