- Total grants
- Total funders
- Total recipients
- Earliest award date
- 17 Oct 2005
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
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.
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.
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.
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.
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.
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.
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
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.
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.
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?
Food as a medical object in Paris, 1670-1815. 10 Nov 2005
The project's central focus is upon the constitution of medical authority over diet in Paris between 1675 and 1815. Against the backdrop of a medical marketplace increasingly dominated by luxury and novelty foods, I will explore the ways in which different medical groups, especially physicians and apothecaries, formulated knowledge about food in relation to rival corporations courting the same clientele. I ask how successful licensed medical practitioners were in reforming domestic eating practices, as well as considering hospitals and soup kitchens as sites for alimentary experiments on the larger scale. While physicians concerned themselves with traditional dietetics, pharmacists turned increasingly to chemical analysis of foodstuffs, producing a successful programme of analysis and industrial exploitation of foods by the First Empire. The project will draw upon recent methodological developments in a variety of fields, including cultural history, anthropology, sociology and literary theory, which offer new ways of writing a history of food and diet. The timescale is chosen to permit a study of the transforming politics of diet during the Revolutionary years. Based on little-known archival and printed materials, the study will provide the first comprehensive account of the various medical understandings of foods and diet in this period.
A combinatorial approach using steroidgenic factor-1 (SF-1, NR5A1) to elucidate novel mechanisms in adrenal and reproductive biology. 05 Jun 2006
We aim to elucidate novel molecular mechanisms involved in human adrenal and reproductive development, and to relate these findings to patients with disorders of adrenal and reproductive function and to variations within normalpopulations. Using microarray and proteomic approaches, we now have the capacity to identify many of the components involved in these systems: the challenge is to focus on those factors relevant to human disease. We will address this using a combinatorial approach (Aims 1-3). In Aim 1, key differentially expressed genes/proteins will be identified in the adrenal, testis and ovary at critical stages of human development between 6-12 weeks gestation. In Aim 2, a subset of important novel genes will be identified by manipulation of the pivotal nuclear receptor sterodiogenic factor-1 (SF-1). InAim 3, genetic loci containing potentially important genes will be mapped using "literature mining" techniques and array analysis of patients with adrenal and reproductive disorders. Taken together, these studies will provideinsight into important biological mechanisms of development and function. Analysis of candidate factors in patients/families with adrenal and reproductive disorders will define novel endocrine syndromes and should identify key factors important in milder clinical phenotypes or physiological variability within a "normal" population (Aim 4).
Conversation Piece. 26 Jul 2006
The Listening Room The Listening Room is a collaboration between artist Alexa Wright and Alf Linney, Professor of Medical Physics at University College London. Within the Centre for Auditory Research at UCL Alexa and Alf are researching an effective means of modelling human communication. With a view to creating an interactive audio installation - an intelligent room that can converse with its occupants - they will bring the latest technologies for sound placement and for speech recognition and synthesis into a clinical environment where they will interact with scientists who are working to understand the physical and neurological aspects of binaural hearing.
Since 1990, in sub-Saharan Africa and many populations in south Asia, there has been almost no progress with Millennium Development Goal (MDG) 5 to improve maternal survival, and a plateauing in the decline in under five mortality rates (MDG 4). Neonatal mortality rates remain stubbornly high. This strategic award programme has three objectives. Building upon existing trials, it will develop a global network of linked epidemiological surveillance sites in Bangladesh, India, Malawi and Nepal to study maternal and child health and survival in high mortality populations. The award will strengthen our network capacity to conduct meta-analyses and cross-country comparisons of data, especially for maternal mortality, to improve understanding of coverage, access and equity of uptake of maternal and newborn care, to collect longitudinal cohort data on growth and development among children, and to analyse linkages between health outcomes and proximate indicators such as poverty, social capita l and the strength of local health systems. Second the award will strengthen capacity to translate research evidence into policy and practice in partner countries and through international agencies. Third, it will strengthen capacity of partner institutions to design, manage and communicate high quality policy-relevant research, especially through south-to-south dialogue and peer-learning.
The London Pain Consortium. 07 Nov 2007
Chronic pain is prevalent and its clinical treatment remains limited. The London Pain Consortium (LPC) will advance knowledge of chronic pain mechanisms through internationally competitive research and provide multidisciplinary training of clinical and biomedical scientists to promote careers in neurobiology in general and pain studies in particular. In man and animals, we will: 1) identify molecular and genetic influences on pain processes; 2) study the integrative functions of these influenc es and their translation as therapeutic targets; 3) provide research and training resources for the wider scientific community.
Hesx1-deficient mouse embryos show a significant reduction of anterior forebrain (AFB) tissue from 8.5 days post coitum (dpc). Recently, we have demonstrated that the absence of Hesx1 leads to a posterior cell fate transformation of AFB. Our data suggest that HESX1 might function to antagonise the activation of Wnt/?-catenin signalling within the AFB. However, the precise molecular mechanism by which Hesx1 modulates this pathway is not known. Moreover, Hesx1 may perform part of its function inde pendently of this signalling pathway, but there is no information on genes potentially regulated by Hesx1. The main goal of this proposal is to expand our knowledge of the role of Hesx1 during forebrain development by combining two complementary approaches: 1. Hypothesis-driven approach. We will dissect at the molecular level how Hesx1 modulates the Wnt/?-catenin signalling pathway within the AFB. We will perform in vitro studies, on transfected cells, and in vivo experiments, on zebrafish an d mouse models with impaired Wnt/??catenin function. 2. Open-ended screening approach. We will perform gene expression profiling studies on three distinct Hesx1-expressing cells to reveal which molecular pathways other than Wnt/?-catenin are regulated by HESX1. We will identify both common and specific genes, which HESX1 regulates in different cell types.
MRC-Wellcome Human Developmental Biology Resource: a unique resource for studies of human embryo and fetal development 10 Jul 2007
Understanding gene function is a major research priority in the post-genomic era. With the completion of the Human Genome Project, comprehensive DNA sequence information is now available via publicly accessible databases, greatly accelerating the process of gene identification. However, the identification of a disease gene is merely the first stage in unravelling a genetic mechanism leading to a disease phenotype. Determining the spatio-temporal expression of a gene during the embryonic/fetal phases of development is a further crucial step that can provide important information about gene function, based on organ, tissue or stage specificity of the expression pattern. Moreover, because of our increasing understanding of species differences (see below), we must study gene expression in early human embryos and fetuses, and cannot solely rely on extrapolation from animal models. As the focus of biomedical research moves towards developing novel treatments, human stem cells have acquired enormous significance in international efforts to develop future cell replacement therapies for childhood and adult disease. The provision of early human embryonic and fetal tissues therefore offers important opportunities for investigating tissue differentiation and developing novel somatic stem cell lines. The MRC-Wellcome Human Developmental Biology Resource (HDBR; www.hdbr.org) began as a national resource but is now international in scope. It provides human embryonic and early fetal material to the research community, for ethically approved and scientifically valid projects involving analysis of human gene expression and tissue differentiation. The HDBR sends embryonic and fetal material to labs that are equipped and experienced in gene expression or related analysis, and offers a customised in-house gene expression service for labs where gene expression analysis is not routine. As well as standard publication outputs, valuable high resolution gene expression data produced by the projects are being stored in a publicly accessible database. The present application seeks a further five years' joint MRC and Wellcome Trust funding to continue to develop the unique HDBR service.
FTICR-Mass spectrometric proteomic analysis of transcriptional and post-translational protein isoforms and protein-protein interactions in neurodegenerative, signal transduction and cell cycle biology. 27 Feb 2007
We would like to apply for an equipment grant for a FTICR mass spectrometer which will function as a central resource for UCL research programmes in the Dept. of Molecular Neuroscience, the Institute of Neurology, the Department ofMedicine, The Institute for Structural Molecular Biology and Birbeck College. The participating groups provide unique expertise, very substantial current funding and extensive international recognition of scientific excellence. The goal of this application is to potentiate strong existing projects through theprovision of a top of the range instrument for top down proteomics analysis. The core scientific projects include studies of kinases involved in neurodegenerative diseases, of arginine methylation in nitric oxide pathways, cell cycle and cellular differentiation, of membrane receptor signaling systems, of cross-regulation of core pathways (initially feed back from glycolysis to the nucleus) in cellular regulation, of applications of chemicalbiology to infectious disease and to synthesis of non-natural proteins, and ofprotein-protein interactions in bacterial secretion systems involved in bacterial virulence. Occasional use by other projects is also envisaged.