- Total grants
- Total funders
- Total recipients
- Earliest award date
- 06 Feb 2007
- Latest award date
- 19 Dec 2007
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Objective measurements of physical activity in primary school children in UK Millineum Cohort 19 Dec 2007
We will measure physical activity using accelerometers at age 7 and again at age 9 in the ethnically diverse UK Millennium Cohort Study and, in a random sample, establish how activity varies by season of year by measuring activity on three further occasions, each a season apart. Two calibration studies will be carried out in 7 and 9 year olds to determine cut-offs defining moderate and vigorous physical activity (MVPA). We hypothesise that MVPA will be inversely related to fat mass, but that this may vary according to sex and ethnic group. We will test the following hypotheses: that children who are physically active have lower fat mass and less central fat; that children who are overweight or obese by school age are less active at primary school; that more active children have higher subsequent self esteem; that children who skip breakfast, drink sugary drinks or eat high energy snacks have higher fat mass and more centrally distributed fat at age 7; and that Body Mass Index is a not reliable indicator of fat mass at this age.
We have recently discovered that cytoplasmic tRNAs can be transported back into the nucleus in human cells, a process called retrograde tRNA transport, and that this process is exploited by HIV-1 to infect non dividing cells. We hypothesize that specific cellular factors drive nuclear import of tRNAs in human cells and that HIV-1 nuclear import is also promoted by the same factors. We aim to investigate this by: 1) Isolating the cellular factors driving tRNA nuclear import by chromatographic an d genetic approaches. 2) Disrupting their function by stable knock down or generation of dominant-negative mutants and examine the impact on HIV-1 infection in dividing and non-dividing cells. 3) Mapping the viral determinants for incorporation of and interaction with tRNAs with nuclear import activity by the generation of HIV-1 and murine leukaemia virus (MLV) mutants.
The role of the mitochondrial endogenous inhibitor, IF-1, in ischaemia and reperfusion injury in the heart. 15 Oct 2007
Mitochondrial dysfunction is central to the pathogenesis of a number of major diseases. At the heart of this proposal is the principle that a decreased mitochondrial membrane potential causes the mitochondrial ATP synthase to operate in 'reverse', switching mitochondria from ATP producers to consumers. The best characterized example of this mechanism is the response of cardiac muscle to ischaemic injury, in which mitochondrial dysfunction defines the borderline between reversible and irreversibl e injury. ATPase activity is modulated by the endogenous inhibitor protein, IF-1, which should be protective by conserving cellular ATP at the expense of allowing the potential to dissipate. As ATP depletion and changes in mitochondrial membrane potential play key roles in defining the progression of ischaemic injury, understanding the processes by which they are regulated is key to understanding the progression of ischaemic injury and so defining therapeutic targets. The proposed experimental w ork will therefore explore the impact of overexpression or suppression (siRNA) of IF-1 protein levels on the evolution of ischaemic injury in cardiac cells and cell lines. Mitochondrial state also defines the pathways of cell death, and so the work will also identify the impact of IF-1 on cell fate.
Identification and characterization of novel regulators of mammalian cell morphogenesis using RNAi. 12 Dec 2007
Actin filaments form a dynamic skeleton beneath the plasma membrane of animal cells and are crucial for cell morphogenesis. As a result, defects in cytokeletal regulation contribute to a variety of human diseases. Until recently, however, efforts to identify the mammalian genes involved were limited by the difficulties of studying essential genes in whole animals, so the set of genes currently investigated are a biased group. But the sequencing of several animal genomes and the discovery of ds RNA-mediated interference (RNAi) has enabled unbiased screens to identify known and novel genes involved. In the past year, the Baum lab has used genomic information to generate a human siRNA library targeting all known conserved actin regulators, and they have performed a genome-wide RNAi screen in Drosophila cell culture for novel actin regulators. Here, I propose to use RNAi to perform a comparative functional analysis of the complete set of actin regulators in fly and mammalian cell culture. I will then characterize several novel genes that play a conserved role in the regulation of the actin cytoskeleton. This will be one of the first studies to use unbiased loss of function genetics to identify genes involved in the regulation of animal cell form.
The study of how hippocampal place cells and entorhinal grid cells represent place largely underpins the cognitive neuroscience of navigation and memory. Previous studies, however, used unrealistic environments in the form of small, two-dimensional enclosures, whereas the real world has an extended, complex, three-dimensional (3-d) structure that complicates navigational processes like path integration. This project will study encoding of 3-d space by manipulating both suface elevation (using sl oped environments including a ramp and a helix) and movement through 3-d, volumetric space, to explore the questions of (1) whether planar place fields and grids are calibrated according to the environment's surface or to the horizontal plane, and (2) of whether in three dimensions, place fields are actually globular and grids are actually lattices in 3-d space. Some of these experiments will exploit newly emerging telemetric technology, which enables recording in spaces too complex for a teth ered animal to explore. The main hypothesis is that the vertical dimension is indeed encoded, but differently from the horizontal ones. The results will not only expand our understanding of the place representation but also shed light on human 3-d navigation processes in aviation, astronautics and undersea exploration, as well as design of artificial navigating agents.
The human visuomotor grasping circuit: distinct contribution of parietal and frontal areas and their interactions with the primary motor cortex. 10 Oct 2007
Object grasping and manipulation involve a complex parieto-frontal cortical network including the anterior intraparietal area (AIP), the ventral premotor cortex (PMv) and the primary motor cortex (M1). However, the precise operations performed by AIP and PMv and both their lateralization and temporal coupling are still unclear. In addition, how grasp-related information, processed in PMv, is conveyed to M1 to generate an appropriate motor command remains unknown. New methods of assessing activi ty and cortico-cortical connectivity in this visuomotor grasping circuit now make it possible to investigate (1) the nature and timing of the interactions between PMv and M1 to visually guided grasping movements (2) the distinct contributions of AIP and PMv to these movements and (3) how contralateral and ipsilateral cortical areas belonging to the visuomotor grasp circuit interact with each other. We propose to use a novel paired-pulse transcranial magnetic stimulation (TMS) to investigate th e functional connectivity between PMv and M1 during different categories of hand movements or action observation and to document the influence of AIP on these PMv-M1 connections. In addition, we will use magnetoencephalography (MEG) to study the lateralization and timing of those interactions to understand the spatio-temporal flow of grasp-related information within the visuomotor circuit.
'The importance of medical history: Transnational and cross-cultural perspectives on a multi-faceted discipline' conference to be held in Mumbai, India from 15th to 17th November 2007. 17 Oct 2007
The importance of medical history: Trans-national and cross-cultural perspectives on a multi-faceted discipline The proposed meeting will be the first of its type in the South Asian sub-continent - dealing with the important questions of historical method and historiography, from trans-national and cross-disciplinary perspectives; it will allow the audience access to a plethora of perspectives on how to study HOM. The projected audience will be university and college teaching, research and administrative staff of all grades, we well as undergraduate and post-graduate students, doctors, print and TV journalists, and independent researchers. A number of well-known scholars have agreed to attend the meeting, as they acknowledge the usefulness of an event like this in popularising HOM in an important education centre in Asia. These academics, who are attached to a number of Wellcome Trust-funded units, will draw upon an important item of their research - dealing with Europe, North America, Asia and further afield - to develop trans-national perspectives of how to study HOM. This meeting will engender a lot of discussion, which is critically important for an endeavour that seeks to provide new insights to post-and under-graduate teachers about important international developments in the discipline, and the most effective ways of teaching and carrying out research. Themes to be covered: History of pharmacology; Anatomy; Global trade and medicine; Medical genetics and gender; Medicine in the early modern period; Public health in 19th and 20th centuries; Global health programmes and disease eradication; War and medicine; International perspectives on rabies; Scottish doctors and British empire; Obstetrics and surgery; Cross-disciplinary perspectives on leprosy and empire; Hospitals; Medicine and 'witchcraft' in the early modern period; Healthcare in colonial Mumbai/India; Health of industrial labour; Oral histories of contemporary medicine and biological science; History of medical practice and multiple meanings of health.
Neurogenesis in the mouse telencephalon. 03 May 2007
The molecular mechanisms regulating neuronal development in the telencephalon are largely unknown. The aims of the project are twofold: (1) examine the role of the transcription factor NKX2.1 in immature postmitotic neurons of the telencephalon and (2) identify genes involved in the development of neuronal populations in the embryonic subcortical telencephalon.
Development of biological motion processing in typically developing children and adolescents and in autism spectrum disorder. 03 May 2007
1. To investigate the nature of biological motion processing in healthy adults. 2. To investigate the neurocognitive development of biological motion processing in typically developing adolescents. 3. To investigate the neurocognitive development of biological motion processing in autism spectrum disorders.
Correlations in Neural Networks. 03 May 2007
A computation in a neural network is a transformation from activity on a set of input fibres to activity on a set of output fibres. Computations depend on the properties of individual neurons in a network and on the connectivity between the neurons. Relating a computation to the connectivity and properties of neurons is one of the central problems in neuroscience. A well known property of neurons is that they are noisy. Recorded activity patterns never repeat, even for the same stimulus. Computations involving neurons in which the noise is uncorrelated have been studied extensively [Averbeck et al., 2006]. By assuming that noise is uncorrelated, the mean activity of a network can be studied and related directly to the computation of interest. This assumption simplifies the study of computation. In the brain, however, noise is correlated. Specifically, the fluctuations in the activity of one neuron about its average are correlated with the fluctuations of other neurons. These noise correlations can increase or decrease the amount of information encoded by a population of neurons [Averbeck et al., 2006]. Correlations may also effect computational strategies of neural networks, learning, and the formation of memories [Roudi and Latham, 2007, Ma et al., 2006] . Correlations are also important as a measure of network structure in experiments [Abeles, 1991]. We will study correlations in neural networks, how they affect the amount of information encoded by a network and the computations it performs. We will relate the connectivity of a network to noise correlations. In this way we will attempt to relate computations to the connectivity and properties of neurons.
Properties of oligodendrocyte precursor cells. 03 May 2007
This project will investigate the properties of oligodendrocyte precursor cells, examining in particular their response to neurotransmitters, their voltage-gated currents, their role in myelination, their developmental fate and their effects on nearby neurons.
The proposed PhD will utilise temporally rich auditory and visual stimuli to obtain a better understanding of the constraints placed upon human perception of temporal correspondence between multisensory inputs, and the impact of this on multisensory integration and on neural responses for both heteromodal and modality-specific brain regions. Psychophysical techniques will be used to investigate how temporal information transmitted in one modality may be used to parse matching stimuli from multiple trains in another modality. fMRI and MEG will identify brain regions and responses involved in such processes.
Characterising the key role played by the sodium/ proton exchanger NHE8 in endosomal protein sorting. 10 Jul 2007
Protein sorting at the multivesicular body (MVB) is essential for many processes including growth factor down regulation and antigen presentation. In addition, many viruses including the human immunodeficiency virus (HIV) exploit the MVB sorting machinery during assembly and release. MVBs are formed by the inward budding of the endosomal membrane to form internal vesicles, and proteins sorted into these vesicles are destined for the lumen of the lysosome. My preliminary results suggest that N HE8 is the mammalian orthologue of Nhx1p, a sodium/ proton exchanger essential for MVB protein sorting in yeast. NHE8 is the first sodium/ proton exchanger implicated in MVB sorting in mammalian cells. This proposal focuses on the characterisation of NHE8 and its role in mammalian cell endosomal protein trafficking. As well as a further investigation of the role of NHE8 in MVB sorting using protein degradation and HIV budding assays, we will study the pH inside MVBs in cells depleted for NHE8 by siRNA. The localisation, trafficking and regulation of NHE8 will also be studied.
I will establish a novel system to study learning-associated neural plasticity that exploits the many advantages of the larval zebrafish model. I will perform live imaging of circuit activity associated with a complex behaviour. This will enable learning-associated changes in neural responses to be followed in real time and integration of changes in behavioural outputs and circuit physiology to be linked to the molecular-cellular properties of identifiable neurons. Specific goals: 1) I will develop an appetitive, associative learning paradigm that utilises a novel method to non-invasively deliver reinforcing stimuli. Specific visual cues will be presented to immobilised larvae, shortly followed by light-stimulated activation of dopaminergic reward circuitry. 2) I will use high-resolution functional imaging to quantify stimulus-evoked neuronal activity at loci throughout the larval brain before, during and after training. This will resolve the spatio-temporal sequence o f changes in neuronal response properties underlying the acquisition of the learned behaviour. 3) I will begin to elucidate how the different neurons comprising the functional circuit interact during learning. How are cells showing related changes in activity interconnected? Which neurons display functional plasticity and represent loci of memory storage? What are the morphological and molecular-genetic changes underlying functional plasticity?
Integrating economic models and cognitive neuroscience: the neurobiology of human decision-making. 30 May 2007
Economic utility theory assumes that people have a stable representation of their own utility leading them to act in order to maximize a return based upon an application of algorithmic rules [1, 2]. My research proposal challenges this view. I propose to test the hypothesis that the neural representation of utility is a dynamic process shaped by emotion, cognitive limitation and contextual information. Little is known how these processes are integrated in the brain and how they affect the con struction of the preference. I will test the hypothesis that the neural representation of utility is not absolute but relative to a reference point that changes according the subject s perception of the available options. For example I will show how the perception of the reference point is influenced by the subject s position in the economic transaction, by his/her emotional states, past memories and future expectations. The final goal of this project is to use this empirical information to re fine and constrain the current utility theory.
Interaction of enterohaemorrhagic Escherichia coli with human intestinal epithelium under polarised intestinal simulated conditions. 05 Jul 2007
Enterohaemorrhagic Escherichia coli (EHEC) are food-borne pathogens that cause diarrhoea, haemorrhagic colitis and severe systemic complications such as haemolytic uraemic syndrome (HUS). Systemic disease is associated with Shiga toxin production (Stx), which is cytotoxic to microvascular endothelium. The mode of translocation of Stx across human intestinal epithelium, which lacks Stx receptors, is unknown, and progress has been hampered by the absence of a suitable model for experimental study. We have established an experimental system based on in vitro organ culture (IVOC) of human intestinal mucosa with EHEC O157:H7, demonstrated ex vivo A/E lesion formation, identified patterns of colonisation and shown a direct effect of Stx2 on human intestinal epithelium. Experimental models use high oxygen levels to maintain cell viability, but this is unlike the intestinal milieu. We have combined cell culture and IVOC techniques with a modified Snapwell Ussing chamber to generate a polarised , intestinal micro-simulator (PIMS) which mimics the conditions in the human gut. In this application we propose to use this system to study the influence of apically restricted experimentation and microaerophilic conditions on EHEC adherence, to determine the major pathway of lesion formation, to identify the virulence gene response, and to investigate bacterial factors affecting Stx translocation.
Behavioural and neurophysiological effects of dopamine antagonists in the caudate nucleus and prefrontal cortex. 28 Jun 2007
We intend to further our understanding of the function of dorsal-lateral prefrontal cortex, and the basal ganglia structure to which it has direct projections, the caudate nucleus. It has been suggested that prefrontal cortex and the basal ganglia have complementary roles in behaviour, with prefrontal cortex playing the dominant role in behaviours requiring cognitive control, and the basal ganglia playing the dominant role in behaviours that proceed automatically, via habit. While evidence has been gathered in support of this hypothesis, conflicting evidence also exists. We will, therefore, utilize a task which differentially taps either controlled or automatic behaviour, and carry out both simultaneous neurophysiology recordings in both areas, and manipulation of the dopamine system, which plays an important role in the physiology of both frontal cortex and the basal ganglia, and has also been linked to both of these behaviours. By examining physiological responses in each area, t he behavioural effects of manipulations of the dopamine system in each area, and the effect of the dopamine manipulations on the physiological responses, we can gain a deeper knowledge of the important function of these frontal brain areas.
New Medical Papyri from Oxyrhynchus. 08 Mar 2007
Thanks to a grant by the Wellcome Trust, a preliminary survey of 180 unpublished papyri provisionally identified as medical in content in the Oxyrhynchus Collection has been completed. Based on evaluations of the extent, interest and difficulty of these papyrus texts, this project will produce scholarly editions of about fifty of the medical papyri that have been examined, all dating from the first to the sixth centuries AD. These are collected and briefly described in Appendix 1. Of these, t hirteen fragments have been identified as containing works of known authors, namely the Hippocratics, Dioscorides and Galen. The remaining papyri preserve a wide range of medical texts that have been lost in the medieval manuscript tradition. These texts, which were read and used by a wealthy Hellenized community in Roman Egypt, will contribute in a variety of ways to our knowledge of the theory and practice of medicine in antiquity. In bringing to light this hitherto unknown material, the pr oject will dramatically supplement the 270 medical papyri from Egypt published in the last hundred years, of which only about two dozen derive from Oxyrhynchus.