- Total grants
- Total funders
- Total recipients
- Earliest award date
- 05 Feb 2008
- Latest award date
- 04 Dec 2008
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Auditory specialization for speech perception. 17 Apr 2008
We will examine the perceptual specialization for native-language phonemes by comparing adults with different native languages, using behavioural measures and MEG. The experiments will test languages and phoneme pairs that our previous work has suggested are affected by cross-language auditory processing differences: English /w/-/v/ for native Sinhala and English speakers, and English /r/-/l/ for native Japanese and English speakers. The first part of the proposal will involve behavioural exp eriments that manipulate the acoustic form of speech. We will construct non-speech stimuli to determine whether cross-language differences can be found for stimuli that fall short of being intelligible speech, and will use transformations of the speech signal (e.g., sinewave speech) to determine whether we can find cross-language differences when the acoustic form of intelligible speech is unnatural. The goal is to determine how acoustically close the stimuli need to be to natural speech in orde r for cross-language patterns of phonetic perception to emerge. The second part of the proposal will investigate these behavioural findings using the mismatch response (MMN) of MEG recordings. Our goal is to determine where and when these cross-language differences in phonetic processing occur.
Assessing the potential of perinatal gene transfer using congenital factor VII deficiency as a model system. 30 Apr 2008
In this study we use congenital factor VII deficiency (CFVIID) to establish the safety and efficacy of perinatal gene transfer of the liver. Self complementary adeno-associated and lenti-virus vectors encoding murine FVII will be used as they show great promise for hepatocyte gene transfer in adults. These vectors will be administered in-utero or in the early neonatal period to FVII knock-out (FVII-/-) mice. This model emulates the cardinal features of CFVIID in humans, especially neonatal death due to haemorrhage. Our primary goal will be to establish if perinatal gene transfer can protect against fatal postnatal haemorrhage. The stability of transgene expression beyond the postnatal period will be determined. The biodistribution profile for the two vector systems and routes of administration will be defined. The potential risk of thrombosis and immune response to the viral and transgenic proteins will be explored. A tumour-prone mouse model will be used to establish the genotoxic pro file of the two vector systems as a function of the route of administration. These results will inform on the risk benefit analysis of perinatal gene transfer which will help in the design of future studies for this and other liver disorders which present during the neonatal period.
Many forms of brain damage, either acute or progressive, can compromise patients ability to move and to communicate. While much work has focused on attempts to reverse the pathological process causing such damage, rather less has sought to provide complementary approaches of circumventing the effects of damage by using brain signals from sensory or motor cortex to control neuroprosthetic devices. Moreover, investigating the neural basis of such signals has direct biological relevance for unders tanding mechanisms of perception and action. Here, I propose to use the new technique of real-time fMRI (rt-fMRI) to address both issues. My proposal thus addresses two inter-related questions of biological and practical significance. First, can attention be decoded in real time from human visual cortex to potentially provide control signals for a neural prosthesis? Second, does the level of attentionally modulated activity in human visual cortex have a causal influence on perception and awarene ss? I will combine real-time functional MRI (rt-fMRI) with on-line neurofeedback in human participants in a series of experiments that both probe the effects of attention on visual cortex and evaluate the potential utility of decoding such signals for communication and control.
This project is to investigate whether slowing cone photoreceptor loss could be used as a widely applicable treatment to preserve sight in inherited retinal degenerations. Neurotrophic factors, apoptosis inhibitors and transplanted rods have previously shown promise, but key questions remain: 1. Are initial rescue effects maintained over time, or subsequently lost by accelerated apoptosis? 2. Can cone cell rescue still be achieved once all rods have degenerated (a common clinical scenario)? 3. Could rods transplanted into the vitreous slow cone degeneration (the vitreous is a clinically attractive site for cell transplantation)? These questions will be addressed using adeno-associated viral (AAV) gene transfer to achieve sustained intraocular levels of a promising neurotrophic factor with a clinical safety profile (GDNF - delivered to inner retinal cells by AAV serotype 2) and cone selective expression of a potent intracellular inhibitor of apoptosis (XIAP - delivered to photo receptors by AAV serotype 5). In the third experiment rod progenitors will be isolated and transplanted into the vitreous cavity. All experiments will be performed in a novel mouse model of rod-cone degeneration in which the cones are genetically labelled with a fluorescent probe, allowing repeated anatomical and functional tracking of the degeneration over time.
REGULATION OF THE ANTIOXIDANT STATUS OF ENDOTHELIAL CELLS BY MITOCHONDRIA AND AMP-ACTIVATED PROTEIN KINASE ALPHA 1. 15 Oct 2008
We propose to investigate the way in which nitric oxide (NO) contributes to the maintenance of the antioxidant status of vascular endothelial cells. To do this we intend to: 1) study the signalling cascade initiated by the generation of mitochondrial reactive oxygen species (ROS) as a result of the interaction of NO with cytochrome c oxidase at 3% O2; 2) identify the role of AMPK (in particular the catalytic alpha 1 subunit) and redox-responsive transcription factors (e.g. Nrf2, FOXO) in this pathway; 3) explore whether this system maintains a constitutive defensive state in these cells which, if impaired, removes their protection against potentially pathophysiological situations, such as hypoxia and oxidative stress, that occur in conditions such as diabetes or metabolic syndrome.
The overall aim of this project is to understand better the role of the transcription factor SOX2 in normal hypothalamo-pituitary development and in the pathogenesis of hypopituitarism in humans. Recently, we have identified a critical role for the transcription factor SOX2 in normal hypothalamo-pituitary development in both mice and humans; however, the molecular mechanism by which SOX2 dictates hypothalamo-pituitary development, namely its target genes and partner proteins, remains unknown. Th e main aims of the proposed research are: 1. To evaluate the ability of SOX2 to directly regulate specific genes known to be involved in forebrain and hypothalamo-pituitary development, and to identify the positions of these genes in the genetic hierarchy leading to normal pituitary development. 2. Identification of novel SOX2 target genes likely to be important in hypothalamo-pituitary development. 3. To investigate suitable co-operative partner factors for SOX2 in the developing pitu itary and their co-expression in human embryos. 4. Selection of candidates for mutation analysis of novel SOX2 target genes in patients with hypopituitarism and associated defects.
Development and maintenance of an optimally functioning vasculature are essential for health. Abnormal vessel responses can result in a range of vascular problems including haemorrhage, vessel dilatation or aneurysm, which may be associated with increased morbidity and mortality, depending on the affected organ. The aim of this project is to understand the role of the essential endothelial receptor endoglin during development of the vasculature. Pathological mutations of the endoglin gene in the familial vascular disorder Hereditary Haemorrhagic Telangiectasia lead to the local formation of arteriovenous malformations and haemorrhagic, dilated and tortuous blood vessels (telangiectases) that often enlarge or become more numerous with age. The molecular mechanisms underlying these events are poorly understood, largely because of a lack of robust animal models. We have recently derived an inducible endoglin knockout mouse which, for the first time, develops arteriovenous malformations in a reproducible manner. We will use this unique model to investigate the underlying cellular and molecular mechanisms responsible for abnormal vascular remodelling. Following this, we aim to investigate repair of these vascular abnormalities. Increased understanding of the central role of endoglin in angiogenesis has wider implications for current therapies to regulate angiogenesis and vascular repair in an extensive range of pathologies.
The UK National Juvenile Dermatomyositis cohort : genotype/phenotype studies, and their application to mechanisms, clinical course and outcomes. 15 Oct 2008
This application is to request funding of a cohort of children with myositis, now one of the largest of its type in the world, that can make a major international contribution to the field. The cohort comprises clinical data linked to biological samples (serum, plasma, DNA, PBMC and muscle biopsy tissue), contributed from a Network of centres across the UK (see Appendix1). Standardised clinical data are collected using validated, internationally agreed, robust, clinical tools. Data and samples f rom several years are available, allowing studies of response to treatment, biomarker and candidate gene discovery, including genotype/phenotype correlations, and long-term disease outcomes. The resource is managed by an independent Steering committee, with patient involvement, and is available to the scientific community through an open application process. The resource is much in demand from UK and International researchers; several research projects are planned and funded. For this resource t o survive, the core needs include an Administrator, a Research Assistant, and running costs. A key objective of this proposal is to further develop availability and visibility of the resource through a website, making it more accessible to the wider scientific community, allowing information and data generated to make a larger impact upon health outcomes.
The role of Schwann cell c-Jun and Notch signalling in neuron guidance and demyelinating neuropathies. 29 Aug 2008
Analysis of changes in shape and cell migration that promote axon growth in Schwann cell mutants with a strong regeneration phenotype A) Can c-Jun -/- Schwann cells form processes to guide growing neurites? B) It the formation of regeneration-promoting process extension enhanced in the absence of Notch signalling? C) Analysis of the importance of neuropilin 1 for Schwann cell division driven by VEGF and neuregulin1.
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.
This project aims to examine the effect of Wnt signalling in protein translation during the formation of dendrites spines, excitatory postsynaptic structures, in the hippocampus. Changes in spines have been observed during long-term plasticity. Moreover, loss of spines has been associated with disorders like autism, schizophrenia and in neurodegenerative diseases. Our new studies reveal for the first time that Wnt7a, a member of the Wnt family expressed in the hippocampus, stimulates the formation of excitatory synapses with no significant effect of inhibitory synapses. Through gain and loss of function studies, we demonstrated that Wnt7a stimulates the formation and growth of spines. Postsynaptically Wnt signalling stimulates the maturation of dendritic spines in the hippocampus through a mechanism that involves Dishevelled-I (Dvll), a scaffold protein that regulates local Wnt signalling. To begin to understand the mechanism by which Wnt signalling regulates spine morphogenesis we performed a yeast two-hybrid screen to look for Dvll interactors. In this screen we identified Microspherules Protein 58 (MSP58), a novel RNA-binding protein that interacts with fragile X mental retardation protein (FMRP). Interestingly, FMRP has been implicated in spine morphogenesis by regulating local translation. In addition, FMRP binds to microRNAs. These findings suggest the interesting possibility that Wnt-Dvl signaling could regulate local translation through MSP58 and FMRP. In this project, the student will examine: I) The role of translation in Wnt mediated spine morphogenesis. 2) The role of MSP58 and FMRP in spine development and their contribution to Wnt-mediated spin morphogenesis. 3) The function ofmicroRNAs in Wnt-mediated function of spine formation and growth.
Molecular and development alterations in circadian clock function in various strains of the Mexican blind cavefish, Astyanax mexicanus. 29 Aug 2008
A major environmental cue for most organisms is the daily cycle of light and darkness Consequently, most organisms have developed a system, synchronised by the light/dark cycle coordinating physiology and behaviour with the environment. This system is known as the circadian clock and was proposed to be a neural phenomenon residing in a region of the central nervous system: the SCN. Over the last decade, research has led to a decentralisation of the circadian clock with discoveries of independent peripheral oscillators both in vivo (Whitmore et al, 1998) and in vitro cell culture (Whitmore et al, 2000; Welsh et al, 2004). Additionally, zebrafish cells can detect light and use this to set the phase of the circadian clock. Recent research in our lab has begun to investigate the workings of the circadian clock in a species of fish that lives in perpetual darkness, and is therefore missing the major environmental cue for most living organisms. This work has been performed using the Mexican tetra, Astyanax mexicanus; a single teleost species consisting of a sighted surface-dwelling form and several independent cave dwelling forms. Cavefish have lost eyes and pigmentation, as well as gaining constructive feature: such as increased jaw size and taste bud number. Selective pressures for retaining light adaptive features such as pigmentation are relaxed in the absence of light, and it is believed that pigmentation is lost through neutral mutations in the Oca2 gene (Protas et al, 2006). Little research has been performed on circadian clocks in cave animals, and particularly not on cave animals with living con-specific surface dwelling ancestors. This is important because when the ancestral surface form is still present, a direct comparison can be made between ancestral and derived developmental states. Astyanax is thus an important model for understanding the molecular basis of developmental changes in the context microevolution. Jeffery suggested "cavefish can be compared with surface fish in essentially the same way as mutants are compared with wild-type phenotypes" (Jeffery, 2008). We possess a model in which we can investigate a range of clock phenotypes. We will use surface fish and the two different populations of cavefish (Pachon and Steinhard) in our proposed research to further understand clock mechanisms in a dark adapted animal and assess whether cavefish really are clock mutants. If they are mutants in the clock me
The aim of this PhD project is to test the hypothesis that Nrl-expressing ES cell derived precursor cells will general new functional photoreceptors after transplantation into the adult mouse retina.
The World Health Organization and the social determinants of health: assessing theory, policy and practice (an international conference). 29 Aug 2008
The World Health Oraganisation and the Social Determinants of Health: Assessing theory, policy and practice (An international conference).
The 1918 influenza pandemic represents the worst outbreak of infectious disease in Britain in modern times. Although the virus swept the world in three waves between March 1918 and April 1919, in Britain the majority of the estimated 228,000 fatalities occurred in the autumn of 1918. In London alone deaths at the peak of the epidemic were 55.5 per 1,000- the highest since the 1849 cholera epidemic. Yet in the capital as in other great cities and towns throughout Britain, there was none of the panic that had accompanied earlier 19th century outbreaks of infectious disease at the heart of urban populations. Instead, the British response to the 'Spanish Lady' as the pandemic strain of flu was familiarly known was remarkably sanguine. As The Times commented at the height of the pandemic: 'Never since the Black Death has such a plague swept over the face of the world, [and] never, perhaps, has a plague been more stoically accepted.' The apparent absence of marked social responses to the 1918 influenza is a phenomenon much remarked on in the literature of the pandemic, as is the apparent paradox that despite the widespread morbidity and high mortality the pandemic had little apparent impact on public institutions and left few traces in public memory. However, to date no one has explored the deeper cultural 'narratives' that informed and conditioned these responses. Was Britain really a more stoical and robust nation in 1918, or was the absence of medical and other social responses a reflection of the particular social and political conditions that prevailed in Britain during the First World War and then medical nosologies and cultural perceptions of influenza? And if the 1918 pandemic was 'overshadowed,' as one writer puts it, by the war and the peace that followed the Armistice, what explains the similarly muted response to the Russian flu pandemic of the early 1890's, a disease outbreak that coincided with a long period of peace and stability in Britain? In this project I aim to show that, contrary to previous studies, both the 1918 and the 1889-92 Russian flu pandemic were the objects of much deeper public concern and anxiety than has previously been acknowledged and that the morbidity of prominent members of British society, coupled with the high mortality, occasioned widespread 'dread' and in some cases alarm. However, in 1918 at least, government departments and public institutions actively suppressed these concerns for the sake of the war effort and the maintenance of national morale.
NT-26 is arsenite-utilizing bacterium whose whole genome sequence has recently become available. Capitalizing on our previous studies on regulation of enzyme arsenate oxidase and the availability of the genome information the aims of this project are: To carry out gene annotation, identify and analyse the sequence of all two-component signaling system pairs in bacterium NT-26; To explore the cross-reactivity between various two-component signaling pathways in this organism; To investigate arsenite binding within AroS histidine kinase; To initiate crystallization and structure determination of selected domains from the identified signaling proteins.
Bridging disulfides with halomaleimides. 29 Aug 2008
The repertoire and functionality of proteins in mammal cells is greatly enhanced by post-translational modifications. These include the addition of polymers and small groups to the protein, the formation and change of the orientation of single bonds and the modification of amino acids. The possibility to artificially mimic the cells' ability to modify proteins yields great opportunities to gain a deeper insight into function and regulation but would also lead to the creation of new applications with a diagnostic and clinical background. One of the main obstacles yet to overcome in the synthetic modification of proteins is the poor selectivity exhibited by the methods that are available at present. In order to sustain the ability of a protein to bind its interaction partner or to accomplish its designated role it is vital that any artificially modification interferes as little as possible with its structure and its function. This can only be achieved if the applied chemistry allows the attachment of one or more functional molecules at one or more well-defined sites with high selectivity. Cysteine is widely considered the easiest amino-acid to selectively modify, due to its high nucleophilicity. However cysteines present in proteins often have a catalytic function or are inaccessible due to their incorporation in disulfide bonds. Free cysteines can be generated by subjecting proteins containing disulfides to mild reducing conditions, but solvent exposed disulfide bridges often fulfil the role of a stabilising feature of the structure and their breakage often leads to denaturation. One possible approach to preserve the protein structure would be the reconnection of the two cysteines after the reaction. We are proposing to develop a new class of reagents, the dihalomaleimides (e.g. dibromomaleimide), for this purpose (Scheme 1). Each cysteine from the disulfide can displace one of the bromines on the maleimide to afford the bridged product. By varying the R group we can, in a highly controlled manner, incorporate a range of functional moieties onto the protein.
Influenza A: Understanding changes in selective constraints occurring during host shifts. 29 Aug 2008
The proposed aims are to: 1) Develop methods of phylogenetic analysis that will allow us to identify changes in selective constraints that occur during host shifts in influenza. 2) Identify locations where such selective constraint shifts have occurred during shifts from avian to human hosts, and the nature of these changes. 3) Expansion of the model to include the selective constraints in swine influenza. 4) Establishment of measures of 'avianicity', 'humanicity', and 'swinicity', the propensity of a virus or genomic segment to undergo host shifts to humans or swine, respectively. 5) Identify whether the viral strains that underwent host shifts were random or exceptional, whether it was a question of mutations that made such a shift more likely, or rather random opportunism. 6) If time permits, develop other models that characterise the changing nature of the selective constraints in other circumstances.
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.