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Recipients:
University College London

Results

Neurobiology of speech communication:cognition, plasticity and social interactions 19 Apr 2010

Functional imaging studies (PET and fMRI) have revealed that human speech is processed along distinct (though interacting) streams, in ways that are analogous to the functional and anatomical auditory streams seen in animal primate studies. I am proposing a series of studies in which aspects of human speech perception and production are investigated, to identify the neural basis of low level and higher-order control of speech perception, the neural basis of production and perception of speech in different masking contexts, and plasticity and individual differences in speech processing. I am particularly interested in how we can apply these results to the understanding of clinical issues (e.g. aphasic stroke and cochlear implantation), and will address the latter with studies of cochlear implant users and simulations. I also aim to extend this work to consider how the importance of social factors, such as how communicative intent affects the neural regions recruited in addition to those involved in the linguistic processing of speech. This is an attempt to integrate the neurobiology of speech perception and production with themes in social neuroscience, and important link to establish, given the central role of speech as a communication tool.

Amount: £1,184,506
Funder: The Wellcome Trust
Recipient: University College London

Mesenchymal Stromal Cells as Therapeutic Vectors for Metastatic Cancer. 02 Jun 2010

I have shown that activation of mesenchymal stromal cells (MSCs) engineered to deliver TNF-related apoptosis-inducing ligand (TRAIL) eliminates lung metastases when delivered systemically. During the following programme of work, I will improve my understanding of the basic mechanisms of MSC homing to tumours, in vivo tumour cell killing and confirm the most effective form of delivery. I will also delineate an imaging strategy for future translational studies in man. This proposal encompasses thr ee aims with the following specific goals. 1) The first aim will determine the efficacy of different forms of TRAIL expressed on syngeneic and allogeneic MSCs, and shed light on the role of the immune system in tumour cell killing in xenograft and endogenous cancer models closely resembling human disease. 2) The second aim will inform on the mechanism of MSC homing to tumours. The goal is to exploit this knowledge to engineer MSCs to home to tumours in an effective and specific manner. 3) The final aim will define the usefulness of magnetic resonance imaging for the detection and quantification of MSC tumour infiltration for future translational studies of this therapy in humans.

Amount: £1,658,140
Funder: The Wellcome Trust
Recipient: University College London

Spine Specific Targeting of Ion Channels in Striatal Neurons. 24 May 2010

My goal is to understand the cellular and molecular organisation of synaptic inputs onto MSNs in the striatum. First, I will use in vivo viral infection to express light-activated ion channels (channelrhodopsins) in functionally distinct brain areas that project to the striatum. I will use whole-cell recording to measure the physiological properties of MSNs in acute slices from these animals. Filling these neurons with morphological markers and calcium-sensitive dyes will enable me to visualise both dendrites and spines using 2-photon microscopy. I will then trigger synaptic transmission by illuminating channelrhodopsin-containing pre-synaptic inputs at specific dendritic locations. By measuring evoked fluorescence transients and exploiting selective pharmacology, I will determine where on the dendrites different inputs form synapses, and which glutamate receptors contribute to their spine calcium signals. Second, I will determine how these specific sets of glutamate receptors are targ eted to particular postsynaptic locations. I will use molecular approaches, including dominant negative expression constructs and synthetic peptides, to interfere with protein interactions controlling receptor trafficking. Receptor function will be assessed using electrophysiology and imaging, and quantum dot single-particle tracking will be used to investigate the lateral mobility and synaptic targeting of proteins.

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University College London

Revisiting Galton 14 Apr 2010

This application is made to meet the escalating interest in the life and work of Francis Galton, a hugely influential figure in the history of biosciences. It is to fund a creative and challenging 6-month research and development period for 3 artists and 1 curator to delve deeply into the extraordinary archives of Francis Galton housed at UCL. With unprecedented access to Galton's collections of objects and papers, the principal outcome of this period will be the development of 3 separate bodies of artwork and a solid curatorial proposal for the production and public exhibition of this new work, as well as a proposed events programme to surround the exhibition. The latter will involve experts from across many biomedical and other disciplines influenced.by Galton. This work is timed to coincide with the centenary year of Galton's death in 2011 and to be realised alongside other academic and creative efforts at UCL to reassess Galton.

Amount: £23,205
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

Automated high-dimensional outcome prediction in stroke 19 Mar 2010

Stroke is a significant cause of death and disability around the world yet patient outcomes are not improving as fast as those for similar conditions such as heart disease.A major cause is the difficulty in providing targeted care in a patient group with hugely diverse treatment needs. Dr Parashkev Nachev of the UCL Institute of Neurology, London has been given a Translation Award to develop a system for predicting outcomes in order to provide advance information on the optimal treatment for each patient. The system uses automated brain image analysis with high-dimensional computer-aided inference and exploits the finely specialized anatomical architecture of the brain, capturing the relation between the pattern of brain damage and the outcome in the patient with high fidelity. The Translation Award to Dr Nachev will be used to develop the technology to the point of direct clinical application.

Amount: £392,444
Funder: The Wellcome Trust
Recipient: University College London

Biomedical Vacation Scholarship 14 Jun 2010

Not available

Amount: £31,160
Funder: The Wellcome Trust
Recipient: University College London

Value in People Award. 29 Mar 2010

Not available

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

Open access award. 22 Sep 2009

Not available

Amount: £150,000
Funder: The Wellcome Trust
Recipient: University College London

Bugs R Us 01 Oct 2008

The "Bugs R Us" project has been devised to bring the excitement of new developments in microbiology to as wide an audience as possible through a travelling exhibition with a 5-year shelf-life. Human beings are a symbiotic association of mammalian and microbial cells with the latter (the indigenous microbiota) outnumbering the former by a factor of ten. The indigenous microbiota is hugely diverse and consists of more than 2,000 different species which are organised into a variety of communities whose composition varies with the anatomical site. Although some species are able to cause disease, our microbial symbionts collectively exert a number of beneficial effects. Hence they protect us against pathogens, provide up to 10% of our energy requirements, supply a range of vitamins and play a key role in the development of our immune system and mucosal surfaces. Few people are aware of the importance of our indigenous microbiota and, because the populist view is "all microbes are dangerous and must be eliminated", it is important that this unwarranted view of microbes is corrected. By using modern exhibition techniques, talks and seminars we intend to: (i) introduce to the general public the concept that a human being is a symbiosis of mammalian and microbial cells (ii) provide new insights into the nature of the microbial communities that reside on our bodies, (iii) explain how the anatomical site governs the composition of the microbial community residing there (iv) describe what benefits these microbial communities confer on humans.

Amount: £29,375
Funder: The Wellcome Trust
Recipient: University College London

How do separate populations of stem cellsinfluence each other in the visual system of the zebrafish? 29 May 2009

1) To investigate how various retinal inputs influence the growth of the optic tectum. How does a lack of retinal input alter the size, shape, proliferation and cellular organization of the tectum? What are the consequences for tectal proliferation and differentiation when retinal ganglion (RGC) axonal activity is abrogated? How does a lack of retinal input affect the pathways that regulate neurogenesis in the optic tectum? 2) To investigate how signalling between the retina and the tectum controls growth and shifting connections. Is the secreted Sonic hedghog (Shh) protein transmitted along retinal ganglion cell axons to the tectum? How does axonal transport of signalling molecules affect growth and differentiation in the optic tectum?

Amount: £152,244
Funder: The Wellcome Trust
Recipient: University College London

Multimodal interactions in the human brain. 21 Apr 2009

The project will focus on two related scientific questions that seek to understand how the brain processes and relates information coming from different sensory modalities. First, what are the functions and mechanisms of multisensory interactions in the human brain? Second, what is the role of awareness in multimodal processing? I will investigate these questions using a combination of non-invasive neuroimaging approaches such as BOLD contrast fMRI and magnetoencephalography (MEG).

Amount: £152,990
Funder: The Wellcome Trust
Recipient: University College London

Structure and function in the human brain. 21 Apr 2009

This project seeks to understand the relationship between structure and function in the human brain. Specifically, we are interested in two scientific questions (1) what is the nature, if any, of the relationship between local brain structure and neuronal signals associated with cognitive processes (2) what is the nature of the relationship between local spontaneous neuronal activity and neuronal signals associated with cognitive processes? We will investigate these questions by using structural and functional magnetic resonance imaging of the human visual system.

Amount: £152,990
Funder: The Wellcome Trust
Recipient: University College London

Functional architectures in the brain. 02 Jun 2009

Our computational neuroscience programme has progressed at two levels: First, we have had considerable success in modelling observed brain responses using biologically plausible models of neuroimaging data. We can now model fMRI, EEG and MEG responses with neural mass models of distributed networks to estimate population dynamics, synaptic efficacy and receptor function. More importantly, we can compare different models using Bayesian model comparison to test competing hypotheses about underl ying functional architectures. The second line of work addresses the basic constraints under which open, self-organising biological systems like the brain operate. This work has led to a formulation (a free-energy principle), that places the Bayesian brain in the larger context of exchange with the environment. This formulation provides a unified account of action and perception and, within perception, perceptual inference, learning and attention. We would now like to bring these two lines o f work together and use neural mass models of empirical data to identify how the free-energy principle is instantiated in neuronal circuits. We have some clear hypotheses that are related formally to predictive coding theories of perception. We want to test these hypotheses using Bayesian model comparison and Dynamic Causal Models of electromagnetic brain responses.

Amount: £2,477,671
Funder: The Wellcome Trust
Recipient: University College London

Competition for membrane phosphoinositides by different potassium channels?. 09 May 2007

Many ion channels require membrane phosphatidylinositol-4,5-bisphosphate (PIP2) to open. This work addresses a hypothesis that PIP2-activated ion channels might affect each other s activity through competition for available PIP2. This hypothesis follows from the applicants recent observations that, in sympathetic neurons, expressing the inwardly-rectifying potassium channel Kir2.1 (for which PIP2 has a high affinity) reduces currents carried by the endogenously-expressed lower-affinity M(Kv7) p otassium channel and sensitizes the M-channel to other forms of PIP2 sequestration. We aim to test this interaction further to determine whether this hypothesis can be substantiated or whether the interaction results from some other cause such as changes in M-channel expression. We shall measure the interaction using electrophysiological membrane current recording and will assess expression using both electrophysiolgical and immunocytochemical methods. We shall test whether the interaction is a dependent on the amount of Kir2.1 protein and (using mutants) on Kir2.1 affinity for PIP2, and how it is affected by changing the amount of available PIP2. If the hypothesis is substantiated, it will represent a new form of ion channel interaction, with important implications regarding the mobility of PIP2, ion channel localization, and receptor/PIP2-mediated signaling in neurons and other cells.

Amount: £48,489
Funder: The Wellcome Trust
Recipient: University College London

Spike timing-based memory in the hippocampus. 06 Feb 2007

Hippocampal area CA3 is widely considered to function as an autoassociative memory, supporting key aspects of episodic storage and recall, in conjunction with other hippocampal and cortical areas. However, previous accounts of this function fail to address the rich dynamical behaviours exhibited in CA3. We have recently suggested, and experimentally validated, a normative account that predicts the relationship between the dynamical interactions among pyramidal neurons during oscillatory memory recall and the characteristics of the spike-timing dependent synaptic plasticity (STDP) rule governing storage. We now propose to investigate three significant theoretical and experimental extensions to this account. First, we will study a model incorporating spiking rates as well as spiking times. Second, we will consider how STDP rules should optimally match the statistics of input patterns. Third, we will consider how coordinated neural oscillations between hippocampal subregions, and between the hippocampus as a whole and the neocortex, may support aspects of memory consolidation.

Amount: £163,593
Funder: The Wellcome Trust
Recipient: University College London

Molecular dissection of the CFTR gating cycle, combining mathematical tools with experimental biophysics. 09 Nov 2006

CFTR, whose dysfunction causes the disease cystic fibrosis, belongs to the superfamily of ABC proteins, which couple hydrolytic cycles at conserved nucleotide-binding domains (NBDs) to diverse cellular functions. CFTR is unique among ABC proteins in that its transmembrane domains comprise an ion channel. Opening and closing (gating) of the ion-permeation pathway is controlled by ATP binding and hydrolysis at its NBDs. But how are conformational signals, originating at the catalytic site, transmi tted to the channel gate? In alignments of homologous sequences one can discern sets of positions at which amino acid distribution has varied in a concerted way. This correlation in evolutionary space likely reflects conservation of a network of energetically coupled residues that mediates transmission of allosteric signals in individual ABC proteins. We will select coevolving positions as targets for mutagenesis and, using new mathematical tools to analyse single channel activity, we will foll ow how the energetic coupling between pairs of side-chains changes during the gating cycle. Together, these studies will compose a molecular description - in both space (within the protein s structure), and time (along the reaction coordinate of CFTR s functional cycle) of the allosteric coupling mechanism that links CFTR s hydrolytic and gating cycles.

Amount: £288,320
Funder: The Wellcome Trust
Recipient: University College London

Descending Serotonergic Control and Neuropathic Pain. 12 Oct 2006

There is now compelling evidence that the maintenance of pain states is dependent on descending facilitation from the brainstem. This facilitation is in part serotonergic and derived from a subset of neurons located in the rostroventral medulla. Ablation of spinal serotonin attenuates peripheral neuropathic pain states in rats. Our first goal is to establish that the serotonergic pathway is distinct from other descending facilitatory pathways. The second goal is to monitor the dynamics of serot onergic activity in normal and neuropathic rats by measuring i) the evoked and spontaneous activity of superficial dorsal horn projection neurons and ii) the influence of serotonin and serotonin receptor antagonists on projection neuron activity. The third related goal will be to monitor changes in serotonergic tone in the dorsal horn of neuropathic rats using microdialysis. Finally, we will apply this data to our research into the activity of the 5HT pathway in mouse models of pancreatic and bone cancer pain where the regulation of 5HT synthesis in the rostroventral medulla appears to be directly correlated with the appearance of the pain state.

Amount: £366,903
Funder: The Wellcome Trust
Recipient: University College London

The Relationship of Visual Perception and Perceptual Binding to Single Cell Activity. 19 Sep 2007

The research project will be to record from the pulvinar nucleus of the thalamus in alert animal models trained to perform a classical conjunction search' task, where the target item is a unique combination of two features (e.g. blue & tilted amidst a display of orange tilted and blue vertical bars, say). Correct performance of the task demonstrates that the target features blue' and tilted' have been correctly bound to each other (and/or to the corresponding object location in space). Individual pulvinar neurons are notexpected to demonstrate pronounced selectivity for either colour, or orientation (although, if they do, the course of the experiment and its validity are not affected). The single unit response, local field potential (LFP - recorded from the same electrode) and the spike-LFP coherence will be monitored while either a target or nontarget is present within the receptive field. The task difficulty will be varied while recording at the same site, inorder to obtain a measure of the neural-behavioural correlate in terms of % correct performance.

Amount: £15,547
Funder: The Wellcome Trust
Recipient: University College London

Pregnancy, antiretroviral therapy and HIV disease progression in women. 05 Dec 2006

Better understanding of the complex relationships between pregnancy, HIV disease progression and antiretroviral therapy (ART) used to prevent mother-to-child transmission (PMTCT) and/or to delay disease progression is essential to understand the longer term risks of pregnancy for HIV infected women. It is unknown whether a potential synergy between HIV and pregnancy-related immune changes, coupled with an indirect effect of less aggressive therapeutic management in pregnancy, could negatively af fect HIV disease progression in the years following delivery. Women with and without pregnancies since their HIV diagnosis will be compared to quantify the impact of pregnancy on HIV disease progression, through data linkage between the UK National Study on HIV in Pregnancy and Childbirth and the UK Collaborative HIV Cohort Study. An individual patient data meta-analysis of data from this and other European cohorts will be performed. A new prospective cohort study of Ukrainian HIV-infected wom en, recruited postnatally but identified antenatally/intrapartum will be established to estimate the impact of exposure to abbreviated antenatal ART for PMTCT, treatment and co-infection on the course of HIV infection and prognostic markers of HIV disease progression in this resource-poor setting. Results will guide the treatment and management of HIV-infected women during and after pregnancy.

Amount: £436,495
Funder: The Wellcome Trust
Recipient: University College London