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Recipients:
University College London

Results

Age-dependent beneficial effects of PI3-Kinase pathway inactivation on glucose and lipid homeostasis: Mechanisms and therapeutic potential in metabolic disease. 12 Oct 2010

Preliminary data demonstrate that inactivation of PI 3-Kinase p110alpha exerts a beneficial effect on glucose and lipid homeostasis in aged mice. We will dissect the mechanism underlying this effect. We will use constitutive or conditionally p110alpha gene-targeted mice. Muscle and adipose tissue are peripheral tissues with key roles in the regulation of glucose and lipid homeostasis. We will therefore specifically inactivate p110alpha in these tissues to assess their contribution to the phenoty pe of global p110alpha inactivation. To achieve this, we will challenge young and aged p110alpha gene-targeted mice with high-fat feeding followed by comprehensive metabolic phenotyping. In order to elucidate the molecular mechanisms underlying these effects, we will characterise signalling pathway activation and perform transcriptome analysis in insulin-sensitive tissues of these mice. We will also assess the effect of p110alpha inactivation on cellular bioenergetic capacity by studying mitoch ondrial biogenesis and function. The genetic experiments will be complemented by pharmacological inhibition and RNA interference of p110alpha expression in primary cells or established cell lines representative of insulin target cells. Our ultimate aim is to provide proof-of-principle that the p110alpha signalling pathway can be therapeutically targeted in the prevention/treatment of age-dependent obesity and type-2 diabetes and promote healthier ageing.

Amount: £567,855
Funder: The Wellcome Trust
Recipient: University College London

Biomedical Vacation Scholarship. 20 May 2011

Not available

Amount: £35,530
Funder: The Wellcome Trust
Recipient: University College London

Magnetic resonance in biology: A new paradigm for local and global structural analysis of nano-machines 14 Jun 2010

Taken together the overall objective is to characterise the energy landscape and reaction coordinate of HDAC8, especially of the active site, by combining experimental and computational work. The combination of all atom simulations and experimental data will allow us to accurately dissect static and dynamic contributions to the catalytic activity of the enzyme, which is a controversial topic in cutting edge enzyme research [Adamczyk et al. 2011 and Bhabha et al. 2011]. A further aspect is the work on HDAC inhibitors and their interaction with the protein. Detection of the binding mode and elucidations of the inhibitory mechanisms can be achieved by employing the above methods, since the currently available inhibitors mainly interfere with the catalytic site. Work on these inhibitors is done in collaboration with Prof. Charles Marson (UCL Chemistry). Furthermore, our research could provide novel ways to inhibit HDACs. On a methodological level the project could include the development of simple, yet accurate, descriptions of the nuclear-electron interactions that will allow for determining the dynamics and local structural fluctuations of paramagnetic metal sites of proteins. The methodology to be developed during the project will be applicable to elucidate the local structure and dynamics of paramagnetic sites of proteins in general. All parts of the project are clearly interdisciplinary in nature since the main objective is to obtain novel information about bio-nano-machines by combining EPR, NMR and simulations, thus bringing together physical, biological, chemical and computational sciences.

Amount: £153,066
Funder: The Wellcome Trust
Recipient: University College London

Olig2 phosphorylation and the regulation of neural stem cell fate 14 Jun 2010

During development of the central nervous system (CNS), neuroepithelial stem cells (NSCs), residing in the ventricular zones (VZ) of the embryonic brain and spinal cord, divide and differentiate to generate all the neurons and glial cells (astrocytes and oligodendrocytes) of the mature CNS. Typically, neurons form before glia. In the ventral spinal cord, for example, embryonic NSCs of the pMN progenitor domain generate several subtypes of motor neurons (MNs) before switching abruptly (at E12.5 in mouse) to production of oligodendrocyte precursors (OLPs). The OLPs then migrate away from the VZ into all parts of the spinal cord before associating with axons, differentiating into post-mitotic oligodendrocytes (OLs) and synthesizing myelin. We aim to address how NSCs switch at a predetermined time from neuron to glial production ? specifically, the mechanism of the MN-OLP fate switch in the ventral spinal cord. Broadly, the proposed project aims to characterize the role and regulation of the basic helix-loophelix transcription factor Olig2 in the MN-OLP fate-switch. Recent work from the Richardson lab showed that a specific serine residue (S147) in Olig2 is phosphorylated during MN specification and de-phosphorylated at the switch to OLP production. What triggers de-phosphorylation of Olig2 at the time of the MN-OLP switch? The sequence surrounding S147 conforms to a protein kinase-A target site, but the identity of the putative phosphatase responsible for dephosphorylation has not been established. What are the targets and co-factors of Olig2 in its different phosphorylated states that coordinate the temporally-defined switch in NSC fate? And what are the functions of the other predicted Olig2 phosphorylation states? This project will involve three distinct lines of investigation. 1: Characterizing the expression of candidate phosphatases/phosphatase inhibitors in the ventral spinal cord at the time of the MNOLP fate-switch. 2: Identifying target genes of Olig2 in its phosphorylated and de-phosphorylated states. 3: Characterizing the developmental function of another Olig2 phosphorylation site, S263, a potential target of p38 mitogen-activated protein kinase (MAPK).

Amount: £153,066
Funder: The Wellcome Trust
Recipient: University College London

The role of planar cell polarity signalling in spinal neurulation. 18 Jan 2010

The purpose of this project is to determine the role of planar cell polarity (PCP) signalling in mammalian neural tube closure and neural crest migration.

Amount: £13,912
Funder: The Wellcome Trust
Recipient: University College London

Computational neuroscience of social behavior and psychopathology. 10 Jun 2010

My proposed research program seeks to uncover the computational and neural mechanisms supporting social cognition in humans for the purpose of understanding and treating psychopathologies. The work in this proposal will use neuroimaging, computational models, and later computational approaches to genetic substrates to pursue these goals. We will make liberal use of economically framed social interaction games as probes of both normal and pathological cognition. Our guiding hypothesis in this p roposal is that interpersonal games can be used to uncover functional imaging endophenotypes for important psychopathologies that involve social exchange or social modeling. Such endophenotypes can provide new objective measures to identify underlying genetic correlates, differentiate diagnostic categories or criteria, or provide brain-based assays of treatment strategies.

Amount: £3,212,648
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

Molecular regulation of NMDA receptors in midbrain dopaminergic neurones. 01 Jul 2010

The proposed research will investigate the molecular regulation of NMDARs in DA neurones of the substantia nigra. Focussing on the substantia nigra pars compacta, where we have previously shown that the receptors are NR2B and NR2D subtypes, our key goals are to determine: (i) The relative importance of dynamin-dependent and dynamin-independent endocytosis and the role of MAGUK protein - NMDAR subunit interactions in NMDAR regulation at synaptic and extrasynaptic locations. (ii) The importanc e of NR2B and NR2D subunits in the intracellular regulation of synaptic and extra-synaptic NMDARs by kinases and phosphatases. (iii) The effects of NR2D subunit deletion on synaptic receptor density synaptic and on the biophysical properties of synaptic and extrasynaptic NMDAR. (iv) The importance of receptor trafficking and NR2D subunit-containing NMDARs in regulating phasic burst firing of DA neurones. Our approach to distinguish subunit-dependent and subunit-independent mechanisms invo lved in regulating synaptic and extrasynaptic receptors will incorporate high resolution patch-clamp recordings of NMDAR biophysical properties and application of appropriate inhibitors, activators and small interfering peptides to manipulate intracellular signalling molecules.

Amount: £134,873
Funder: The Wellcome Trust
Recipient: University College London

Anti-CD20 therapy in SLE patients: what can we learn from the B cells-repopulation phase. 08 Feb 2010

What is the mechanism of action of B cell depletion in the context of SLE? Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease significantly affecting both the quality of life and life expectancy of suffers. Recently, a number of groups, including our own, have reported the efficacy of treating SLE patients with rituximab, a monoclonal antibody that targets CD20 and leads to significant B cell depletion. While there is growing evidence that B cell depletion has an effect on T c ell activation, the immunological mechanisms related to the therapeutic effect of rituximab remain to be fully elucidated. For this study we propose to investigate the effect of rituximab treatment on subsequently repopulating B cells, and the effect of these B cells on T cell activation and differentiation, in patients who respond to B cell depletion and those who do not. The key goals of this research are to further understanding of how rituximab treatment works and the antibody-independent co ntribution of B cells to SLE.

Amount: £193,664
Funder: The Wellcome Trust
Recipient: University College London

Psychophysical investigation of visual time perception. 18 Feb 2010

Traditionally time perception has been considered the product of a central, supramodal, content-independent cognitive mechanism (Creelman, 1962; Treisman, 1963): a pacemaker generates impulses at a set rate and the duration of an interval is determined by gating the impulses to an accumulator. This model attributes duration distortions to changes in state variables such as arousal. However, recent research (Johnston et al., 2006; Burr et al., 2007; Johnston et al., 2008) has shown that the appar ent duration of a visual stimulus can be compressed at a unique spatial location by a magno-specific visual adaptation (high temporal frequency, low spatial frequency flicker or drifting motion). These observations motivate a new modality-specific approach to the study of time perception. We aim to investigate how the estimated duration of a visual interval can be influenced by its content and by the adaptive state of the visual system. We will study (a) how changes in the temporal tuning charac teristics of the early visual pathway are related to adaptation-induced time distortions; (b) whether time distortions occur in a retinocentric or headcentric frame of reference; (c) what role attention plays in these effects.

Amount: £184,114
Funder: The Wellcome Trust
Recipient: University College London

Cortical pain responses in human infants. 18 Feb 2010

We propose to investigate the development and plasticity of pain processing in the infant human brain. Cortical pain activity in will be measured using nociceptive event related potentials (nERPs) triggered by routine heel lances and other clinically required noxious stimuli. The studies will be performed in preterm infants in intensive care (aged 25-45 postmenstrual weeks) and older infants (aged 3-18 months) in hospital clinics. First we will perform parallel recordings of nERPs and other c urrent physiological pain measures (cortical haemodynamic signals, spinal reflex EMGs and facial expression scores) to establish the accuracy and reliability of nERPs as a measure of infant pain. We will then study the developmental profile of nERPs and test whether they undergo distinct changes in morphology and topography from 25 weeks onwards, consistent with underlying cortical maturation. We also will test whether nERPs can be used more widely to measure pain evoked by other skin-breakin g clinical procedures, such as venepuncture, and in older infants returning to clinic for innoculation. Finally we will test whether nERPs can be used to explore differences in pain processing in children that have experienced repeated intensive care procedures. The results will directly improve pain control in vulnerable paediatric populations.

Amount: £556,885
Funder: The Wellcome Trust
Recipient: University College London

Neural network analysis using a novel multichannel "SMART" neuroprobe. 12 Oct 2012

Neuroscience is entering an exciting period when it will be possible to decipher the neural codes underlying perception and cognition. Novel genetic, molecular, physiological, optical and behavioural approaches will allow the monitoring of activity across ensembles of neurons in behaving rodents, and the manipulation of this activity in a temporally and spatially precise manner. For the first time we will establish causal links between patterns of neural activity and behaviour, and carry out decisive tests of both new and long-standing hypotheses about the computational properties of neural circuits. Members of the consortia seek to understand thepatterns of neural activity underlying sensory, motor and cognitive representations, and the rules by which they are assembled. The core of the present proposal is the development and testing of a major stepchange in silicon-based electrode technology to rapidly accelerate the pace of this work by greatly increasing the simultaneous sampling of extracellular electrical signals within and across multiple brain regions.

Amount: £632,865
Funder: The Wellcome Trust
Recipient: University College London

Neural network analysis using a novel multichannel "SMART" neuroprobe 12 Oct 2012

Neuroscience is entering an exciting period when it will be possible to decipher the neural codes underlying perception and cognition. Novel genetic, molecular, physiological, optical and behavioural approaches will allow the monitoring of activity across ensembles of neurons in behaving rodents, and the manipulation of this activity in a temporally and spatially precise manner. For the first time we will establish causal links between patterns of neural activity and behaviour, and carry out decisive tests of both new and long-standing hypotheses about the computational properties of neural circuits. Members of the consortia seek to understand the patterns of neural activity underlying sensory, motor and cognitive representations, and the rules by which they are assembled. The core of the present proposal is the development and testing of a major stepchange in silicon-based electrode technology to rapidly accelerate the pace of this work by greatly increasing the simultaneous sampling of extracellular electrical signals within and across multiple brain regions.

Amount: £127,475
Funder: The Wellcome Trust
Recipient: University College London

Sainsburys Wellcome Centre for Neural Circuits and Behaviour; Core Grant Award-Part 2. 24 Jun 2013

Neuroscience is entering a new and exciting period in which it will be possible to decipher the neural codes underlying cognition and emotion. Our aim is to position the Sainsbury Wellcome Centre at the heart of this development. The convergence of novel genetic, molecular, physiological, optical and behavioural approaches will enable scientists in the Sainsbury Wellcome Centre to monitor activity across genetically-defined ensembles of neurons in behaving animals, and to manipulate this activity in a temporally and spatially precise manner. This will make it possible for the first time to establish causal links between patterns of neural activity and behaviour, and to allow decisive tests of new theories about the computational properties of neural circuits. The new Centre will use model systems including rodents, and perhaps fish, and will maintain close contact with the fly research conducted at the Centre for Neural Circuits and Behaviour in Oxford. The animal models under consideration are excellent candidates for linking activity in neural circuits with well-defined behaviours. Drawing on current strengths at UCL and with the intention of maximizing collaborations with existing UCL neuroscientists, we envisage focusing on neural circuits underlying visual, motor, spatial, social and affective behaviours, during development and maturity, and for experience-dependent plastic changes. One advantage of such behaviours is that they can be studied across multiple species with different levels of complexity, allowing models with simpler nervous systems such as larva and adult zebrafish to facilitate conceptual development. They also provide a tractable methodological testbed before implementation in more complex systems (e.g. rodents). This blue sky research undertaken in the Centre will address some of the key problems in neuroscience and the basic understanding gained will have the additional benefit of providing the foundations for understanding neurological and psychiatric diseases which are emerging as some of the major epidemics of our time.

Amount: £8,300,000
Funder: The Wellcome Trust
Recipient: University College London

Human Developmental Biology Resource (HDBR): an embryonic and fetal tissue bank for the new genetics technologies. 22 May 2012

The Human Developmental Biology Resource (HDBR; www.hdbr.org) is unique, being the only tissue-bank that provides the international scientific community with access to: -High-quality materials from human embryonic and early fetal stages, including tissues for cell culture, RNAs from sub-organ specific regions and slides for spatial gene expression studies; -An in-house gene expression service (IHGES) that undertakes studies for registered researchers; -A un ique web-based database for dissemination of human gene expression data spatially mapped to 3D models. To develop HDBR activities, and extend them to meet new challenges and opportunities, our key objectives are: -increase sample collection with a focus on intact specimens; -expand the range of IHGES studies, to include studies of non- coding RNAs and alternative spliced products, and to develop techniques to maximize expression information obtained from rare human tissues; -expand the range of materials provided, e.g. RNA, DNA and protein, from specific tissues to support sequencing, transcriptomics and proteomics projects; -interact strategically with large-scale initiatives focusing on human development and disease. By also improving our engagement with current and potential users, we will adapt the HDBR to meet the needs of functional gene characterisation, for the new genetics technologies.

Amount: £725,374
Funder: The Wellcome Trust
Recipient: University College London

Novel multimodality imaging techniques for neurosurgical planning and stereotactic navigation in epilepsy surgery 02 Dec 2011

Successful neurosurgery for epilepsy depends on removing the parts of the brain that give rise to seizures, and avoiding damaging areas undertaking vital functions such as language, movement and vision. Current techniques to direct surgery are based on MRI scans to show brain structure, but do not show areas needed for vital tasks, and do not permit interactive simulations of placement of recording electrodes in the brain.A research group headed by Professor John Duncan at University College London and Dr Sebastien Ourselin of UCL Centre for Medical Image Computing has implemented methods to identify critical areas of brain function, connections and blood vessels and display these in 3D. They plan to develop this system to enable the neurosurgeon to plan the best operative approach for inserting recording electrodes and for planning surgical resections. This information will be made available in the MRI scan guidance system in the operating room so that operations are more precise. They will produce a new system that will result in epilepsy surgery being planned more effectively, resulting in a higher cure rate and fewer complications.

Amount: £523,615
Funder: The Wellcome Trust
Recipient: University College London

Studies of linear ubiquitin and different modes of cell death induction by TNFfamily members in aetiology and treatment of auto-immunity 04 Oct 2011

I. What are the inducers, mechanisms and immunological consequences of proinflammatorycell death when ubiquitin-signalling is perturbed and how can they beinhibited?II. Can type-II auto-immunity be treated by preventing pro-inflammatory cell death and/orits immunological consequences?III. Can we identify auto-immune patients who may benefit from a therapy that preventsnecroptosis and/or its pro-inflammatory consequences?

Amount: £2,654,537
Funder: The Wellcome Trust
Recipient: University College London

A centralized platform for validation of genomic and epigenomic targets from clinical and non-clinical studies. 22 May 2012

Over 1000 associations have recently been identified in over 100 traits and common human diseases using GWAS/EWAS. To further advance this research towards identification of the underlying causal variations for therapeutic targeting, requires follow-up on several levels. In the first instance, the identified associations need to be validated, ideally by an independent method and in additional samples. Secondly, the haplotypes, hepitypes and other genomic intervals in which the associations were found need to be further analysed for functional variations in as many samples as possible. The main objective, therefore, is to establish a centralized high-throughput facility for validation and targeted functional analysis that is directly compatible with next-generation sequencing, the method of choice for downstream processes. We believe that the requested equipment from RainDance Technologies satisfies all the technical requirements for accuracy, sensitivity and specificity. It also curre ntly offers best value with respect to throughput, flexibility and future integration with GCLP settings which is a requirement for clinical and future personalized medicine programmes. Under the guidance of the lead applicant, the experienced UCL Core Facility (UCL Genomics) will operate and maintain the equipment ensuring fair access to the 20 named co-applicants and collaborators and beyond if capacity allows.

Amount: £352,437
Funder: The Wellcome Trust
Recipient: University College London

The Role of Exported Malaria Parasite Proteins in Pathogenesis. 25 Jun 2012

Understanding the molecular mechanism of protein export by the malaria parasite and the role of exported proteins in parasite survival.

Amount: £162,047
Funder: The Wellcome Trust
Recipient: University College London