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Results

Amount: £76,508
Funder: The Wellcome Trust
Recipient: University of Exeter

The cellular and molecular basis for the impact of vitamin A on immunity. 10 Jun 2010

While blindness is an apparent consequence of vitamin A deficiency, incapacitation of the immune system is another devastating result. The studies presented investigate the role of retinoic A (RA) on the development of immunity. We hypothesize that RA exerts a profound impact on the lineage commitment of mature leukocytes. At a systems level, we study its essential role in the development of acquired immunity, and in the complex diseases of cancer, graft rejection and autoimmunity. At a cellular level, responding leukocytes will be studied in vivo at the single cell level, permitting the visualization of antigen-specific immunity in RA-replete or deficient environments. Through the conditional ablation of RA signaling, the RA responsiveness of defined leukocyte subsets will be genetically controlled in vivo, allowing us to define strict cause and effect relationships between RA signaling, specific cell type and overall immunity. A picture of the temporal and spatial synthesis of RA and RA signaling will emerge using engineered reporting mice . Finally, the genetic and epigenetic basis for how RA programs leukocyte differentiation will be determined. These studies span from the fundamental molecular regulation of the immune system by RA to the translational use of regulatory T cells to treat disease.

Amount: £4,692,044
Funder: The Wellcome Trust
Recipient: King's College London

Neurobiological factors underlying the onset of psychosis. 05 May 2010

Dysfunction of the medial temporal lobe (MTL) and of the subcortical dopamine system are key pathophysiological features of psychosis. Animal models propose that psychosis develops as a result of MTL dysfunction driving subcortical dopaminergic hyperactivity through glutamatergic projections to the striatum. MTL, glutamate and dopamine function can all be measured in patients with psychosis using neuroimaging techniques, but to date they have largely been studied separately. A key objective of t he present proposal is to combine functional MRI, MR spectroscopy and PET in the same individual, so that the relationship between these pathophysiological factors can be examined directly. We will do this in subjects with an At Risk Mental State, who have a 20-45% risk of developing psychosis within 2 years. After scanning, the sample will be followed up clinically to determine which of the subjects subsequently becomes psychotic. This will clarify the extent to which these pathophysiological f actors, and their interaction, are critical to the onset of illness. A further objective is to assess whether these neuroimaging measures can be used in a clinical setting to predict which individuals will later develop psychosis.

Amount: £1,054,325
Funder: The Wellcome Trust
Recipient: King's College London

Mental illness and returning patient care in the early National Health Service: a comparative study of the admission and treatment of multiple-entry patients in English mental hospitals, c.1948-1970. 12 Nov 2009

The project addresses complex research problems of mental health care in the post-war years by concentrating on admissions, and more particularly multiple-admission patients who used mental hospitals after 1948. By examining their entry to hospital, the previous social environment of the patient as well as their clinical diagnosis can be ascertained. In addition to considering the influence of kinship and other relations, the role of medical professionals as well as inside hospital is evaluate d. The re-admission patients are examined in depth, including pattern of treatment in hospital and the circumstances of discharge. Particular attention is paid to drug dosages and specific treatments such as ECT. A chronology of admission patterns will be established to track changes affecting the patient population at large as well as the particular experience of readmissions. Control groups will be established among single-admission patients and a detailed comparison is undertaken of two s imilar but distinct regions of England, compiling a comprehensive data set of patients in each area with three levels of specific information. Contemporary rhetoric and societal changes are identified as contexts, institutional practices and patient experiences being monitored to consider the significance of therapeutic and policy initiatives.

Amount: £96,668
Funder: The Wellcome Trust
Recipient: University of Exeter

The roles of TRPM8 in mechanotransduction and osmosensation. 01 Jul 2010

The mechanisms and the ion channels involved in mechanotransduction are poorly understood. Transient receptor potential (TRP) channels expressed in peripheral sensory nerves have been shown to play important roles in sensory transduction. The project is focussed on four related questions based on the hypotheses that the transient receptor potential (TRP) ion channel, TRPM8, plays a role in mechanotransduction and can act as a peripheral osmosensor in some peripheral sensory neurons. 1. Chang es in intracellular calcium concentration or membrane currents evoked by hyperosmotic and mechanical stimuli in identified DRG neurons and TRPM8 CHO cells will be used to determine if TRPM8 has a primary role in mechanotransduction. 2. Intrathecal administration of TRPM8 siRNA and pharmacological inhibition of TRPM8 with a novel antagonist will be used to determine if TRPM8 plays a role in the maintenance of neuropathic and inflammatory mechanical hypersensitivities. 3. Functional and protein /mRNA expression studies will determine if a change in TRPM8 expression contributes to increased mechanosensitivity in pathophysiological conditions. 4. Functional and immunocytochemical studies will reveal if TRPM8 is expressed in sensory neurons at key sites for peripheral osmosensation and is responsible for sensing changes in blood osmolarity in these regions.

Amount: £322,021
Funder: The Wellcome Trust
Recipient: King's College London

Foxg1-dependent regulatory network controlling telencephalic boundary and neuronal fate specification. 01 Jul 2010

Telencephalic neuronal cell fates are dependent upon reception of secreted signals that establish graded expression of transcription factors such as Foxg1. However, the mechanism by which these are controlling cell type decisions is still elusive. We recently found that Foxg1 is a central integrator of two key signaling centres, and drew a coherent model of the genetic interactions controlling subpallial/pallial patterning in vertebrates. Identifying the mechanisms by which Foxg1 is carrying its integrative function is key to understanding both telencephalic neuronal specification and neurologic dysfunctions found in human disorders such as the congenital form of Rett syndrome. This proposal aims to dissect the molecular mechanisms by which Foxg1 controls subpallial/pallial fate specification. The specific questions addressed here are: - Are Eph/Ephrins targets of Foxg1, acting upon both boundary formation and neurogenesis? - Is the mechanism by which Foxg1 drives telencephalic f ates Gli-dependent? - Are discreet levels of Foxg1 activity driving distinct telencephalic fates? - What are Foxg1 partners and targets involved in DV fate specification and boundary formation? High throughput technologies will be used to identify Foxg1 partners (in vivo cross-linking and large scale mass spectrometry) and targets (ChIP-Seq). The experimental models chosen are zebrafish and mouse.

Amount: £424,729
Funder: The Wellcome Trust
Recipient: King's College London

Is hydrogen sulfide a novel endogenous anti-inflammatory mediator? 06 Jul 2010

The gaseous mediator hydrogen sulfide (H2S), formed via the enzyme cystathionine-gamma-lyase (CSE), has been proposed as a novel mediator of inflammation. However, the precise role of H2S (and CSE) in the inflammatory process have yet to be investigated. We propose that in the inflamed human joint, increased expression and activity of CSE in cultured human fibroblast-like synoviocytes (HLFS) increases synovial H2S levels as a novel endogenous anti-inflammatory response to pro-inflammatory mediat ors. Our previous work supports this hypothesis since (i) H2S levels were markedly increased in synovial fluid (SF) aspirates from patients with chronic inflammatory joint diseases and in adjuvant-treated rats compared to matched blood and non-inflammatory SF controls. Furthermore SF H2S levels correlated with clinical indices of inflammation, (ii) CSE expression and activity were induced by several pro-inflammatory mediators (i.e. LPS, IL-1beta,IL-6,TNF-alpha) and (iii) slow generation of H2S u sing a novel infusion technique or our H2S generating molecule GYY4137 inhibited the synthesis of pro-inflammatory mediators. Using cultured HLFS we propose to investigate the mechanisms by which (a) endogenous (CSE-derived) H2S and (b) exogenous (pharmacological) H2S is anti-inflammatory. This project will provide the scientific groundwork for the development of novel therapeutic approaches to chronic inflammatory disorders including rheumatoid arthritis.

Amount: £143,094
Funder: The Wellcome Trust
Recipient: University of Exeter

Alpha2-chimaerin as a molecular switch which regulates motor axon growth and guidance. 05 May 2010

We will first establish that Semaphorin3A/C and CXCL12 signal in oculomotor development, by assessing the responses of oculomotor neurons in vitro to Semaphorin3A/C and CXCL12 ligands, singly and in combination. We will then evaluate the role of the cognate receptors and of alpha2-chimaerin signalling, by determining whether these responses are abolished/modified when neurons express appropriate dominant-negative receptors (Plexins/Neuropilins/CXCR4), or alpha2-chimaerin gain- or loss-of-functi on mutant forms. Secondly, we will analyse the molecular basis of changes in alpha2-chimaerin dynamics and trafficking in response to Semaphorins/CXCL12. We will use fluorescent live cell imaging to visualise and quantify the interaction of aplha2-chimaerin with Plexin and CXCR4 receptors in response to their physiological ligands. Using photoconvertible fluorescent tags and subcellular markers we will analyse how alpha2-chimaerin signalling is controlled and how the mutated proteins escape these regulatory mechanisms. Finally we will determine the in vivo role of CXCL12/Sema3A/C signalling via alpha2-chimaerin by electroporation of appropriate gain- or loss-of-function constructs into the oculomotor/abducens nerves of the chick embryo in ovo, singly or in combination. We will assess phenotypes of axon guidance defects and nerve-muscle patterning and look for evidence of complementation or rescue of defects by manipulation of molecules which lie within the same pathway.

Amount: £223,170
Funder: The Wellcome Trust
Recipient: King's College London

Using Drosophila to uncover dendrite self-destruction programs. 05 May 2010

We still now little about the molecular mechanisms that control the orderly developmental degeneration of axons and dendrites during pruning. Current thinking suggests that neurite degeneration, like apoptosis, is an active and tightly controlled self-destruction event. In this proposal I describe a strategy that uses Drosophila to identify molecules that orchestrate the developmental degeneration of dendrites. This approach combines the strength of Drosophila forward genetics with the detailed in vivo imaging of the class IV dendritic arborizing sensory neuron ddaC. These neurons require the nuclear receptor EcR to remodel during metamorphosis. We have exploited this biology to design a genome-wide interaction screen that will reveal evolutionarily conserved downstream target genes. We will 1) identify candidate genes required for dendrite pruning using a deficiency-based genetic interaction screen. 2) Functionally characterize the candidate genes and perform genetic epistasis studies to determine how these co-operate with known regulators of the pruning pathway. This will allow us to gain a deeper understanding of this fundamental, but little understood, developmental process.

Amount: £334,474
Funder: The Wellcome Trust
Recipient: King's College London

Genetic dissection of intercellular signalling during development of the mammalian cerebellum. 05 May 2010

The cerebellum is an attractive system for investigating fundamental processes in developmental neurobiology. A key question is how different neuronal and glial cell types communicate with each other to coordinate processes such as cell proliferation. To determine whether cells in the developing cerebellum utilise the Fibroblast Growth Factor (FGF) signalling pathway to communicate, we produced mice in which FGF antagonists, encoded by the Sprouty genes, had been deleted from the onset of cerebe llar development. We uncovered a novel route through which the proliferation of granule cell precursors (GCps) could be regulated. We hypothesise that Bergmann glia, previously only thought to have roles in guiding cell migration, are important sources of the GCp mitogen, Sonic Hedgehog (SHH) and that the differentiation of these glia and their ability to produce SHH, are controlled by the level of FGF signalling. We will use cell type-specific gene deletion experiments to dissect the roles of F GF and SHH signalling in Bergmann glia and other cells like Purkinje neurons in the developing cerebellum. Our studies will provide insights into how different cell types utilise these conserved signalling molecules to communicate with each other to coordinate the formation of a vital part of the central nervous system.

Amount: £440,214
Funder: The Wellcome Trust
Recipient: King's College London

Role of IgE in the Pathogenesis of Non-Atopic Asthma. 27 Apr 2010

We propose the first comprehensive analysis of all potential mechanisms of mast cell activation by IgE in the blood and bronchial mucosa of 12 non-atopic and 12 atopic asthmatics and 12 controls. We plan to analyse IgE specificities in serum and protein extracts from the bronchial mucosa of routinely tested (common) allergens and rare allergens, including super-allergens from S. aureus, using an allergen microarrays and ELISA, and unknown, (possibly auto-allergens) using a random peptide phage display library. We will assay serum and extracts for pseudo-allergens anti-IgE and the anti-high affinity IgE receptor. We will clone patient B cells to examine the monoclonal IgEs for cytokinergic activity, VH-region families (to look for evidence B cell super-allergen activity) and the activity of free light-chains. Our study will make use of novel techniques that we or our collaborators have developed, such as B cell cloning, screening for all known allergens using allergen microar rays and for unknown allergens using phage display of a peptide library, and assays of cytokinergic IgE. This research will provide the first definitive test of the pathogenic activity of IgE in non-atopic asthma with the added value of defining a diversity of mechanisms to inform future diagnosis and therapy.

Amount: £368,312
Funder: The Wellcome Trust
Recipient: King's College London

Glutamate and GABA in adults with autism; an in vivo study using magnetic resonance spectroscopy. 05 May 2010

The biological associates of ASD are poorly understood. There is, nevertheless, increasing indirect evidence from genetic [3-12], neuroanatomical [5, 13-15], and peripheral metabolic studies [16-19] that abnormalities in glutamate and GABA may be central. Until recently, however, we could not directly measure their brain concentration in vivo. Proton Magnetic Resonance Spectroscopy (1H MRS) now allows that. We reported pilot evidence that ASD adults have a significant elevation in the combined signal of glutamate and glutamine (Glx) in the amygdala-hippocampal region [20]. However, the field strength of the MRI scanner, and technical methods, then available did not allow clear distinction between the two metabolites or assessment of GABA. Recent developments in 1H MRS now make it possible. Hence we wish to extend our work using new 1H MRS techniques at higher magnetic field strengths. We will measure, for the first time, both glutamate and GABA in brain regions freque ntly implicated in ASD (the amygdala-hippocampal complex and cerebellum), and an occipital control region. We will test the hypothesis that medication na ve young people with ASD have a significant elevation in glutamate and GABA concentration compared to controls; and the subsidiary hypothesis that regional increases in these neurochemicals are associated with clinical symptoms.

Amount: £354,175
Funder: The Wellcome Trust
Recipient: King's College London

Transcriptional regulation of human T cell differentiation. 08 Feb 2010

CD4+ T cells differentiate into a number of effector types that define the immune response to different pathogens. Differentiation into specialized effectors is linked to changes in chromatin structure at key genes and transcription factors have been identified that are critical for this process. These epigenetic modifications provide a memory of cellular state passed onto cellular descendents. T cell effector types are also remarkably plastic and this combination of specificity and plasticity i s likely to be critical for the normal regulation of T cell effector function. We will identify the changes in histone methylation that occur across the genome during differentiation of primary human CD4+ T cells. We will test the hypothesis that lineage-specific gene expression is regulated primarily at the level of transcriptional elongation and determine the role of master regulator transcription factors. From these data, we will develop a conceptual framework that explains the specificity an d plasticity of the helper T cell response. All aspects of this proposal are underpinned by significant amounts of preliminary data. We will define these mechanisms with a combination of established in vitro and in vivo genomic, genetic and biochemical methods and this work will significantly enhance our understanding of human disease processes.

Amount: £251,635
Funder: The Wellcome Trust
Recipient: King's College London

Can genetic variation in microRNA sequences impact on the normal function of the pancreatic beta cell?. 06 Oct 2009

Small regulatory RNA species are important in the fine control of gene expression, which may have implications for complex diseases like diabetes. MicroRNAs are endogenously coded throughout the genome and exhibit genetic variation like other genes. We will determine whether single nucleotide polymorphisms (SNPs) in mature miRNAs or in their precursors (pre-miRNAs) can influence microRNA processing, microRNA structure or target gene regulation. We will determine the microRNA expression profile o f human islets from normal and type 2 diabetic subjects and those in islets from db/db and control mice. MicroRNAs that are found to be deregulated in diabetes and those known from the literature to be important in endocrine function will be screened for sequence variants in regions important for target recognition or miRNA processing. We have already identified two potential variants in the islet-specific miR-375, and miR-376b genes. We will determine the target genes for newly-identified SNPs both in silico and empirically, followed by in vitro knockdown of each allele in isolated beta cells. This will allow us to determine the effect of polymorphisms on target gene expression, microRNA stability and on measures of beta-cell function like glucose-stimulated insulin release, ATP production and intracellular calcium flux.

Amount: £152,071
Funder: The Wellcome Trust
Recipient: University of Exeter

Insights into pore-formation from studies of Clostridium perfringens Epsilon-toxin 01 Oct 2009

Clostridium perfringens epsilon-toxin is uniquely lethal and exquisitely specific. It causes pulpy kidney disease which in unvaccinated livestock can devastate herds in a few days. Pathological changes associated with epsilon-toxin occur mainly in the brain, and it binds MDCK and rat brain synaptosomal cells. Our structure of the monomeric proto-toxin revealed that it is a beta-pore-forming toxin. This family generally shows activity against a broad range of cell types with much larger lethal doses than epsilon-toxin. Understanding why epsilon-toxin shows this atypical behaviour could help the design of a specific, efficient cytolytic agent. We will study oligomerization and receptor interaction. Micro-array analysis has revealed candidate genes for epsilon-toxin sensitivity. We will use siRNA to suppress expression of these genes in MDCK cells and assess their contribution to toxin recognition. We will mutate residues previously identified by structure comparison and conser vation analysis to assess their involvement in receptor interaction. We will determine the heptamer structure by cryo-electron microscopy and crystallography. We already have promising negative stain EM images. Residues revealed to be in the heptamer interface will be mutated and any changes in oligomerization investigated. Non-oligomerizing variants will be used in models of disease to assess their suitability as molecular vaccines.

Amount: £165,749
Funder: The Wellcome Trust
Recipient: University of Exeter

Neurotrophin receptors in ephrinA reverse signaling: Investigating axon branching and synaptogenesis. 08 Oct 2009

The retinotectal/collicular projection represents a key model system for studying the formation of topographic projections. Recent data suggest that topographic mapping is controlled through a balance between EphA forward and ephrinA reverse signaling. We are interested in elucidating the mechanisms of ephrinA reverse signaling, in which the neurotrophin receptors TrkB and p75 are involved as candidate ephrinA co-receptors. Our working hypothesis is that both ephrinA/TrkB and ephrinA/p75 inter actions are ligand-inducible. Here the ephrinA/TrkB interaction promotes primarily branching, while the ephrinA/p75 interaction primarily suppresses branching. We would like to demonstrate that on RGC axons the level of ephrinA expression is crucial for the function of TrkB and p75. We then would like to understand on a molecular level the antagonism between ephrinA/TrkB and ephrinA/p75 by analysing their downstream signaling pathways controlling axon branching. We would like to investigate descriptively and functionally the relationship between axon branching and presynapse formation, and their possible regulation by ephrinAs and neurotrophin receptors. Finally we would like to analyse in vivo neurotrophin receptor function in topographic mapping by investigating the retinocollicular projection in TrkB and TrkB/p75 knockout mice.

Amount: £410,122
Funder: The Wellcome Trust
Recipient: King's College London

Interpreting the Mental Capacity Act (2005) in mental health care. 13 Jul 2010

The Mental Capacity Act (2005) has been in force since 2007. It applies to people who lack capacity from whatever cause. It has been lauded as an impressive and important piece of legislation which deserves ongoing parliamentary review . The Act aims to safeguard the principle that people, when they have capacity to do so, should be able to decide for themselves in relation to health and social care. This emphasis on patient autonomy has led to concerns being raised in areas where traditionally a more paternalistic approach to care has been the norm and where the application of the Mental Capacity Act has been novel and more able to create confusion. Two examples of this are: 1) presentations to accident and emergency departments by people with self-harming behaviour and 2) ?Deprivation of Liberty? in people without capacity to decide treatment in care facilities.

Amount: £23,797
Funder: The Wellcome Trust
Recipient: King's College London

Health and Masculinity in Post War Britain. 24 Mar 2010

The aim of this project is to undertake a detailed analysis of the shifting relationship between notions of masculinity and psychological illness during the second half of the twentieth-century. By focusing both on psychosomatic symptoms (in particular, gastric disorders, insomnia, headache), alcohol abuse, tranquillizer addiction and psychological disorders (depression and anxiety), the research will explore medical understandings, patient experiences and broader representations of men s healt h from the Second World War to the late 1980s and the emergence of the alleged crisis in masculinity . Drawing on a wide range of documentary, visual and oral sources, this research will explore the complex terrain of male psychological illness. It will thus address an imbalance in the historiography that has previously focused on the contradictions inherent in the female role and women s health. The study will result in the publication of a monograph and three journal articles.

Amount: £123,450
Funder: The Wellcome Trust
Recipient: University of Exeter

Envisioning Migraine and the Migraineur , c. 1873 2004. 24 Mar 2010

This research is based on in-depth analysis of diverse archives and published sources relating to migraine in key periods between 1873 - 2004. The project incorporates public engagement, will generate three research articles, and culminate in an accessible book of interest to an audience of historians, medical professionals and migraineurs . In one sense this is a classic medical history: grounded in archival historical analysis, it will trace a disorder whose history is often currently unde rstood only in terms of retrospective neurological diagnosis of famous sufferers. However, by applying methodological insights from medical history, as well as sociology of health and phenomenology, the project s goal is much more than a corrective biography of a disease. Migraine straddles an unstable division between acute and chronic disorder: this project will reveal that its history encompasses important switches in class and gender; plays an important role in contemporary pharmaceutical history, and has a significant contribution to make to our historical understanding of chronic diseases and their sufferers as they come to dominate the health agenda.

Amount: £148,274
Funder: The Wellcome Trust
Recipient: King's College London

A geneticist's library: the collection of Reginald Ruggles Gates (1882-1962) 30 Jun 2010

The Ruggles Gates Collection is an outstanding example of a geneticist's working library. Reginald Ruggles Gates (1882-1962) was a leading plant, animal and human geneticist, whose life and work reflect the often controversial debates that surround the history of genetics. After his death his library and private papers were acquired by King's. While his papers have been fully catalogued, his library - the Ruggles Gates Collection - has not. The proposed project will address this deficiency by sorting and cataloguing the collection, taking steps to ensure its long-term preservation and promoting to the scholarly community what has hitherto been an invisible piece in the jigsaw of world class collections on the history of genetics held at King's. In so doing, the project will help to increase our historical understanding of a man criticised in some quarters during his lifetime for what were deemed unacceptable views on race and heredity. Key project goals include: " The provision of access, by the creation of copy-specific online catalogue records, to approximately 1,090 currently inaccessible items (1,000 pamphlets and 90 monographs), many of them unrecorded elsewhere " The re-housing of approximately 1,000 pamphlets to ensure their long-term preservation " The promotion of the collection by web and printed publicity and by a dissemination event. We will build on the work of another Wellcome Trust-funded project at King's, DNA and social responsibility, to optimise understanding of the ways in which the links between plant and human genetics have informed the development of genetics as a discipline.

Amount: £25,858
Funder: The Wellcome Trust
Recipient: King's College London