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Funders:
Paul Hamlyn Foundation
The Wellcome Trust
Scottish Council For Voluntary Organisations
Recipients:
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 medical and scientific letters of Dr. David Livingstone online. 22 Nov 2005

Interim (pilot) funding is required to sustain and develop a major online initiative whilst a full grant proposal is researched and written to publish the medical and scientific letters of Dr David Livingstone. The start-up funding (which ends in July) has been provided by the Wellcome Trust Centre for the History of Medicine at UCL and used to support Dr Michael Hawkins whose technical expertise has been essential to initiating the project. We have already established editorial policies and encoding guidelines, transcribed the 70 Livingstone letters held in the Wellcome Library's collection and constructed an alpha version of the site for in-house testing and review. This period of development will involve: Establish an open review process to refine technological policies to ensure best web practice for the beta version of the site. Consolidate links with the National Library of Scotland and Blantyre and also explore links with the archives containing relevant Livingstone material, including the British Library and SOAS. Refine our editorial and transcription policies so that the letters can be put to best scholarly use. Explore online archiving and digital preservation with both UCL and the Arts and Humanities Data Service. Establish outreach potential and identify key means of presenting the material to a wider audience.

Amount: £15,418
Funder: The Wellcome Trust
Recipient: University College London

KSHV manipulation of the B-cell differentiation programme to establish lytic and latent viral replication. 24 Apr 2006

The human gamma herpesviruses, Kaposi s sarcoma associated herpesvirus (KSHV) and Epstein Barr Virus (EBV) maintain their latent life cycle in B-cells. Infectious virus is produced by lytic reactivation from latency to allow onward virus transmission despite a functioning immune system. To do this EBV is proposed to usurp B-cell developmental programmes and functional gene networks. We hypothesis KSHV adopts a similar strategy. When errors occur in this B-cell manipulation lymphoproliferations and lymphomas develop. We have shown that KSHV Primary Effusion Lymphoma (PEL) is a tumour of mature B cell plasmablasts that are blocked at the final stage of B-cell differentiation into plasma cells by a non-activated XBP-1 pathway. When XBP-1 is supplied to PEL, terminal PC differentiation occurs and KSHV lytic cycle is induced. This project will determine the mechanistic differences in gene expression programmes between PEL and the normal cellular counterparts, plasmablasts and plasma cel ls. To interpret these integrated gene expression programmes we will produce computational systems models of mature B-cell transcription factor networks to identify additional B-cell processes that KSHV proteins manipulate. Exemplifying this strategy we will investigate the role of XBP-1 in the induction of KSHV lytic replication and PEL terminal differentiation to plasma cells.

Amount: £327,041
Funder: The Wellcome Trust
Recipient: University College London

Wnt signalling in central synaptogenesis. 27 Feb 2006

The formation of synapses requires a proper dialogue between the presynaptic axon and its postsynaptic target cell. Although great progress has been made in understanding the mechanisms that regulate the formation of peripheral synapses much less is known about central synapses. My laboratory has been studying the role of Wnt signalling in the formation of neuronal connections in the vertebrate nervous system. We have demonstrated that Wnts function as retrograde signals that regulate presynapt ic differentiation. Our new studies in the cerebellum have demonstrated that deficiency in Wnt7a and Dvl1, a cytoplasmic protein required for Wnt signalling, results in significant defects in the structure and function of cerebellar synapses. Electrophysiological recordings at the mossy fibre-granule cell synapse reveal a defect in the rate of neurotransmitter release. In the present grant proposal we are taking a multidisciplinary approach that combines transgenic technology, cellular and imag ining techniques and electrophysiology to address the role of Wnt signalling in the assembly and function of central synapses. As Wnt factors are expressed in different areas of the central nervous system, we believe that our studies in the cerebellum will shed light on important general principles used during the assembly of central synapses.

Amount: £296,126
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

Dissecting the telomere-independent pathways underlying cellular senescence. 17 Oct 2005

Cellular senescence is an irreversible program of cell cycle arrest that is triggered in normal somatic cells in response to a variety of intrinsic and extrinsic stimuli including alteration in telomere length and structure, DNA damage, physiological stress and activation of certain oncogenes. It can compromise tissue repair and regeneration and contribute to tissue and organismal ageing due to depletion of stem/progenitor cell compartments. It can also lead to removal of defective and potentially cancerous cells from the proliferating pool thereby preventing tumour development. The underlying mechanism that controls cellular senescence and the signal transduction pathways involved are not fully understood. We have developed a novel human mammary fibroblast cell system for dissecting the telomere-independent pathways that underlie this process and initiated a systematic analysis to identify the associated changes in the transcriptome. Our aim is to functionally validate genes that we have already identified, extend the transcriptional profiling to encompass all human genes and to carry out a genome wide gain of function RNA interference screen. Collectively, implementation of these strategies will enable us to dissect the telomere independent activities and pathways critical for regulating the finite proliferative potential of normal human cells.

Amount: £250,123
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

Investigation of the regulation of adipose ADMA during weight change. 07 Nov 2005

Signals from adipose tissue may underlie the relationship between obesity and metabolic diseases through their effects on insulin sensitivity and endothelial function. Asymmetric dimethylarginine (ADMA) is a novel risk factor for cardiovascular disease that inhibits nitric oxide bioavailability and causes endothelial dysfunction. ADMA is primarily cleared by catabolism through the activity of dimethylarginine dimethylaminohydrolase (DDAH). We found that adipose tissue expresses DDAH to high levels and generates significant amounts of ADMA, and the release is modifiable by changes in weight and insulin sensitizers. We propose to investigate the ADMA/DDAH pathway in adipose tissue of DDAH-1 +/- mice, and their wild-type littermates,to explore its relationship to the development of endothelial dysfunction in diet-induced obesity and to assess the reversibility of these changes by weight loss. Adipose tissue distribution and detailed quantification of changes in energy expenditure will be determined, as well as organ cultures toevaluate adipose ADMA secretion. Understanding the effects of the dynamic changes in weight on the adipose tissue DDAH/ADMA pathway and its regulation will increase our understanding of this novel product of this organ, explain the close link between body fat and endothelial dysfunction and provide a valuable basis for designing strategies in the treatment of obesity-associatedpathologies.

Amount: £236,395
Funder: The Wellcome Trust
Recipient: University College London

The nature and role of structural changes underlying experience-dependent plasticity in visual cortex. 13 Dec 2005

The rewiring of synaptic connections is considered to be one fundamental way by which the mammalian neocortex stores information and recovers from injury. The likely substrates of cortical plasticity are dendritic spines, since they bear the majority of excitatory synapses and are influenced by synaptic plasticity in vitro. How experience influences the dynamics of spines remains largely unexplored in the living animal. By combining long-term, intrinsic signal imaging and two-photon microscopy in mouse visual cortex, I will correlate the structural dynamics of dendritic spines to functional changes accompanying monocular deprivation (MD). In mice, the shift in ocular dominance (OD) after MD is based on different physiological mechanisms in juvenile and adult animals, is fully reversible, and can be substantially enhanced in adults by MD experience earlier in life. This experimental model therefore provides an excellent context in which to determine how experience-enabled changes in the number, turnover and geometry of spines are affected by age or prior experience. Since LTD and LTP are selectively associated with OD plasticity in juvenile and adult animals, respectively, I will investigate whether the induction of these forms of synaptic plasticity in visual cortex slices induces spine changes similar to those in vivo after MD.

Amount: £566,350
Funder: The Wellcome Trust
Recipient: University College London

Global Health Histories/WHO anniversary Lectures, organized in association with the Wellcome Trust and the Wellcome Trust Centre for the History of Medicine at UCL, UK to be held at the WHO in Geneva March to December 2008. 16 Jan 2008

Title of the meeting: 'Global Health Histories/WHO anniversary Lectures, organized in association with the Wellcome Trust and the Wellcome Trust Centre for the History of Medicine at UCL, UK', WHO headquarters, Geneva. This will be the first lecture series of its kind within the headquarters of the World Health Organization in Geneva, Switzerland. The aim is to engage those involved in formulating and implementing health policies with historians of medicine working on policy-related issues, in the expectation that these interactions will be useful to all concerned. The usefulness of historical findings is being increasingly acknowledged within the WHO, as its employees have become more enthusiastic about carrying out more detailed political and social negotiations in the countries and regions where public health and medical schemes are being put into place. The work of the invited speakers is, therefore, likely to be instructive to WHO workers of different ranks and departments, including those seconded to the different Regional Offices on advisory capacities.

Amount: £4,000
Funder: The Wellcome Trust
Recipient: University College London

'The importance of medical history: Transnational and cross-cultural perspectives on a multi-faceted discipline' conference to be held in Mumbai, India from 15th to 17th November 2007. 17 Oct 2007

The importance of medical history: Trans-national and cross-cultural perspectives on a multi-faceted discipline The proposed meeting will be the first of its type in the South Asian sub-continent - dealing with the important questions of historical method and historiography, from trans-national and cross-disciplinary perspectives; it will allow the audience access to a plethora of perspectives on how to study HOM. The projected audience will be university and college teaching, research and administrative staff of all grades, we well as undergraduate and post-graduate students, doctors, print and TV journalists, and independent researchers. A number of well-known scholars have agreed to attend the meeting, as they acknowledge the usefulness of an event like this in popularising HOM in an important education centre in Asia. These academics, who are attached to a number of Wellcome Trust-funded units, will draw upon an important item of their research - dealing with Europe, North America, Asia and further afield - to develop trans-national perspectives of how to study HOM. This meeting will engender a lot of discussion, which is critically important for an endeavour that seeks to provide new insights to post-and under-graduate teachers about important international developments in the discipline, and the most effective ways of teaching and carrying out research. Themes to be covered: History of pharmacology; Anatomy; Global trade and medicine; Medical genetics and gender; Medicine in the early modern period; Public health in 19th and 20th centuries; Global health programmes and disease eradication; War and medicine; International perspectives on rabies; Scottish doctors and British empire; Obstetrics and surgery; Cross-disciplinary perspectives on leprosy and empire; Hospitals; Medicine and 'witchcraft' in the early modern period; Healthcare in colonial Mumbai/India; Health of industrial labour; Oral histories of contemporary medicine and biological science; History of medical practice and multiple meanings of health.

Amount: £600
Funder: The Wellcome Trust
Recipient: University College London

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.

Amount: £1,522,432
Funder: The Wellcome Trust
Recipient: University College London

Student Elective Prize for Ms Leonora Weil 29 Aug 2008

The Epidemiology and Public Health of Mlaria in Vanuatu

Amount: £1,000
Funder: The Wellcome Trust
Recipient: University College London

Student Elective Prize for Ms Katy Walsh 29 Aug 2008

Sexually Transmitted Infections Among Antenatal Women in Vanuatu.

Amount: £1,000
Funder: The Wellcome Trust
Recipient: University College London

Student Elective Prize for Ms Maria-Charlotte Campbell 29 Aug 2008

Management and rehabilitation of patients with socially incompatible personality disorders at Broadmoor Hospital. Secondly an audit into the outcomes of people bought into the emergency department by police who are under the influence of methamphetamine and have suicidal ideation, at St Vincents Hospital in Sydney.

Amount: £1,000
Funder: The Wellcome Trust
Recipient: University College London

Development of a novel mammography system based on X-ray phase contrast imaging 11 Apr 2008

The objective of this proposal is to build a laboratory prototype X-ray phase contrast imaging (XPCi) system so that the potential of the technique can be demonstrated to interested commercial partners by imaging ex-vivo breast tissue. Synchrotron radiation (SR) experiments have demonstrated that XPCi solves one of the basic problems of diagnostic radiology, i.e. poor image contrast due to small X-ray absorption differences. This problem is particularly significant in mammography where most lesions have absorption characteristics close to those of healthy tissue. XPCi overcomes this limitation because it uses a different physical effect, i.e. refraction/interference of X-rays rather than their absorption. Exploitation of these effects has led to an increase in image contrast and lesion detecability as reported by clinical radiologists. A novel technique, recently developed by the applicants, makes the advantages of XPCi attainable with conventional x-ray sources and detectors. The technique uses coded apertures placed either side of the tissue to be imaged that splits the beam into micro-shafts of photons. These individual beams are aligned with the edges of pixels to ensure that when phase effects occur they cause significant changes in the pixel response. Unlike SR based XPCi this technique can be used with polychromatic, divergent X-ray beams and hence will allow XPCi based upon a conventional mammography source to be transferred into clinical practice. It is this technology that will be exploited and evaluated in the current proposal.

Amount: £460,735
Funder: The Wellcome Trust
Recipient: University College London

Vacation Scholarships 2008. 27 May 2008

Not available

Amount: £22,800
Funder: The Wellcome Trust
Recipient: University College London

Value in People Award. 17 Oct 2007

Not available

Amount: £350,000
Funder: The Wellcome Trust
Recipient: University College London

Elucidating the regulation of homologue disjunction in mammalian oocytes. 07 Jun 2007

First meiotic division errors in human oocytes underlie 80-90% of aneuploidies and are acutely susceptible to aging. During mammalian mitosis, aneuploidy is averted by a spindle assembly checkpoint (SAC) which delays anaphase-onset until chromosomes have completed proper alignment or congressed. Mitotic congression is orchestrated by the microtubule motor CENP-E which establishes chromosome-microtubule attachments and facilitates chromosomal movement towards the spindle equator. Notably, reduced SAC transcripts and congression failure are features of aged human oocytes. We hypothesise that dysfunction of the SAC and of CENP-E contribute to age-related aneuploidy. Although the SAC is required for averting aneuploidy in mammalian oocytes (Homer et al., 2005, Genes Dev.), no oocyte molecular system has been functionally related either to congression or to human female aging. As a first step towards exploring the molecular basis for congression failure, we will use high-resolution fluore scence imaging and gene-silencing to examine the requirement of CENP-E for chromosome alignment in mouse oocytes. We will also determine if the SAC in human oocytes succumbs with aging by measuring SAC protein levels and evaluating SAC integrity in oocytes from women of differing ages. This project will greatly expand our understanding of human aneugenesis and pave the way for new fertility-related therapies.

Amount: £684,139
Funder: The Wellcome Trust
Recipient: University College London

New genetic knowledge and 'lay' expertise in cancer research: exmaining the cultural context of ethics and legitimacy. 31 Aug 2007

The project examines the social parameters of 'lay expertise' in relation to cancer research charities. It seeks to explore how lay consumers', fundraisers' or patients' perspectives and involvement are being incorporated within organisational practices and research agendas of charities that are funding research into cancer genetics. This initiative provides a vantage point from which to explore the pursuit and problems surrounding ethical legitimacy in the cultural context of the new genetics. This issue will be addressed by examining how emerging genetic knowledge and the development of lay expertise affect: The pre-existing balance between lay and expert and the nature of the 'gift' relationship in cancer research charities Attempts to incorporate lay perspectives and sustain 'hope' Social relations among different fundraisers and personhood in the context of lay expertise. The transactional social spaces of cancer research charities offer an important arena for ethnographic inquiry and therefore the opportunity to contribute to an understanding of science as a social process.

Amount: £4,814
Funder: The Wellcome Trust
Recipient: University College London