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Recipients:
University College London
Award Year:
2009

Results

Development of a Biophysical Mass Spectrometry Facility at ISMB. 06 Oct 2009

In the last decade the use of mass spectrometry as a biophysical tool for the characterisation of protein complexes and protein-ligand interactions has emerged as a powerful complementary technique in structural biology. This rise to prominence is due to technical advances in instrumentation. Initially, the availability of extended m/z range quadrupoles, within quadrupole-time-of-flight mass spectrometers (Q-ToFs), enabled studies on large ions. Most recently, the coupling of ion-mobility with m ass spectrometry (IM-MS) in QToF instruments has combined these structural studies with the ability to elucidate shape information. This has dramatically increased the information available from a single experiment and opened up new avenues of investigation. We will establish a biophysical mass spectrometry facility at the Institute of Structural and Molecular Biology through the purchase of a state-of-the-art ion-mobility mass spectrometer and ancillary equipment. This will deliver a new biophy sical facility for the structural analysis of protein interactions, a small molecule screening platform together with an enhanced omics capability. We will offer a range of biophysical and proteomic MS services to the wider physical, medical and life science research community. These services will focus on promoting collaborative links between chemists, biomedical researchers and structural biologists in the area of structural proteomics.

Amount: £232,798
Funder: The Wellcome Trust
Recipient: University College London

'The influence of network activity on the spatiotemporal receptive fields of mouse V1 neurons'. 15 Dec 2009

The project will investigate the influence of neuronal population activity on receptive field properties of individual neurons in mouse visual cortex at different developmental ages in order to understand how this region of the brain becomes specialised for sensory processing. Particular emphasis will be made on characterising the synaptic mechanisms which shape receptive fields in response to different types of visual stimuli.

Amount: £14,138
Funder: The Wellcome Trust
Recipient: University College London

'Mechanisms of transplanted photoreceptor precursor migration and integration'. 15 Dec 2009

To examine the mechanisms by which transplanted photoreceptor precursor cell migrate into the recipient retina and to compare these mechanisms with those by immature photoreceptors in embryonic development

Amount: £39,182
Funder: The Wellcome Trust
Recipient: University College London

Dissecting alpha-synuclein pathology in Drosophila models of Parkinson's Disease: aids to understanding idiopathic Parkinson's Disease. 03 Dec 2009

My research project will use Drosophila melanogaster to model novel mutations in the GBA, PANK2 and PLA2G6 genes known to cause parkinsonism and ?-synuclein pathology in humans, in order to identify common pathogenic pathways in idiopathic PD. This will involve knockout of the GBA, PANK2 and PLA2G6 genes and also expression of PD-associated mutant forms of these genes in Drosophila neural tissue, both in the presence and absence of ?-synuclein expression. These fly models will be characterised, including the effect on longevity, locomotor ability and neuronal viability. I will then study the role of ceramide metabolism in these PD models by comparing the temporo-spatial relationships between these neurotoxic phenotypes and abnormalities in ceramide metabolism. Furthermore I will identify links between ceramide levels and downstream effectors such as mitochondrial, autophagy-lysosomal and proteasomal pathways. In addition, I will determine how loss of function of GBA, PANK2 and PLA2G6 gene products affect the onset and severity of ?-synuclein pathology in flies co-expressing ?- synuclein. In particular, I am interested to determine how these mutations differentially affect the soluble and insoluble pools of ?-synuclein in fly brains. Finally, I will use these fly models as a platform of drug discovery to screen compounds that are predicted to interfere and protect against neurodegeneration by altering ceramide and autophagy pathways.

Amount: £192,279
Funder: The Wellcome Trust
Recipient: University College London

Defining common mechanisms that guide tangential neuronal migration in the mammalian brain. 08 Oct 2009

Neuronal migration plays an essential role in organising the brain into functional domains. Two distinct modes of neuronal migration have been identified in the developing forebrain: radial and tangential. Three distinct neuronal systems in the forebrain exhibit the tangential mode of migration: cortical interneurons, gonadotropin-releasing hormone (GnRH) neurons and interneuron progenitors of the olfactory bulb. We have been investigating for some time the molecular mechanisms that guide cortic al interneurons and have more recently begun to study the migration of the GnRH neurons. Our work raises the possibility that similar molecular guidance mechanisms control movement of both types of neurons. Here, we propose interrelated lines of investigation to study the involvement of two classes of chemorepulsive molecules (slits and semaphorins) and their corresponding receptors (robos and neuropilins) in the migration of all three neuronal systems. Further, we intend to study how these mole cules interact functionally to orchestrate the complex migratory behaviour of these neurons. The proposed research programme will elucidate novel mechanisms in tangential neuronal migration and shed light on the aetiology of some neuronal migration disorders in humans.

Amount: £904,921
Funder: The Wellcome Trust
Recipient: University College London

Biomedical research into clinical innovation: translation, uptake and impact. 30 Nov 2009

This proposal is to use a unique source for the history of modern medical science, the edited transcripts of the Wellcome Witnesses to Twentieth Century Medicine series, to analyse the process or processes by which science is transformed into accepted medical practice and to identify the major determinants of, and influences on, those processes, ranging from Government policies at one end of the scale to professional demarcation lines at the other.

Amount: £24,153
Funder: The Wellcome Trust
Recipient: University College London

Protein interactions and functional properties of P2Y1 nucleotide receptors in neurons (revised). 08 Oct 2009

In previous and current work we have shown that the G-protein-coupled P2Y1 receptors (P2Y1Rs) for ATP are located in some CA1-3 pyramidal neurons, as is the scaffolding protein, NHERF-2, to which they can bind, and that they mediate inhibition of the neuronal M(Kv7)-current therein to increase neuronal firing. This is likely to be important because ATP has recently been reported to be constantly released onto central neurons by neighbouring astrocytes. We now propose: (1) to apply transgenic tec hnology to reveal the cellular location of P2Y1 and selected other identified P2Y subtypes in mouse brain in situ by pre-attached fluorophores; (2) to use these (with other approaches) to study (a) the neuronal function of P2Y1Rs by electrophysiology on identified P2YR-expressing neurons, (b) the sites of scaffolding protein NHERF-2 interaction with P2Y1Rs, (c) possible P2YR heterodimerization, and (d) to test the hypothesis (based on observations on hippocampal neurons and sympathetic neurons, which are devoid of NHERF-2) that NHERF-2 serves to confine P2Y1Rs (and possibly some mGluRs) to neuronal microdomains which facilitate coupling to M(Kv7)-channels and preclude coupling to Ca2+-channels and Kir(GIRK) K+-channels. If true, this will have major implications for neuronal receptor-ion channel regulation and pharmacology through membrane-linked microdomains.

Amount: £200,185
Funder: The Wellcome Trust
Recipient: University College London

Investigation of endothelial cell ICAM-1 signalling pathways and their role in controlling lymphocyte migration to the CNS. 08 Oct 2009

The endothelial cells of the brain and retina play an important part in the development of neuroinflammatory lesions as they capture leukocytes from the circulation and support transendothelial migration via mechanisms that require induction of outside-in signalling. The cell adhesion molecule ICAM-1 is believed to be a critical molecule in this setting. Our key goals in this project will be to characterise in greater detail the constituents of the proximal ICAM-1 signalling complex in order to define their contribution to propagation of various downstream signalling pathways. We will investigate the induction of signals initiated through ICAM-1 and putative members of the multi-molecular complex with which it associates and how this regulates lymphocyte diapedesis via the paracellular and transcellular routes. This work will extend significantly our understanding of the inflammatory process in the CNS, reveal potential therapeutic targets and address a number of highly topical and gen eric questions facing researchers in the field of leukocyte recruitment.

Amount: £290,139
Funder: The Wellcome Trust
Recipient: University College London

Investigating and targeting monocyte-macrophage cellular effectors in ANCA associated vasculitis 13 Oct 2009

The pathophysiology of ANCA associated vasculitis remains incompletely understood but with the development of novel animal models we have the tools to investigate the key processes initiating and propogating disease. Monocytes/macrophages are frequently found in affected organs. However, the precise role they play and the effect their differental states of activation play in disease are still unclear. This proposal seeks to investigate the role of monocyte/macrophage activation and polarisation in ANCA associated disease, using our autoimmune immunised rat model and patient material. Our hypothesis is that the state of macrophage activation dictates disease phenotype and outcome. As such targeting the key processes in macrophage activation should provide a novel rational therapeutic approach. We will make use of the model we have developed to investigate the genetic predisposition to disease using a series of congenic animals we have generated, the role of signalling pathways in vivo a nd the macrophage phenotype. These results will be compared with patients and the correlation between macrophage activation and disease phenotype will be made.

Amount: £161,126
Funder: The Wellcome Trust
Recipient: University College London

Molecular mechanisms of repression mediated by Groucho family proteins. 06 Oct 2009

Control of gene expression is crucial for the development and survival of all animals. Incorrect gene expression can lead to death or severe abnormalities during development, and in adult life may cause cancer. We will focus on investigating the mechanism of transcriptional repression mediated by the evolutionarily conserved Groucho family of corepressors. Although it is well established that Groucho family proteins interact with many transcription factors to mediate repression, the molecular me chanisms through which they inhibit transcription are not well understood. We propose molecular and genetic approaches to dissect Groucho family corepressor function using Drosophila as a model system. To study the role of oligomerization of Groucho proteins in vivo, we will generate mutations that disrupt oligomerization or replace the native oligomerization domain with an exogenous one, and assay the effects during Drosophila development. We will use a combination of chromatin immunoprecipi tation and sequencing (ChIP-Seq) in a cell culture system to determine whether Groucho is recruited to discrete sites or if it spreads along the chromatin at target genes. We will also use ChIP-Seq to establish if recruitment of Groucho leads to chromatin modifications that may induce target gene repression.

Amount: £214,876
Funder: The Wellcome Trust
Recipient: University College London

Optogenetic manipulation of interneuron function. 08 Oct 2009

Our broad goal is to understand how different populations of interneurons contribute to signal processing and oscillations. We will also apply the tools developed here to interrupt experimental seizure activity. Briefly, we will: (1) apply our insights in interneuron lineage to target expression of channelrhodopsin2 (ChR2) to distinct populations of interneurons, focusing initially on those dependent on the transcription factor Lhx6; (2) complement mouse genetics with an existing AAV-based me thod to achieve conditional expression of ChR2 in mice expressing Cre recombinase under the control of Lhx6, parvalbumin and somatostatin; (3) investigate the roles of Lhx6-, parvalbumin- and somatostatin-positive interneurons in oscillatory synchrony in the hippocampus; (4) understand how long-term plasticity of synaptic transmission between principal cells and interneurons affects signal processing; (5) examine the roles of interneurons in the early stages of cortical visual processing; and (6) test the feasibility of a new anti-epileptic strategy that relies on optical activation of interneurons to interrupt seizures

Amount: £497,024
Funder: The Wellcome Trust
Recipient: University College London

Health of Children Born to Older Mothers. 16 Oct 2009

In view of an almost total absence of data in what is a new social phenomena, the recently held 56th study group of the RCOG has recommended research to investigate the health of children born to older mothers* and in particular those born to mothers over 40 years. Our proposed project aims to:- 1) Provide detailed initial analysis of any effect of increasing maternal age on health outcomes of children, specifically of children* born to mothers of 40 years or older. 2) Investigate if mater nal and paternal parenting experience alters with increasing parental age at birth. The study will utilise data from the 9 month, 3 year and 5 year sweeps of the Millennium Birth Cohort Study (MCS) and the 9 month and 3 year sweeps of the National Evaluation of Sure Start (NESS). Analysis of existing MCS/NESS health outcomes will include growth, neurodevelopment, temperament and behaviour. Information on parent-child, parent-parent relations and parent mental health will also be analysed. Should this initial analysis provide evidence of health threats or benefits, a further more detailed study involving individual assessments will be made. *Please note this study will consider health of all children born to older Mothers NOT just first borns

Amount: £131,279
Funder: The Wellcome Trust
Recipient: University College London

Role of c-jun in damage to neonatal central nervous system. 08 Oct 2009

For scientifically qualified assessors (no more than 200 words) The key research goals will be to: (A) determine the full scale of c-Jun effects on white and grey matter damage following hypoxic-ischemic insult and the functional repair, using neural deletion of floxed jun gene with nestin:.cre recombinase (B) explore, whether c-Jun and/or the JNKs are involved in mediating the synergy between infectious and HI stimuli in mediating the neonatal injury (C) indentify, which of the c-Jun expres sing cells (neurons, astrocytes, oligodendroglia and their precursors, or microglia) act as a pacemaker, in mediating c-Jun dependent, HI neonatal brain damage, using cell-type specific promoters for cre recombinase (syn::cre, gfap::cre, plp::cre, mac1::cre). (D) assess, whether these effects require or do not require JNK-dependent Jun phosphorylation using blood-brain permeable JNK inhibitors SP600125 and DJNKI1, AND whether these inhibitors exhibit additional c-Jun independent effects

Amount: £278,118
Funder: The Wellcome Trust
Recipient: University College London

A new systems approach to therapeutic target selection in degenerative neurological disease. 08 Oct 2009

We will develop a new approach to selecting and verifying novel therapeutic targets in degenerative neurological diseases, piloting this innovation in Parkinson s disease (PD). To this end, we will use dynamic causal models (DCMs) that allow electrophysiological data to be fitted by biologically plausible (conductance-based), neural-mass models of coupled sources. Data will be derived from simultaneous electrophysiological recordings of neuronal network activity at multiple sites in the basal ga nglia and cortex in dopamine-intact (control) rats and 6-hydroxydopamine-lesioned (Parkinsonian) rats, as well as from simultaneous recordings from more restricted sites in patients undergoing functional neurosurgery. Bayesian inversion will then be used to derive estimates of extrinsic parameters (internuclear connectivities) and intrinsic parameters (intranuclear connectivities and conductances) in the DCMs. We will focus on those parameters that are similar in Parkinsonian rodents and PD pati ents, but differ in control rodents and in patients without PD. The importance of candidate differences will then be confirmed using techniques drawn from neuroeconomics and finally targeted in the Parkonsonian rodents to confirm their utility as candidate therapeutic approaches. Importantly, we will not restrict ourselves to the modeling and testing of pharmacological interventions, but also exploit the potential for surgical intervention through lesioning and deep brain stimulation.

Amount: £324,686
Funder: The Wellcome Trust
Recipient: University College London

Pharmacodynamic testing of a prototype cytomegalovirus vaccine in a human challenge model. 01 Oct 2009

In this study, we will use our well characterised model of HCMV pathogenesis to evaluate a novel candidate HCMV vaccine. Our model, developed by studying this virus directly in humans, identifies exploitable vulnerabilities in the viral lifecycle. Specifically, natural immunity protects, albeit less than 100%, against infection, disease requires a high viral load and measurement of viral dynamics provides a biomarker of immune control. We hypothesise that inducing or boosting immune responses before viral challenge will significantly decrease viral replication. Natural immune responses to HCMV are heterogeneous and vary with time after virus challenge. We will control this variability by studying patients at defined times after transplantation and by using fresh lymphocytes in standardised immunological assays. We will achieve this within the rigours of a randomised controlled trial where patients receive vaccine or placebo. They will consent to close follow-up and research nur ses will proactively contact them to obtain samples. This study design will definitely produce extensive natural history data to define immune correlates of protection against HCMV and will validate the immune biomarkers we identified in previous studies. It may also identify a vaccine preparation with the ability to produce some immunological control of CMV replication.

Amount: £131,583
Funder: The Wellcome Trust
Recipient: University College London

Frontostriatal contributions to reward and value processing. 03 Dec 2009

I have designed experiments to compare automatic vs. controlled allocation of attention under conditions of reward, extending recent studies that show alterations in reward and salience processing in Parkinson s disease and frontal lobe lesions. I will record eye movements and behavioural performance, to measure oculomotor capture by salient stimuli, reward-related speeding and biases, and pupillary responses. I will study the differential effects of reward or penalty, reward expectatio n, motivation, timing, and error awareness. I will study healthy individuals, patients with focal lesions, and Parkinson s patients on and off medication. I will test the following hypotheses: 1. Automatic orienting of gaze is modulated by previous reward at a given location in healthy people 2. Ventromedial (vmPFC) patients have impaired reward sensitivity on oculomotor capture paradigm 3. Pupillary responses to rewards and penalties are different in vmPFC patients, DLPFC patients and controls 4. Patients with Parkinson s disease have altered pupillary responses and reward processing 5. vmPFC patients exhibit exaggerated speeding of eye movements toward valued locations 6. In healthy subjects, dopamine agonists increase reward sensitivity As a result, we will test and develop current neurobiological models of reward-driven behaviour to explain the findings in health and in disease.

Amount: £231,790
Funder: The Wellcome Trust
Recipient: University College London

Does glycosylation play a role in adaptation to altered oxygenation?. 03 Dec 2009

Altering oxygen tension results in major adaptive changes in cell phenotype, metabolism and intercellular signalling. Hypoxia inducible factor (HIF) plays a central role in regulating the expression of many genes leading to these adaptive responses. Cells with constitutive HIF activation are a powerful system for investigating how HIF is regulated; previously leading to the recognition of the central role of VHL in HIF ubiquitylation. I will investigate a Chinese hamster ovary (CHO) cell li ne M6.19, which has constitutively activated HIF and harbours a glycosylation defect, analogous to that of the glycosylation mutant, Lec8. Furthermore these mutants display enhanced clonogenic survival in hypoxic conditions. My hypothesis is that glycosylation plays a role in adaptation to altered oxygenation. I aim to: i) Determine the underlying genetic defect in glycosylation in M6.19. ii) Determine which glycosylation gene(s) enhance clonogenic growth in hypoxia, and the role of HIF in this growth adaptation. iii) Investigate whether humans with evidence of an aberrant hypoxic response have mutations in the gene(s) identified in ii). This study will determine whether defective glycosylation leads to an adaptation in growth responses in hypoxia and HIF activation, and may provide new insights for the treatment of cancer, ischemia and renal disease.

Amount: £220,627
Funder: The Wellcome Trust
Recipient: University College London

Trying and Trying and Trying. 07 Oct 2009

Gethan Dick will work with six UCL scientists to write six song poems, each one based on the experience and research of a single scientist. She will then work with six bands, each with their own fans and community of interest, to record the pieces. The songs will be made available for free on CD at a number of venues around London and wider afield, as well as via popular download sites. The final CD will feature text and images from each scientist as a response to the song poem about their work.

Amount: £8,000
Funder: The Wellcome Trust
Recipient: University College London

Revisiting Jebel Moya: Social and biological evolution in south-central Sudan 30 Nov 2009

Description of the project and its relevance Jebel Moya is a combined cemetery and settlement locality in the south-central Sudan which was excavated in the early 20th century by the founder of the Wellcome Trust, Sir Henry Wellcome. The excavation was overseen by different field directors, employing variable excavation, recording and surveying techniques, over the course of the four seasons from January 1911 - April 1914. Plans for further expeditions were first placed on hold by the outbreak of World War I and subsequently ended by Sir Henry's death in 1936. Around a fifth of the estimated 10.4 hectares of deposits were excavated. It still stands as one of the largest British excavations ever undertaken in Africa and one of the largest cemeteries yet excavated in North-East Africa. Overall, 2792 graves were excavated and recorded. A site report was eventually published by Frank Addison in 1949, followed by Ramkrishna Mukherjee, C. Rao and J. Trevor's 1955 analysis of the osteological remains. Limited re-analyses have since been conducted. Rudolf Gerharz (1994), Isabella Caneva (1991) and Joel Irish (2007). Gerharz only utilised the information contained in Addison's 1949 report, particularly the limited Registrar of Graves, to propose a new tentative chronology; he never re-examined any of the excavation records and materials firsthand. Caneva examined a small sample of pottery, curated at the British Museum, from the earliest settlement period. Irish looked at the remaining teeth to test Mukherjee's hypothesis on population heterogeneity. No previous study has re-examined the excavation records and materials to test the validity of the original site reports, and to re-analyse the social implications of the individual burial assemblages and distribution of graves. Furthermore, there has been no attempt to ascertain the probability of conducting radiometric dating on either the osteological or pottery remains, for example using Accelerator Mass Spectrometry (organic materials) and Thermoluminescence (inorganic materials, including pottery). My accompanying paper from Sudan & Nubia (2009) provides a critical overview of the previous publications mentioned above, details my investigations to date, demonstrates that there remains much information to glean from studies of the materials - both skeletal and associated artefacts - and presents preliminary ideas resulting from analysing the grave card data which I am cataloguing into the first ever electronic database for the site. In addition, I am re-examining the excavated grave, settlement and skeletal materials firsthand. The majority of the grave objects' positions are recorded on the grave and anatomical cards, and also in Addison's register of graves. These factors are also being entered into the database under together with data on the strata, attitude of the burials and the condition of the skeletal remains. Furthermore, Dr Kevin MacDonald (Institute of Archaeology, UCL) will be assisting me in the Petrie and British Museums to analyse the associated settlement and grave pottery which is of chronological, spatial and social interest; this has never been comprehensively undertaken before. Moreover, as a result of research presented at the May 2009 Sudanese Archaeological Research Society's conference (British Museum), Professor Abdel Rahman Ali extended an open invitation to visit the National Museum of Sudan (Khartoum) and work on the housed Jebel Moya materials which remain unstudied. The accompanying Table 1, derived from Frank Addison's registrar of graves in his 1949 publication, summarises the distribution of the artefacts from Wellcome's expedition which are primarily held in museums in Cambridge, Khartoum and London.I will also be using the information provided in the archived records on the skeletal and associated grave artefacts to reconstruct behavioural patterns, social structures and population histories. The previous Jebel Moya publications did not adequately integrate different subsets of data, resulting in an incomplete reconstruction of the social and biological transformations which occurred over the millennia. Theoretical modelling of social and biological evolution has advanced considerably in the 60 years since Addison's publication. Mortuary systems can provide information on social variability through analysing spatial dimensions, in comparison with biological and cultural affiliations: human (biological) bodies are loci of identity at individual and group levels, and are situated within the wider culturally constructed landscape. Places were defined and made significant not just by their physical location but also by materiality, including the skeletal remains. There are two additional avenues which my research encompasses: bone chemistry and DNA analyses. The human skeletal and faunal remains are curated in the Duckworth Laboratory, Cambridge, and some are in a condition where bone chemical analyses could be attempted. Such analyses, if successful, would help shed light on marriage patterns and possible migratory patterns by disentangling intra-site and regional relationships, and also provide information on diet. DNA would help test previous hypotheses of genetic closeness in, for example, the proposed elite cemetery from the late first millennium BC. Dr Tamsin O'Connell (Wellcome Trust Research Fellow, MacDonald Institute) and Professor Martin Jones (Department of Archaeology) will be approached for their assistance. A third avenue, that of disease, could be looked at as a possible future research question. Therefore, the interdisciplinary approach which I employ involves interpreting the relationships between mortuary behaviour, memory and material culture by utilising aspects of bioarchaeology (such as radiocarbon dating and isotopic studies), ethnography, Wellcome's expedition records and the archaeological artefacts housed in different museums. The re-examination of the nature of burial distributions will assist in establishing relative chronologies of graves, cultural histories, patterns of pastoral migrations and interactions with the surrounding regions. There is also the possibility of conducting radiometric dating on appropriate skeletal remains in order to arrive at a firmer chronology than what is currently available. These avenues for research are also detailed in the sub-section 'What can be done with the data' in my accompanying paper.

Amount: £8,300
Funder: The Wellcome Trust
Recipient: University College London