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Recipients:
University College London

Results

Elucidating the regulation of homologue disjunction in mammalian oocytes. 07 Jun 2007

First meiotic division errors in human oocytes underlie 80-90% of aneuploidies and are acutely susceptible to aging. During mammalian mitosis, aneuploidy is averted by a spindle assembly checkpoint (SAC) which delays anaphase-onset until chromosomes have completed proper alignment or congressed. Mitotic congression is orchestrated by the microtubule motor CENP-E which establishes chromosome-microtubule attachments and facilitates chromosomal movement towards the spindle equator. Notably, reduced SAC transcripts and congression failure are features of aged human oocytes. We hypothesise that dysfunction of the SAC and of CENP-E contribute to age-related aneuploidy. Although the SAC is required for averting aneuploidy in mammalian oocytes (Homer et al., 2005, Genes Dev.), no oocyte molecular system has been functionally related either to congression or to human female aging. As a first step towards exploring the molecular basis for congression failure, we will use high-resolution fluore scence imaging and gene-silencing to examine the requirement of CENP-E for chromosome alignment in mouse oocytes. We will also determine if the SAC in human oocytes succumbs with aging by measuring SAC protein levels and evaluating SAC integrity in oocytes from women of differing ages. This project will greatly expand our understanding of human aneugenesis and pave the way for new fertility-related therapies.

Amount: £684,139
Funder: The Wellcome Trust
Recipient: University College London

Prefrontal and hippocampal contributions to goal coding during navigation. 13 Dec 2006

Keeping track of goals is vitally important for survival, particularly if the goals are locations in the world where we can find food or shelter. In order to navigate to these goals we need to know where we are and where the goals are. Whereas considerable evidence suggests that the hippocampus provides a signal for our current location, the neural coding of goal-relevant information is much less certain. Recent evidence suggests that the medial prefrontal cortex may represent goal locations, bu t how it interacts with the hippocampus to achieve this remains an open question. Moreover, the mechanism by which goals are represented in different environmental contexts has not been explored. The proposed research will use single neuron recording, reversible brain inactivation and behaviour in rats to explore how hippocampal and prefrontal regions interact in producing spatially guided behaviour. Different spatial tasks will be used to assess how the medial prefrontal cells signal informatio n about goal locations, allow the animal to switch between navigation strategies and provide a feedback signal to the hippocampus about future goals. The results will enhance our understanding of how the hippocampus and prefrontal cortex contribute individually, and through functional interactions, to the representation of goal-related information.

Amount: £230,410
Funder: The Wellcome Trust
Recipient: University College London

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.

Amount: £145,950
Funder: The Wellcome Trust
Recipient: University College London

Ion channels related to neutrophil NADPH oxidase. 22 Feb 2007

The neutrophil leukocyte is the primary cell involved in the killing and digestion of bacteria and fungi. The NADPH oxidase is an electron transport chain in the wall of the phagocytic vacuole which is essential for the killing of the contained microbe, and when defective, causes severe immunodeficiency. The oxidase passes electrons onto O2 to produce reactive oxygen species (ROS) and these ROS were thought to be responsible for microbial killing. We have shown that this is not the case and tha t the microbes are killed by granule enzymes released into the vacuole from cytoplasmic granules, and that the oxidase activates these enzymes by altering the pH and ionic composition in the vacuole. The ion fluxes are driven by the requirement to compensate the charge generated across the phagosomal membrane by electron transport which was thought to be accomplished by H+ flux through proton channels. K+ flux through BKCa-like channels is essential for oxidase activity, and consequently, microb ial killing and Cl- fluxes compensate most of the charge. In addition Na+/H+ exchange is important for the regulation of pH. We propose to characterise these ion channels, and to elucidate the mechanisms underlying the coupling of these processes to the oxidase.

Amount: £778,157
Funder: The Wellcome Trust
Recipient: University College London

Epigenomics of common disease. 31 Aug 2007

The major histocompatibility complex (MHC) and leukocyte receptor complex (LRC) are the two most polymorphic immune loci in the human genome. Both are associated with multiple disease pathologies including most if not all autoimmune diseases. As part of the MHC and LRC Haplotype projects, we have generated the only multi-Mb single haplotype sequences in the human genome, comprehensive gene and variation maps, high-resolution (1.6 kb) and population-specific linkage disequilibrium maps and a first generation of MHC and HLA allele tag SNPs. Building on this existing resource, the following projects are proposed: (1) MHC Haplotype Project, (2) HLA tagSNPs; (3) Reconstructio of the ancestral MHC haplotype sequence in Europeans; (4) LREC Haplotype Project, and (5) Identification of MHC/LRC tans-acting variants.

Amount: £1,051,000
Funder: The Wellcome Trust
Recipient: University College London

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.

Amount: £233,034
Funder: The Wellcome Trust
Recipient: University College London

The role of VAP in ER-plasma membrane bridges. 16 May 2007

We will study how the major yeast homologue of VAP (Scs2) plays a critical role in bridging from the ER to the plasma membrane (PM). The most important goal of the project is to identify the PM receptor for Scs2, likely to be an important discovery, because it binds human VAP, indicating conservation throughout eukaryotes. Our current data shows that this receptor is a PM component concentrated at sites of polarised growth (such as bud-tips) by the polarisome, but the receptor is not a previousl y defined polarisome component. Using a simple candidate approach (testing all proteins annotated to localise to the bud-tip, and all suggested interactors of Scs2) we have not found the PM receptor. Here, we will carry out a series of experimental approaches of ever-increasing complexity to identify the PM receptor of Scs2. In addition, we will use mutants made in our lab, in which ER-PM contacts are critically defective, to study how lack of ER-PM contact affects specific cellular activities. Finally, if work identifying the PM receptor of Scs2 is successful and time allows, we will apply similar techniques to discovering the interactors of Ice2, another ER protein involved in ER-PM bridges.

Amount: £208,133
Funder: The Wellcome Trust
Recipient: University College London

Engineered derivatives of Hepatocyte Growth Factor in the prevention and treatment of liver disease. 22 Feb 2007

In experimental systems Hepatocyte Growth Factor/scatter factor induces hepatocyte proliferation and prevents apoptosis; in animal models (HGF/sf) can prevent and reverse acute and chronic liver damage. Native HGF/sf is a large complex protein; we have engineered truncated forms which are smaller, and potentially much more attractive molecules to develop for therapeutic purposes, reflecting their less complex tertiary structure and ease of production. We shall therefore characterise their effe cts in two sets of studies. Firstly we will assess the activity of wild-type and engineered forms of hgf/sf on human liver cells in order to confirm that they elicit the same biological responses as they do on rodent cells, and identify the most active engineered form. Secondly we will explore the activity of the proteins in established and validated pre-clinical models of (i) acute liver failure, (ii) chronic, progressive liver disease and, (iii) survival and recovery from large surgical resec tion. The two sets of studies should provide the data necessary and sufficient for subsequent clinical studies in patients with acute liver failure, advanced cirrhosis and in patients undergoing large liver surgery, opening the prospect of taking hgf/sf into the clinic.

Amount: £221,744
Funder: The Wellcome Trust
Recipient: University College London

Regulation of Nav1.7 function. 12 Oct 2006

Gene knock-out studies have shown that the voltage-gated sodium channel Nav1.7 plays an essential role in inflammatory pain and noxious mechanosensation. Human heritable inflammatory pain conditions have also been mapped to gain-of-function mutations in Nav1.7. A range of inflammatory mediators (e.g. NGF, carrageenan, formalin) acting through different second messenger systems all require Nav1.7 to alter pain thresholds in the periphery by unknown mechanisms. We will investigate how inflammat ory mediators alter Nav1.7 activity and neuronal excitability in the hope of finding new routes to interfere with Nav1.7 function. To do this we will study epitope-tagged and fluorescent forms of a mutated (TTX-resistant) Nav1.7 expressed in native sensory neurons lacking other TTX-resistant channels. We will investigate the effects of inflammatory mediators on Nav1.7 function and expression using electrophysiological and trafficking assays. The major role of Nav1.7 in noxious mechanosensation suggests that Nav1.7 could be part of macro-molecular complex in nerve terminals that controls pain thresholds. We will identify proteins interacting with Nav1.7 using a yeast-2-hybrid screen employing an excellent DRG-derived yeast library and investigate the role of validated accessory proteins on Nav1.7 trafficking, and function as well as their possible contribution to mechanosensation.

Amount: £370,877
Funder: The Wellcome Trust
Recipient: University College London

Probing ribosome-nascent chain complexes by NMR spectroscopy and molecular dynamics. 29 Aug 2008

Protein synthesis occurs on ribosomes within all living organisms. The newly synthesized 'nascent chain' emerges from the ribosome one amino acid at a time and explores conformations that eventually lead to its folded structure. This project aims to use structural methods, in particular NMR spectroscopy combined with molecular dynamics simulations to determine structures of emerging nascent chains on their parent ribosomes. Biochemical/biophysical studies have shown that nascent chains can obtain native-like structure on their ribosomes and display activity. We have shown [e.g. 1 ,2] that NMR can uniquely provide structure and dynamics of ribosome nascent chain complexes (RNCs), allowing monitoring the emergence of folded structure. Among the RNCs to be considered here will be the biosynthesis of a disease-associated intrinsically disordered proteins (lOPs). We will answer questions such as how they avoid aggregation/degradation, what conformations are sampled on the pathway, how these differ from those in isolated solution, whether molecular chaperones interact with them, and whether protein targets of these proteins can interact with them before their ribosomal release. Protein conformational diseases include a range of degenerative disorders in which specific peptides or proteins - often lOPs - misfold and aberrantly self-assemble, often in the form of amyloid fibrils. These include Alzheimer's, Parkinson's, and Huntington's diseases. a-synuclein is a well-studied and increasingly prominent protein, the aggregation of which is linked to the pathogenesis of Parkinson's disease. Indeed, a-synuclein is the major component of Lewy bodies, the protein-rich aggregates found post-mortem in the brains of patients suffering from Parkinson's disease or a number of related diseases. By preparing a-synuclein-RNCs, high-resolution snapshots of the conformational properties sampled by asyn as it is synthesized on the ribosome will be obtained as well as it's interactions with the molecular chaperone, Trigger Factor (TF). Such structural data will be combined with novel MD simulations to provide a detailed structural/dynamical information the ensemble of structures sampled during the progressive emergence of the nascent chain and it's interactions with the ribosome. Additionally, the pathological conversion of misfolded proteins into cytotoxic species is modulated by interactions with several proteins, among them molecular chaperones such as the Trigger Factor (TF}, which will also be studied. This work will provide detailed insights into protein folding at the level of synthesis and will have applications to understanding protein misfolding and its links to biology and the onset of disease.

Amount: £148,911
Funder: The Wellcome Trust
Recipient: University College London

Inhibitory processes in human voluntary action. 17 Apr 2008

The phenomenon of the conscious intention to act is an elusive but interesting aspect of cognition. Actions can be classified as being either stimulus driven or voluntary (Goldberg, 1985). In this context, stimulus driven actions are those that are done in response to an external stimulus. This external stimulus, through an association however arbitrary, unequivocally specifies the movement to be done. Voluntary actions, on the other hand, do not appear to be elicited by any obvious external stimulus. Instead, they arise as a result of the integration of many different sources of information. (Cunnington et al., 2002, Haggard, 2008). According to one recent model, three main components characterise voluntary action (Brass and Haggard, 2008). These are decisions regarding not only the identity (what) and the timing (when) of the action, plus a final check that allows withholding a prepared action (whether decision). This final ?veto? or Intentional Inhibition (II) would be important not only as a self-control mechanism, but also in situations where the task environment has changed. As actions are planned with some anticipation, it is reasonable to expect an online checking mechanism to be advantageous for flexible and appropriate behaviour. Experimental paradigms designed to address voluntary action are very often subject to criticism. Because experiments should be reproducible and interpretable, they tend to be simple, artificial in nature and of a low ecological value (Libet et al., 1983, Haggard and Eimer, 1999, Lafargue and Duffau, 2008). A genuine ?urge? to perform an action is hard to generate in the laboratory environment. Objective methods for studying intentions and convincing measures of the subjective experience of intention are thus relatively scarce. Increasing interest has arisen in the potential mechanisms for II, but in order to experimentally address II, one needs to achieve four things: - generate the urge to perform a movement, - induce participants to prepare to make the movement - allow them to choose to refrain from doing the movement at the very last moment, and - have an appropriate measure of this inhibition. By definition, there is no behavioural outcome to this kind of paradigm. Despite this methodological problem, some experimental paradigms have yielded robust results. Brass and Haggard (2007) asked participants to prepare a button press and to inhibit the prepared action in some trials. They have shown the selective activation of a brain area, associated with an endogenous cancellation function. An area of the anterior frontomedian cortex (dFMC), rostral to the presupplementary motor area (preSMA), was activated more when subjects had to cancel a prepared action than when they carried on with it. We propose to develop a more naturalistic and physiologically plausible paradigm for intentional inhibition, based on inhibiting the urge to scratch following electrically induced itch. In this proposed paradigm, although the urge to move is driven by a specific itch stimulus, the inhibition of the scratching is self-generated, and related to the urge to scratch. This combination therefore represents a significant improvement to the traditional paradigms of II used thus far.

Amount: £148,655
Funder: The Wellcome Trust
Recipient: University College London

Electrophysiological and imaging studies of hite mechanisms underlying brain white matter pathology. 10 Oct 2007

Electrophysiological and imaging studies of mechanisms underlying brain white matter pathology This project will investigate in depth the mechanisms leading to oligodendrocyte damage in pathological conditions, and some properties of oligodendrocyte precursor cells relevant to normal myelination during development and to remyelination in pathological conditions.

Amount: £5,430
Funder: The Wellcome Trust
Recipient: University College London

The National Survey of Sexual Attitudes and Lifestyles 2010 (Natsal 2010). 15 May 2008

As requested, to ensure that both the Wellcome Trust and the MRC have the same information, the summaries submitted to the MRC have been uploaded (Document 4).

Amount: £2,000,000
Funder: The Wellcome Trust
Recipient: University College London

Determinants of physical activity in the UK Millennium Cohort Study 06 Feb 2008

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 th is 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 no t reliable indicator of fat mass at this age.

Amount: £1,297,375
Funder: The Wellcome Trust
Recipient: University College London

The consequences of temporal lobe epilepsy surgery . 10 Oct 2007

We will investigate the effects of temporal lobe epilepsy and surgical removal of the anterior temporal lobe on cognitive functions that involve the temporal and the frontal lobes, and mood. We will investigate the functional neuroanatomy of these processes and how the frontal and temporal lobes are interconnected in terms of function and the white matter tracts that provide structural connectivity. We will implement and evaluate methods to predict the effects of anterior temporal lobe resecti on on cognition, mood and the field of vision, and how to subsequently minimise these risks. We will advance the technology of tractography and its integration with anatomical imaging, and will use temporal lobe surgery as a test-bed to implement combined serial fMRI and tractography after cerebral insults to determine the basis of recovery and plasticity.

Amount: £1,487,687
Funder: The Wellcome Trust
Recipient: University College London

Higher resolution cardiovascular epidemiology: unique insights from linking the national cardiac event register with primary care records and highly phenotyped cohorts. 16 Jul 2008

Background Our understanding of the aetiology of coronary disease in populations has been limited by low resolution in three key dimensions: phenotyping different coronary syndromes, the timing and evolution of risk, and the interplay between different risk factor domains. This uncertainty motivates each of our aims: Aim I Curation of novel research platform We will establish, validate and curate for the wider research community new, internationally unique, large-scale resources based on link ing the national myocardial infarction register to the rich longitudinal primary care record and highly phenotyped cohorts in the UCL genetics consortium. We will focus on stable angina, unstable angina, non-STEMI and STEMI (about 146,000 linked cases). Aim II Research To what extent are risk factors for specific chronic or acute coronary syndromes different from those of undifferentiated coronary disease aggregates? Across short and long-term risk periods, in aetiologic and prognostic set tings, we will address major aetiological domains including: social and psychosocial factors, physical environment, inflammation, biological markers and genetics. Aim III Training and education We will develop, deliver and evaluate new training opportunities at short course, MSc and PhD level to spawn a new cadre of academics trained in exploiting multiple sources of EPR for health research.

Amount: £1,159,056
Funder: The Wellcome Trust
Recipient: University College London

Regulation of M-type (Kv7) potassium channels by transmitters and messengers: is PIP2 the final common pathway?. 26 Jun 2008

Our question is: do different intracellular and extracellular Kv7 channel regulators act by changing the ability of membrane PIP2 to activate the channels? We will use two complementary approaches to answer this electrophysiological recording of M/Kv7 channel behaviour, and biochemical measurements of PIP2 binding to Kv7 fusion proteins. The rationale behind the electrophysiological experiments is that, if different intracellular and extracellular signals ultimately converge on changes in PIP2 channel interaction, they should show similar and predictable effects on channel kinetic behaviour. We have developed a provisional model of PIP2 regulated channel kinetics and will assess how far this predicts the changes produced by altering the amounts or availability of PIP2, and compare this with the effects of other regulators and of different transmitters. This will be done using sympathetic neurons in which the various regulators, receptors and transducers common to nerve cells are al ready extant. Additionally, we will test responses of Kv7.2/7.3 channels, channel subunits and mutated subunits expressed in CHO cells to PIP2 and other regulators. Quantitative binding studies of Kv7.2 and Kv7.3 C-terminus fusion proteins (already prepared) to PIP2 and other anionic phospholipids will be undertaken using phospholipid arrays and surface plasmon resonance.

Amount: £472,228
Funder: The Wellcome Trust
Recipient: University College London

The mechanism of action and significance of RIC-3, a selective molecular chaperone for nicotinic and 5-HT3 receptors. 17 Apr 2008

RIC-3 is a recently discovered selective molecular chaperone of nicotinic acetylcholine receptors (nAChRs) and 5-hydroxytryptamine type 3 receptors (5-HT3Rs). The influence of RIC-3 is illustrated most dramatically by its effect on homomeric alpha7 nAChRs. In many host cell types the alpha7 subunit fails to produce functional receptors. In some, but not all, cell lines this can be rectified by the co-expression of RIC-3. RIC-3 also modulates the functional expression level of some, but not all , heteromeric nAChR subtypes. Importantly, RIC-3 promotes the formation of homomeric 5-HT3A, but inhibits the formation of heteromeric 5-HT3AB, receptors. Accumulating evidence suggests that RIC-3 exerts these effects by modulating receptor maturation, but there is considerable uncertainty about its precise mechanism of action. We will explore the mechanisms by which RIC-3 modulates receptor maturation and function. In addition, we will generate a RIC-3-DsRed knock-in transgenic animal to enab le us to explore RIC-3 function and expression on endogenous receptors. To explore the in vivo significance of RIC-3, we will examine the phenotype of RIC-3 null mutants, using a conditional knockout approach. We will concentrate our initial characterisation on learning and memory, indicators of anxiety and schizophrenia and animals responses to nicotine.

Amount: £228,430
Funder: The Wellcome Trust
Recipient: University College London

Neural Correlates of Auditory Processing Deficits in Auditory Cortex and Thalamus of BXSB/MpJ Mice. 11 Feb 2008

Our aim is to determine whether behavioural deficits in auditory temporal processing are correlated with abnormalities in the responses of auditory cortical and thalamic neurones in BXSB/MpJ mice. These mice are considered to be an animal model for human developmental disorders associated with auditory processing deficits. Approximately half the animals within a BXSB/MpJ litter are ectopic; they have cortical malformations (ectopia) and thalamic abnormalities that resemble those observed in hu mans with developmental disorders like dyslexia. Despite having normal hearing sensitivity, male ectopic mice have difficulty with perception of rapidly changing sounds; such deficits are also typical of dyslexia. We will compare auditory behaviour and auditory cortical and thalamic responses in ectopic male mice with those in non-ectopic males, which do not have auditory processing deficits and therefore serve as genetically matched controls. Key goals are to determine whether neuronal thres holds for gap detection and detection of rapid two-tone oddball stimuli correlate with behavioural thresholds, and whether neuronal minimum response latencies and limits for synchronised following differ between ectopic and non-ectopic mice. These experiments will produce important information about auditory temporal processing in the mouse, and provide insights into the neuronal basis for auditory processing deficits in humans.

Amount: £211,787
Funder: The Wellcome Trust
Recipient: University College London

tRNA retrograde transport and HIV-1 nuclear trafficking: a surprising connection. 24 Oct 2007

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.

Amount: £367,002
Funder: The Wellcome Trust
Recipient: University College London