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Recipients:
University College London

Results

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

Perceptual reorganisation in macular disease 27 Feb 2006

Macular Disease (MD) is the leading cause of visual impairment in developed countries. MD causes blind spots in central vision that cannot be cured and for which conventional ophthalmological treatment is of limited benefit. Furthermore, residual vision surrounding the blind spots can suffer from visual distortions and the scotomas themselves can appear "filled in". These perceptual changes are thought to be related to changes in the responses of cortical neurons whose responses recover and remap following damage to their retinal inputs, but analogous evidence in humans is lacking. This proposal examines perceptual reorganization following retinal damage in MD. We develop a new paradigm that will measure if and how remapping occurs in humans with central visual impairment. We use novel quantitative techniques to measure perceptual distortions accurately in patients. We will develop a technique for mapping scotomas with a non-invasive procedure that will be evaluated against existing, slower techniques. These results will be used to develop and test algorithms that geometrically transform images in a manner that will correct the perceptual distortions of the observer. This research aims to increase the efficiency of clinical assessment and maximise residual visual function in low vision observers

Amount: £193,827
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

Development and application of fluorescent use-dependent NMDA receptor ligands 27 Feb 2006

An important unresolved question in excitatory neurotransmission is the spatial extent of activation of NMDA receptors following presynaptic glutamate release: is NMDA receptor activation confined to local postsynaptic receptors, or does glutamate spread to and activate extrasynaptic NMDA receptors or even receptors within other synapses in the vicinity? This question has hitherto been addressed only tangentially by applying neuroanatomical and in vitro electrophysiological and pharmacological methods, or by performing simulations constrained by quantitative estimates of presynaptic glutamate release, uptake, diffusion and receptor properties. Fluorescence microscopy in acute brain slices potentially offers a complementary approach, but it has only been applied to probe the down-stream consequences of NMDA receptor activation for Ca2+ transients inside neurons, which are indirectly related to NMDA receptor binding. We propose a new method based on fluorescence microscopy of receptor ligands. We will attach a fluorescent moiety to molecules derived from the high-affinity use-dependent ligand MK-801 (dizocilpine), and screen them for biological activity in a recombinant expression system. We will then apply the most promising candidates to acute hippocampal slices and evoke glutamate release at a subset of synapses to label activated NMDA receptors. By imaging the spatial distribution of fluorescence we will obtain a read-out of the history of activation of NMDA receptors for comparison to electrophysiological signals.

Amount: £126,547
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

Regulation of transcription elongation by Spt4/5 and NusA. 27 Apr 2006

Gene expression is regulated during the three principal stages of the transcription cycle: initiation, elongation and termination. General transcription factors interact with RNA polymerase (RNAP, the enzyme that catalyses RNA synthesis) during these stages and modulate its catalytic properties. Whereas the process of transcription initiation is reasonably well understood, not much is known about the mechanisms of transcription elongation. The archaeal RNAP is homologous to eukaryotic RNAPII in terms of its subunit composition and overall architecture, and quite distinct from the bacterial enzyme. However, both bacterial- (NusA) and eukaryote-like (Spt4/5) factors govern transcription elongation of the archaeal RNAP. I have recently developed protocols for the in vitro reconstitution of the archaeal transcription machinery, including its 12-subunit RNAP, from purely recombinant components. My laboratory now wants to apply this system to investigate the molecular mechanisms of transcription elongation. Using both biochemical and molecular biological tools we want to (1) resolve the interaction network between the three elongation factors, the twelve RNAP subunits and the nucleic acid scaffold (DNA/RNA) of the elongation complex and (2) characterise the molecular mechanisms by which these interactions regulate the nucleic acid binding and catalytic properties of RNAP during transcription elongation.

Amount: £185,013
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

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

An investigation of risk factors for and outcomes of hypermetropia in the 1958 British birth cohort. 16 May 2006

About 5% of children, 7% of working-age adults and 20% of older people have hypermetropia (long-sight) of a severity that requires optical correction for normal visual development and subsequently for vision dependent activities of daily living such as education, occupation, driving, sports and other social activities. Although a common condition, with an important role in other eye diseases of childhood (especially strabismus and amblyopia) and of late adult life, there is a paucity of research on its causes and its attendant biomedical and social associations. A life-course approach to investigating risk factors for, and outcomes of, complex disease, well-established in other chronic disease epidemiology, is novel in ophthalmology. We propose to study the biological, environmental, and lifestyle factors which influence hypermetropia from birth to mid-adult life and its health and social outcomes at different ages in order to understand their influences on basic mechanisms underlying development of refractive error. Thus we anticipate that the findings will be relevant to clinical practice and to further research, both epidemiological and genetic, on refractive errors, to further improve strategies for prevention and treatment. The 1958 British birth cohort study offers unparalleled opportunities for such work, having proven to be a critically important resource for the longitudinal study of natural history, predictors and health and social outcomes of a diverse range of disorders.

Amount: £51,674
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

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

Cellular and molecular mechanisms of central chemosensory control of breathing. Central chemosensitivity and the reaction theory revisited. 05 Apr 2006

Breathing is the vital rhythmic activity which supports life of an individual by maintaining appropriate rates of oxygen uptake and CO2 elimination. This project addresses one of the most fundamental processes in respiratory physiology - central respiratory CO2 chemosensitivity, which is essential to adjust breathing to the needs of metabolism. Despite significant progress in this field the specific mechanisms of central respiratory chemosensitivity remain largely unknown. In order to pinpoint these mechanisms I propose to usea unique combination of experimental models ranging from cell culture to in vivo animal preparations. Cutting-edge optical imaging and electrophysiological recording techniques will be used to re-evaluate the relative roles of CO2, H+, and HCO3- as potential stimuli for central respiratory chemoreceptors. I shall then identify within the brainstem the populations of cells which respond first to physiologically relevant chemosensory stimulation in physiologically appropriate experimental conditions. To determine how the chemosensory stimulus is transduced I shall use pharmacological approaches to screen through potential intracellular and membrane targets to identify the mechanisms responsible for cellular chemosensitivity. When the candidate central respiratory chemoreceptors and putative chemosensory transduction mechanisms are identified, their physiological roles in mediating respiratory responses to CO2 will be tested using in vivo models.

Amount: £856,154
Funder: The Wellcome Trust
Recipient: University College London

Regulation of lung fibroblast and epithelial cell apoptosis by cyclooxygenase-2 and prostaglandin E2 and their role in the pathogenesis of pulmonary fibrosis. 06 Dec 2005

Pulmonary fibrosis represents the end stage of a heterogeneous group of conditions with poor prognosis and no effective treatment. Recent studies suggest increased epithelial cell (EC) apoptosis and fibroblast resistance to apoptosis contributes to the pathogenesis of fibrosis but the mechanisms are incompletely understood. However, the host laboratory has shown that patients with idiopathic pulmonary fibrosis (IPF) have a decreased capacity to synthesise cyclooxygenase (COX)-2 and prostaglandin E2 (PGE2). COX-2/PGE2 induce fibroblast apoptosis and protect epithelial cells from apoptosis but their role in regulating apoptosis in fibrotic lung is unknown. I therefore hypothesise that the decreased capacity to induce COX-2/PGE2 in patients with IPF contributes to pathogenesis by increasing EC apoptosis and decreasing fibroblast apoptosis. To address this hypothesis I will determine whether COX-2/PGE2 deficiency contributes to human fibrotic lung fibroblast resistanceto apoptosis and induction of EC apoptosis in vitro. I will also examine the effect of COX-2 deficiency on EC and fibroblast apoptosis in an animal model

Amount: £242,197
Funder: The Wellcome Trust
Recipient: University College London

Regulation of N type calcium channel expression, trafficking and modulation 20 Oct 2005

Voltage-gated calcium channels are essential to numerous aspects of the function of excitable cells. In neurons they are involved in the release of neurotransmitters, and in a number of other processes in which a rise in intracellular Ca2+ is the primary signal. Two very important neuronal subtypes of calcium channels are N-type (CaV2.2) and P/Q-type (CaV2.1), with the former being particularly important at peripheral synapses and neuro-effector junctions, in the autonomic and sensory nervous systems. In nociceptive dorsal root ganglion neurons they are a therapeutic target for anti-nociceptive drugs. The function of these voltage-gated calcium channels may be modulated by several means, for example their expression is controlled by the auxiliary ß as well as a2d subunits, and in the short term they are inhibited by the activation of G-proteins via a variety of G-protein coupled receptors. Over a number of years, my group has examined the properties of cloned calcium channels, expressed both in non-neuronal heterologous expression systems and in neurons. The key goals of the current proposed programme of work relate to four interlinked themes involving CaV2.2 calcium channels: (i) examination of CaV2.2 calcium channel mRNA trafficking and stability, since the mRNA for these channels has particular trafficking motifs in it, (ii) examination of CaV2.2 calcium channel protein trafficking and the role of the auxiliary ß subunits and (iii) study of the mechanism of G-protein modulation of plasma membrane CaV2.2 calcium channels. Finally (iv) we will study the pathophysiological consequences of mis-assembly of CaV2.2 calcium channels. The last theme could also generalise to CaV2.1 calcium channels and may relate to the calcium channelopathy, episodic ataxia-type 2, which is caused by mutations in this channel that are often truncating mutations

Amount: £1,375,208
Funder: The Wellcome Trust
Recipient: University College London

An integrated quantitative virological and immunological approach to optimise treatment and define correlates of immune protection against cytomegalovirus in allograft recipients. 25 Oct 2005

In a unique collaboration with transplant clinicians we have produced a paradigm shift in understanding the pathogenesis of HCMV infection. Specifically, we have shown that: a) this virus replicates with rapid dynamics; b) it causes disease in individuals once a critical threshold value of viral load has been reached in the blood; c) patients with rapid replication have a HCMV-specific CD8+ immune defect ("specific interferon gamma impairment; SIGI") which precedes the onset of viraemia. These novel findings will be taken forward in four ways: i) we will conduct randomised controlled trials to optimise treatment based on real time measurement of HCMVviral load; ii) we will determine if SIGI explains why some patients have a slow response to treatment; iii) we will determine if reinfection with a different strain of HCMV can induce SIGI; iv) we will systematically extend immunological studies to determine if other specific immune responses against additional HCMV proteins, restricted by class I and class II HLA molecules, also correlate with full control of HCMV replication.

Amount: £605,793
Funder: The Wellcome Trust
Recipient: University College London

The role of emotion in decision making. 27 Feb 2006

My goal is to understand, from a neurobiological perspective, how emotion influences decision making processes. The idea that emotion influences our decisions is captured in psychological terms by Thorndike's law of effect, which states that actions followed by feelings of satisfaction are more likely to be generated in the future than those followed by negative feelings. A more recent neuropsychological literature suggests maladaptive decision making is associated with pathology to brain regions mediating emotion, as exemplified by OFC damage. An emerging theoretical framework suggests that multiple systems, in the most simple model an emotional and a rational system, compete for behavioural control. I propose a research programme that addresses how emotion influences decision making informed by theoretical perspectives, from reinforcement learning and behavioural economics, to explore an hypothesis that emotion provides predictive, competing and biasing influences on decision making processes. My experimental approach will involve behavioural, neuropharmacological and functional neuroimaging experiments in healthy volunteer subjects. I will also study patients with focal lesions to regions implicated in mediating between emotion and decision making. In the latter I propose an hypothesis based approach to test predictions arising out of functional neuroimaging findings, to determine the precise contribution of identified regions to emotional modulation of decision making.

Amount: £902,600
Funder: The Wellcome Trust
Recipient: University College London

A genetic dissection of brain and heart phenotypes in the Tc1 transchromosomic mouse model of Down syndrome. 27 Jun 2006

Down syndrome (DS) arises from trisomy of human chromosome 21 (Hsa21), and thus from an abnormal gene dosage of unmutated Hsa21 genes, giving rise to the many phenotypes that are found in DS individuals. However, it remains unknown which genes need to be present in three copies to cause particular phenotypes, such as heart malformation. The genotype-phenotype relationships in DS have proven extremely difficult to tease out, yet are important as individuals with DS succumb to a range of disorders such as dementia, heart disorders, etc., that may be treatable if we know which cellular pathways are involved.We have recently established a novel transchromosomic mouse model of DS termed Tc1, which carries a freely segregating Hsa21. Tc1mice have defects in behaviour, synaptic plasticity, and brain and heart development. We now propose to investigate these brain and heart defects in much more depth and to combine this with chromosome engineering of mouse embryonic stem cells to dissect the molecular genetics of these phenotypes. We will combine our knowledge of mouse embryonic stem cell manipulation and the creation of transchromosomic mice, with specialist knowledge from three laboratories studying brain and heart. Working together, we will initially map regions of Hsa21 and ultimately identify specific genes which when present in three copies are responsible for the brain and heart phenotypes.

Amount: £606,749
Funder: The Wellcome Trust
Recipient: University College London

Physicke for mind, body and soul: the diagnosis, treatment and experience of melancholy in early modern England. 14 Jun 2006

This research will explore the links between early modern medical and religious practices and their respective efforts to diagnose and treat psychological dysfunction associated with discontent and depression. Interdisciplinary in its scope, the thesis will draw upon contemporary medical, theological and literary works in an attempt to understand better early modern perceptions of human interiority and its relationship to the body, mind and soul. This project will include an examination of conditions during the period associated with chronic unhappiness (such as melancholy, grief and despair) and a subsequent analysis of how these various forms of depression were understood within both medical and religious contexts. The thesis will aim to demonstrate how contemporary understandings of sadness and discontent emerged from both medical-physical and spiritual-supernatural teachings on human existence and, in turn, how such a multi-discipline paradigm resulted in a highly eclectic approach to psychological therapy.

Amount: £76,648
Funder: The Wellcome Trust
Recipient: University College London

The roles of glial cells in models of neurodegenerative disease. 14 Dec 2005

My own work, using fluorescent imaging techniques during the rotation project, showed that Ab increases ROS generation by activation of the NADPH oxidase in BV2 cells and that inhibition of the CLIC1-mediated chloride conductance - with IAA-94, by transfecting cells with an siRNA against the CLIC1 protein or by substitution of Cl with non-permeant anions almost completely prevents that response. We propose that the activity of the NADPH oxidase is limited by charge compensation and that the chloride conductance plays a key role in augmenting the activity of the enzyme by providing a route for the compensation of electron flow across the membrane. CLIC1 is also expressed in astrocytes, but at present we have no data regarding its possible functions. The functions of this CLIC1-mediated chloride conductance, its mode of activation, the means by which its inhibition can reduce ROS production and neuronal death and its potential ubiquity and general importance in glial cell physiology will form the basis of the research to be undertaken during the course of this PhD.

Amount: £4,890
Funder: The Wellcome Trust
Recipient: University College London