- Total grants
- Total funders
- Total recipients
- Earliest award date
- 20 Oct 2005
- Latest award date
- 30 Sep 2019
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Strong evidence now implicates DTNBP1 as a susceptibility gene for schizophrenia. However its pathogenic role remains unclear. We aim to translate this strong genetic evidence to a real understanding of pathogenesis by first identifying the specific genetic variants at DTNBP1 responsible for reported haplotypic associations with schizophrenia and then determining their effect upon DTNBP1 function. To achieve this, DTNBP1 will be re-sequenced and all DNA variants genotyped in our large sample of 860 cases and 860 matched controls. Positive associations will be replicated in two independent samples of 219 Irish cases and 231 matched controls and 600 Bulgarian parent-proband trios. The pathological mechanism of these DTNBP1 risk variants will then be established via functional genomic methodologies. This proposal also aims to establish whether any of the genes encoding proteins functionally related to dysbindin themselves confer susceptibility to schizophrenia. We will identify known and novel proteins from the literature and via immunoprecipitation assays respectively, that interact with dysbindin and then seek associations between schizophrenia and variations in the genes that encode the dysbindin interacting proteins. This will establish which dysbindin related mechanisms are involved in the pathogenesis of schizophrenia, improving our understanding of the origins of this disorder.
The Imp2 mRNA binding protein: Roles in morphogenesis and differentiation of the mammalian inner ear. 20 Oct 2005
The inner ear develops from the otic placode, a specialised patch of neuroectoderm adjacent to the developing hindbrain. A major goal is to understand the molecular mechanisms that convert this patch of cells into the complex adult structure. IGF signalling is associated with inner ear development, but how inner ear IGF activity is controlled is not known. Previously we isolated the Igf2 mRNA binding protein, Imp2, and have shown it is expressed in different sensory epithelia during development, including the inner ear. In this project we will use gain and loss of function approaches in transgenic mice to determine the function of Imp2 in inner ear development. We will test the hypothesis that Imp2 is a key regulator of IGF activity, controlling morphogenesis and differentiation in the developing inner ear. Key Goals: Determine whether Imp2 regulates localised differential growth of cells in the otic epithelium Determine whether Imp2 affects hair cell differentiation Determine the effects of Imp2 on IGF1 & IGF2 expression Determine whether Imp2 regulates otic neuroblast proliferation and/or migration Determine the fate of Imp2 expressing cells in the mature inner ear Investigate the association of Imp2 with hair cell repair/regeneration
Dissecting and disrupting Epstein-Barr virus transcription initiation and elongation during latent infection. 09 Feb 2006
This research will test the hypothesis that the switch from W to C promoter usage during initial EBV infection represents a switch from non-processive transcription to EBNA 2-activated CDK9-dependent processive transcription necessary for the efficient production of the long primary transcript and the establishment of latency. We will also investigate whether the requirement for CDK9 for the efficient activation of transcription by EBNA 2 makes the anti-cancer drug and CDK9 inhibitor, Flavopiridol, an effective anti-EBV agent. Additional studies will further dissect the way in which pol II phosphorylation is regulated by EBNA 2. Key goals 1. Determine whether EBNA 2 stimulates transcriptional elongation in addition to initiation. 2. Determine whether EBNA 2 activated transcription can be blocked using Flavopiridol. 3. Dissect how pol II phosphorylation is regulated by EBNA 2.
An in vitro study of the cellular and network basis of the cortical and subcortical pacemakers of key brain rhythms. 13 Dec 2005
Rhythmic EEG activity is generated by the concerted action of neuronal networks in both cortical and subcortical areas. One area which is crucial in promoting EEG rhythms is the thalamus. However, how the cortex and thalamus interact to form coherent oscillations is largely unknown. This is mainly because in vivo preparations do not provide a controlled enough environment for dissecting different mechanistic components whereas in vitro preparations do not normally contain sufficiently intact circuitry for realistically examining thalamocortical oscillations. I will bridge this gap by combining traditional in vitro approaches with multisite electrophysiological recording in a mouse thalamocortical slice which preserves portions of the somatosensorycortex and thalamus as well as viable thalamocortical and corticothalamic fibres between the two. The thalamocortical slice will combine the flexibilityof the in vitro environment with the option of examining realistic network oscillations. I will focus my attention on three types of thalamocortical oscillations: slow (<1 Hz) waves, alpha/theta oscillations and cyclic paroxysms. For each of these, my primary goals are (i) to conduct a thorough study of their spatiotemporal properties and (ii) to obtain a detailed insightinto how different neurones and networks in the cortex and thalamus interact to form coherent oscillations.
Neuronal thalamic gap junctions: identity, location and role in slow EEG rhythms of (patho)physiological states 20 Oct 2005
Synchronized activity among thalamic and cortical neurones underlies the EEG expression of different behavioural state-dependent rhythms, whereas its alterations may lead to EEG paroxysms such as the spike-and-wave discharges (SWDs) of absence epilepsy. Our in vitro studies have identified a key role for gap junctions (GJs) among the glutamatergic thalamocortical (TC) neurones in the expression of synchronized, low-frequency thalamic oscillations, that define two behavioural states, i.e. the alpha rhythm and the slow (<1 Hz) sleep rhythm. In addition, connexin 36 (Cx-36)-based GJs among GABAergic nucleus reticularis thalami (NRT) neurones is known to support synchronized oscillations in this thalamic nucleus in vitro. Here we propose:1. to identify in vivo the contribution of GJs among TC neurones and among NRT cells to the expression of SWDs and of three EEG rhythms: the alpha rhythm, sleep spindles and the slow (<1 Hz) sleep rhythm;2. to identify the sites of GJ coupling in TC and NRT neurones, and the molecular identity of the Cx(s) present in TC neurones using electron microscopy, and triple labelling of dye-coupled neurones and immunocytochemistry with specific Cx antibodies.This multi-disciplinary approach from two laboratories with established expertise in their respective field will shed light into the role of thalamic GJs in EEG rhythms of fundamental importance in health and in one of the generalized epilepsies.
The key goal of this research project can be summarised as being to ensure preservation of the 20th century history of human and medical genetics by: 1. Identifying and conserving key written records, including personal scientific records of workers, records of societies and institutions, and images. 2. Developing and cataloguing a collection of key monographs and other books on human and medical genetics. 3. Consolidation of an international network of interested historians and scientists across Europe, the Genetics and Medicine Historical Network, through international workshops, an electronic newsletter and a website (genmedhist.net). 4. To make the history of this field more accessible to the wider public, through our website and our links with Science Centres in Cardiff and across the UK. The project can be regarded as the first step towards forming a virtual British human genetics archive; this will become a research resource that should stimulate historians and others to explore specific historical aspects of this important field of science and medicine. The network should itself result in collaborations that will initiate such research.
We propose a programme that builds upon our previous work in mood disorders and psychosis and encompasses clinical and laboratory aspects. We will recruit 600 individuals with an illness characterized by a mix of features typically found in schizophrenia and bipolar disorder - few such individuals have been collected in samples to date but are very important for understanding the relationship between mood disorder and psychosis. We will follow up (by questionnaire and interview) 3000 participants previously recruited to our studies - illness features may vary over time and up-to-date information optimizes analytic power. We will investigate genes already implicated in mood disorders or psychosis by detailed genetic study in 5000 individuals (diagnosed with bipolar disorder, schizophrenia, depression or controls). A major part of our programme is detailed study, within individuals representing a broad range of mood and psychotic illness, of genes implicated in the Wellcome Trust Case Control Consortium (WTCCC) study (a systematic study of the whole genome including 2000 bipolar cases and 3000 controls). In addition to analysing traditional diagnostic categories we will use statistical methods capable of identifying completely new approaches to diagnosis that are biologically valid - we view this as key to our programme. We will pilot new clinical approaches to diagnostic assessment in our clinics. Our focus throughout is on achieving clinically relevant outcomes over realistic timescales.
The increased incidence of antibiotic resistant bacterial strains such as MRSA and VRSAover the past few years has identified the necessity for development of alternative therapeutic strategies. Professor Nicholas Topley and Dr Simon Jones at the University of Wales have been awarded translational funding to further develop a therapeutic to supplement the body's existing defence system to help clear various types of bacterial infection.
Fibroblast growth factors (FGFs) have multiple and complex roles in vertebrate development. One of these factors, Fgf3, is required for normal development of the mammalian inner ear. How this growth factor or the additional FGFs required for inner ear development are integrated into the other established signalling and transcription factor pathways directing ear development is not yet known. We previously defined a minimal enhancer from mouse Fgf3, containing regulatory elements governing most aspects of the dynamic and complex spatio-temporal pattern of normal expression. Binding sites for transcription factors from a number of the already characterised pathways directing inner ear development are located in the minimal enhancer. In this project, we will use mouse transgenesis to test these candidates, and define those factors that directly regulate the different domains of inner-ear Fgf3 expression. We have also detected regions of conserved DNA sequence in introns 1 and 2, which may contain the DNA elements controlling the late domains of inner-ear expression. We will test the regulatory activity of these introns, and their relationship with the minimal enhancer in controlling Fgf3 expression. Together, these data will precisely position Fgf3 in the molecular programme of inner ear development.
CD59 as a modulator of T cell activity in vivo. 09 Feb 2006
Identification of molecules that influence T cell activation either positively or negatively will facilitate manipulation of T cell responses in order to amplify those that are beneficial and to inhibit those that are harmful. Preliminary experiments indicate that a complement regulator protein, CD59, downmodulates T cell activity in mice. Mice lacking CD59 show enhanced antiviral CD4+ T cell responses and an enhanced ability to clear virus infections. These studies have led us to hypothesise that lack of CD59 expression on T cells 1) exacerbates virus-induced immunopathology and 2) promotes anti-tumour immunity. The first hypothesis will be tested by comparing virus-specific immune responses and pathology in influenza-infected CD59-deficient and CD59-sufficient mice. In a separate set of experiments we will address whether CD59 expression on T cells limits their anti-tumour potential. Using tumour models already established within the laboratory, we will address whether a) CD59-deficient T cells are more effective than CD59-sufficient T cells at tumour rejection and b) whether silencing of CD59 using siRNA technology enhances the anti-tumour capacity of T cells isolated from CD59-sufficient mice. Lastly, a phenotypic and functional analysis of CD59 expression in human T cell activities in vitro will be undertaken.
Veterinary science, transboundary animal diseases and markets: pathways for policy in Southern Africa. 28 Feb 2006
Key to the future of livestock production in Africa - and constraints on meeting the high hopes of a 'livestock revolution' as a spur to stagnant agricultural sector growth - are the presence of transboundary animal diseases and the consequent escalating costs of regulation and meeting export standards. Focusing on the case of foot and mouth disease (FMD) in southern Africa - and specifically Botswana, Nambia, South Africa and Zimbabwe - this research will explore the economic, social and political trade-offs arising from disease control strategies focused on promoting commercial beef exports which are premised on the ability to separate a 'disease free' commercial sector from endemic areas through strictly enforced buffer and surveillance zones, and movement control. The key question is: given limited resources and capacities and growing costs, does it make sense to persist with this status quo and ensure disease freedom? Or are there alternatives that benefit a wider group of producers, are easier to implement, yet maintain access to important export markets and so foreign exchange revenues? Four country-based teams, coordinated by IDS and supported by project advisors, will investigate the policy processes in each country: how choices are made and by whom and with what criteria, to uncover the different scientific and economic arguments, policy actors and interest positions involved. The project will then bring the different players together in a series of policy dialogue workshops to explore different future policy scenarios (and their trade-offs), through a deliberative and participatory process. The main audience for both the analysis and methodological approach will be national and regional (SADC) level policymakers working on the intersections of animal health/disease control and marketing/trade policy. The policy dialogues will engage diverse stakeholders - livestock producers, regulators, processors, exporters and scientists - with a view to encouraging dialogue across usually divided sectors and across the region.
Investigation into the pathogenesis of ischaemic brain damage, by live imaging of peri-lesion spreading depression (SD) in stroke models. 10 May 2006
Studies with stroke models showed that recurrent spreading depression (SDs, waves of cellular depolarisation that propagate slowly across grey matter regions) occur in the vicinity of the ischaemic core and contribute to lesion progression. Peri-lesion SDs were also found in patients suffering from a stroke or traumatic brain injury. It is often speculated that SDs are initiated in the ischaemic penumbra (i.e. where residual blood supply is insufficient for synaptic function but still capable of sustaining vital biological processes) but this hypothesis conflicts with robust data. Two important questions must be answered: - Are peri-lesion SDs elicited in the penumbra, or only at sharp interfaces between severely ischaemic regions and spared regions? - How do SDs contribute to lesion progression? We have identified a new experimental strategy that should produce definite answers: Live imaging of the ischaemic region and of peri-lesion SDs, using two fluorescent dyes, one voltage-sensitive and the other pH-sensitive. This pilot study will aim to: (i) Adapt existing fluorescent-dye imaging technology for this specific application; (ii) Validate this novel approach in models where the pattern of focal ischaemia can be accurately controlled; (iii) Obtain preliminary data that will allow us to seek financial support for a full project.
Identifying susceptibility genes for Attention Deficit Hyperactivity Disorder with antisocial behaviour as a covariate. 31 May 2006
Attention Deficit Hyperactivity Disorder (ADHD) is a common, neurodevelopmental childhood-onset disorder that has life-long adverse consequences. ADHD is highly heritable but the pathogenesis of the disorder remains unknown. Identifying susceptibility genes and examining how these, together with environmental factors, influence ADHD is extremely important if novel, effective methods of prevention and therapeutic intervention are to be developed. ADHD is commonly accompanied by antisocial behavio ur that is not only a major public health and societal problem itself but also indexes greater clinical severity, a poorer outcome, greater persistence in adult life and higher familiality and genetic loading of ADHD. The aims of this proposal are to identify genes that increase susceptibility for ADHD, have effects on associated antisocial behaviour and that have effects which are conditional on exposure to environmental risk factors. The study design is a traditional genetics approach that is enhanced by evidence from clinical and epidemiological studies. Specifically the design is a whole-genome SNP-based linkage study of a UK sample of affected sib pairs followed up by linkage disequilibrium mapping. The search is refined by using covariate-based linkage analysis with antisocial behaviour as the clinical covariate and including environmental factors that are robustly associated with ADHD.
A textual & qualitative study of the ethical, legal & clinical implications of use of the concept by multiagency mental health teams focusing on the management of people perceived to be dangerous. 22 May 2006
The original study was designed to inform the development of public policy and law around the concept of 'treatability' of people who have Severe Personality Disorder and are perceived as dangerous, as well as being relevant to clinical practice and academic debates. Although an initial paper on the policy implications was published, the untimely death of the principal researcher meant that the rich data collected from 47 in-depth interviews with relevant professionals has been left unanalysed and not disseminated. The aim of this proposed project is to update the literature collection, perform analysis on the interview data, and to disseminate the findings to academic, policy and user groups.
Podoconiosis (endemic non-filarial elephantiasis) is a common geochemical disease resulting in severe lower limb deformity, debilitation and economic loss for affected families. Our studies to date provide convincing evidence that the disease results from the interaction between a host gene (or possibly genes) and an environmental factor, probably silica, found in the red clay soils to which susceptible individuals are exposed. The aim of this study is to identify the gene(s) responsible for this condition using a robust affected sibling pair genetic linkage study design. The high familial aggregation of cases, the distinctive phenotype and lack of phenocopies, coupled with the evidence for a single major gene mode of inheritance in this population significantly enhance the likelihood of successful outcome. Identification of the gene(s) involved will lead to better understanding of the pathogenesis of this condition including mechanisms of fibrosis that are common to other disorders such as filiarial elephantiasis and causes of pulmonary fibrosis, including silicosis. Elucidation of the molecular mechanisms involved in podoconiosis could also broaden our understanding of gene-environment interactions in the development of complex disorders more generally where the genetic and environmental factors are less clearly defined.
Coreceptor control of T cell cross-reactivity. 12 Jul 2006
T cells recognise foreign' peptide fragments, in the context of self' major histocompatibility complex (MHC) molecules on the surface of host cells. Recognition orchestrates the immune response to protect against pathogen attack. The detection of T-cell antigens is unique inreceptor recognition because it involves the binding of both receptor (T-cell receptor; TCR) and coreceptor (CD8 or CD4). The TCR is also unique in that it must cross-react with >106 different peptide antigens to ensure complete coverage of the array of possible permutations generated from 20 amino acid residues. This inherent cross-reactivity requires precise developmental regulation to ensure that the peripheral T-cell repertoire is optimally poised to respond in the face ofT cells recognise foreign' peptide fragments, in the context of self' major histocompatibility complex (MHC) molecules on the surface of host cells. Recognition orchestrates the immune response to protect against pathogen attack. The detection of T-cell antigens is unique inreceptor recognition because it involves the binding of both receptor (T-cell receptor; TCR) and coreceptor (CD8 or CD4). The TCR is also unique in that it must cross-react with >106 different peptide antigens to ensure complete coverage of the array of possible permutations generated from 20 amino acid residues. This inherent cross-reactivity requires precise developmental regulation to ensure that the peripheral T-cell repertoire is optimally poised to respond in the face ofdanger while remaining continuously quiescent in the presence of self. Preliminary data indicate thatthe coreceptor controls and optimizes T-cell cross-reactivity. I will use a combinatorial peptide library approach and mutant MHC molecules that exhibit >1000-fold range of coreceptor binding whilemaintaining faithful TCR interactions to: Assess how the coreceptors influence T-cell cross-reactivity Examine the role of CD8 sialylation in cross-reactivity Assess coreceptor-mediated T cell cross-reactivity in different species. This work has potentially important implications for our understanding of autoimmunity and could inform therapeutic interventions.
iC3b-accelerated phagocytosis of infecting micro-organisms by neutrophils is the first line of defence by the innate immune system in vivo, yet the mechanism for iC3b-mediated acceleration of phagocytosis is still unresolved. However, we have provided evidence that it involves changes in Ca2+ and subsequent calpain activity. Several key questions are raised by our work. Firstly, does calpain activity within neutrophils increase during phagocytosis with a timing and sub-cellular location c onsistent with it playing a signalling role in accelerating iC3b mediated phagocytosis? Secondly, does the Ca2+ signal for calpain activation reach a sufficient level and at an appropriate sub-cellular location to act as the signal for on/off switching of calpain activity? Thirdly, can the cellular location of phagocytosis-important targets for calpain activity be identified within the neutrophil? As we have developed some novel technologies to address this, we are now in a position to test the calpain-phagocytosis hypothesis. These novel technologies include monitoring of (i) calpain activity using a luminescent probe, (ii) sub-cellular translocation by expression of a fluorescently tagged calpain sub-unit (iii) the location of calpain activation using fluorescent affinity probes and (iv) manipulation of calpain activity using caged inhibitors.
Structural and biological characterisation of novel phosphatidylethanolamine lipids generated by 12/15-lipoxygenase in monocytes and macrophages. 11 Jul 2006
12/15-Lipoxygenase (LOX) is a macrophage enzyme whose deficiency protects against atherosclerosis, hypertension and diabetes. Recently it has been proposed to play a role in promoting inflammation resolution. Using liquid chromatography-mass spectrometry (LC/ESI/MS/MS) we have identified 4 novel lipids generated by 12/15-lipoxygenase (LOX) in IL-4-treated human monocytes (m/z 738 - 782), and MS/MS analysis indicates that they comprise 15-hydro(pero)xyeicosatetraenoic acid esterified to various forms of phosphatidylethanolamine (15-HETE-PE). Levels of these products are considerably (4-10-fold) higher than levels of free 15-HETE released, making them the predominant 12/15-LOX lipids generated by human monocytes. Similarly, in murine peritoneal macrophages, considerably higher levels of esterified 12-HETE than free are detected following activation (10-fold). In this project, we will use LC/ESI/MS/MS to fully characterise the structures of these 12/15-LOX products in monocyte/macrophages. Receptor/agonist-dependent signaling pathways leading to their generation will be determined. Finally, their signaling activities will be characterised in vitro using cultured macrophages/monocytes, and in vivo using an established murine peritonitis model. The structural and biological characterisation of these novel lipids will further our knowledge of the roles of 12/15-LOX in inflammation and may provide new therapies for promotion of resolution and wound healing.
Working title: "Boy Genius". 01 Jun 2006
'BOY GENIUS'Boy Genius' is an innovative approach to the exploration of contemporary developments in human genetics related to mental health. This activity encourages an appreciation of different views about this complex area of science and associated social and ethical issues through interactive participation in the story of a young man's experience of mental illness. UWitWithin an exciting and stimulating'installation' drama environment, participants embark on a complex set of investigative tasks, which make demands on their cognitive, emotional and artistic faculties. An initial encounter with anpowerful intriguing and challenging theatre stimulus awakens participants' desire to undertake this demanding journey of learning and understanding. Interpretations and decision-making within the activity are determined by the participants' in-role contributions. The activity is task driven and structured to enable it to be an intellectually and emotionally stimulating approach to learning. A collaboration between the Wales Gene Park and Gwent Theatre, 'Boy Genius' will be offered to schools and colleges for students, aged 16 -18, from science, humanities and art subjects as concepts and skill elements relate to cross-curricular citizenship requirements. Complementary support material will be developed for teachers and tailored for use across different disciplines, both to draw students into the activity and to extend the learning experience beyond the activity itself. The development, delivery and outcomes of the activity will be evaluated to feed into the on-going development of the project and as a final analysis of the success of the activity.