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Recipients:
University College London
University of Cambridge

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

MARCH-VII, a regulator of transcriptional activity and immune cell activation? 22 May 2006

MARCH-VII, a regulator of transcriptional activity and immune cell activation? The aims of my project are: (i) To determine the role of MARCH7 in the ubiquitylation and transcriptional activity of NFAT. (ii) To determine the role of MARCH7 in T-cell activation and immune regulation in vivo.

Amount: £141,232
Funder: The Wellcome Trust
Recipient: University of Cambridge

In vivo dynamics of BRCA2 and Rad51. 26 Apr 2006

WT Studentship 4-year PhD Project Grant Project title: In vivo dynamics of BRCA2 and Rad51 A combination of biochemical, structural, cell biological and biophysical data have suggested a model whereby BRCA2 is able to sequester Rad51 monomers, with direct binding holding them at highly conserved motifs within exon 11 (the BRC repeats: Bignell et all 1997; Wong et al., 1997). However in response to DNA damage, BRCA2 is thought to directly facilitate Rad51 targeting and oligomerisation during HR. The biophysical support for this model comes from a fluorescence recovery after photobleaching (FRAP) study of GFP tagged Rad51. Rad51 was detected in an immobile fraction in living cells due to self association and also due to the interaction with BRCA2, and it was the BRCA2 population which was found to specifically increase in mobility in response to DNA damage. Biochemical data showing that the expression of individual BRCA2 BRC repeats can block Rad51 filament formation to varying degrees in vitro is also in agreement with this model. However, it raises a further question about the significance of this observed heterogeneity in the Rad51 binding regions, which is also implicit in the observation that mutations in different BRC repeats are associated with varying risks of carcinogenesis. To study the dynamic switch in BRCA2 function from sequestration to mobilization, recent unpublished work in the Venkitaraman lab has begun to study the in vivo dynamics of the protein using FCS. FCS measures fluctuations in fluorescence intensity inside an illuminated volume in the order of one femtoliter, using a confocal microscopy setup. Through a time correlation of the signal, the hydrodynamic and photophysical properties of a fluorescently tagged species can be determined as it diffuses through the observation volume. Typically, mobility coefficients and local concentrations are calculated. Although less well established than other non invasive fluorescence-based imaging techniques such as FRAP, FCS provides more powerful insight into certain parameters.

Amount: £141,232
Funder: The Wellcome Trust
Recipient: University of Cambridge

Epigenetic Programming of the mouse germ line. 23 Jan 2006

Epigenetic Programming of the mouse germ line Major epigenetic reprogramming of the germ line occurs in the primodial germ cells (PGCs) in which parental imprints are erased. This is brought about by the dynamic removal and re-establishment of epigenetic marks in the nucleus, essentially involving histone modifications, DNA (de)methylation and chromatin remodelling. Both arginine and lysine residues can be methylated and one of the ways these histone modifications transmit their biological signals is through local binding factors (effector proteins) that recognise the distinct methylation marks. Currently, little is known about the identity of effectors that recognise methyl-arginine modifications. Very recently, tudor-domain containing proteins were shown to be able to bind to symmetric methylated arginines in polypeptides and were postulated to be general methyl-binding proteins. These are strong candidates that may be general effectors of methylarginine on histone tails. I will examine if this putative histone methyl-binding capability exists, and if so, how tudor proteins may potentially contribute to the germ line chromatin state during epigenetic reprogramming. Notably, my preliminary data have shown that several of these tudor-domain containing proteins appear to be restricted to the germ line, and absent in the soma. This strongly suggests that tudor family of proteins may have uncharacterised functions in germ line development in addition to a putative methyl-arginine binding ability. Although it remains to be established if tudor proteins are methylarginine effectors, their potential involvements in germ line development are interesting in their own rights. Finally, I am also aware of the possible wider roles of tudor proteins in pluripotency, and will address this possibility.

Amount: £23,661
Funder: The Wellcome Trust
Recipient: University of Cambridge

The structural biology of cell signalling and regulation: multiprotein systems and the achievement of high signal-to-noise ratios. 27 Apr 2006

The control of cell differentiation, growth and proliferation is mediated by the assembly and disassembly of multiprotein complexes. My group has studied the 3-D structures of many such complexes in order to understand the nature ofthe interactions, organisation and cooperativity; examples are FGFR, human recombinase Rad51, the breast cancer associated gene product BRCA2, and Cdk6 with cell cycle inhibitor p19INK4d. We have shown that pair-wise interactions are often weak and ill-defined but lead to cooperative assembly of multiprotein complexes with well defined structures, so providing better signal-to-noise ratios in signalling. In this proposal I focus on other features that are shared between multiprotein systems at the cell surface, in the cytoplasm and in the nucleus. I plan to investigate 3-D structural features of complexes where: 1. One or more components are disordered prior tobinding. 2. Higher order clustering modulates signal transduction.3. Glycosylation controls receptor interactions. 4. Different assemblies regulatedifferent signalling pathways. In order to achieve these objectives I plan notonly to extend studies on systems where we have worked before, for example FGFR, Met receptor and Xrcc4; but also to initiate work on others where we have only preliminary studies, such as the Notch receptor. The research involves protein expression, purification, characterisation of complexes, crystallisation, X-ray analysis and bioinformatics.

Amount: £1,454,930
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

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

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

The role of Z alpha-1 antitrypsin in the pathogenesis of emphysema. 23 Feb 2006

Alpha-1 antitrypsin (AT) is a major serine proteinase inhibitor whose main function is to protect the lung from proteolysis by neutrophil elastase. The Z variant (E342K) is prone to form polymers which accumulate as inclusions in the hepatocyte predisposing Z-AT homozygotes to cirrhosis. The low plasma levels of Z-AT predispose early onset panacinar emphysema. Polymeric AT may in part be responsible for the previously described exaggerated inflammatory response in Z-AT homozygotes. Polymers of Z-AT are present emphysematous lungs, and are chemotactic to neutrophils and preliminary data suggests that they also induce the secretion of interleukin-8 from type II alveolar cells. The factors that cause the formation of polymers within the lung are not known. In vitro, their formation is accelerated by increasing concentration and temperature. Furthermore, Based on the structural biology of polymerisation we have identified peptide inhibitors of polymerisation. The key scientific objectiv es of this work are to (1). elucidate the factors that cause polymerisation of Z-AT within the lung (2). assess whether polymeric AT causes Interleukin-8 secretion from type II pneumocytes (3). to assess whether potential therapeutic agents are efficacious in vivo.

Amount: £126,420
Funder: The Wellcome Trust
Recipient: University of Cambridge

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

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.

Amount: £170,483
Funder: The Wellcome Trust
Recipient: University College London

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).

Amount: £1,215,824
Funder: The Wellcome Trust
Recipient: University College London

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.

Amount: £96,052
Funder: The Wellcome Trust
Recipient: University College London

Cambridge Institute for Medical Research (CIMR). 20 Sep 2006

A major objective for CIMR over the next 5 years is to better understand protein localisation, function and metabolism in a range of diseases in which genetic studies have identified the causative genes. Underpinning our core facilities is essential to achieve this objective and will provide added value to the considerable investment that the Wellcome Trust is already making to our scientific activities. Our present scientific goals are: (i) determination of the molecular mechanisms of intracellular protein aggregate formation and breakdown in health and disease, including the identification of novel therapeutic targets for protein conformational diseases; (ii) identifying and characterising the molecular machinery of intracellular membrane traffic and determining how traffic pathways are coordinated, regulated and modified in health and disease; (iii) the identification of genes, proteins and pathways increasing susceptibility to, or protection from, autoimmune diseases; (iv) determining the transcriptional regulation of haematopoietic stem cells. Our proposal includes funding of core specialist scientific staff, annual research retreats, funds to encourage young clinicians back into research and a case for 2 PhD students per annum. We aim to make CIMR a flagship in the UK for interdisciplinary research at the interface between clinical and basic research.

Amount: £4,084,076
Funder: The Wellcome Trust
Recipient: University of Cambridge