- Total grants
- Total funders
- Total recipients
- Earliest award date
- 10 Apr 2001
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
Zeiss LSM 880 confocal microscope with Airyscan detector for super-resolution imaging at the University of Aberdeen 06 Jul 2017
We seek funds for a Zeiss LSM 880 confocal microscope with Airyscan detector and Airyscan Fast Acquisition Module to advance a diverse range of interdisciplinary Wellcome Trust funded projects with a focus on medical microbiology and immunology that are central to the University’s strategic plan. Compared to conventional confocal microscopes, the LSM 880 with Airyscan provides greatly improved image quality and super-resolution imaging by simultaneously increasing signal to noise (4-8x) and resolution (1.7x) while enabling faster scanning (4x). Notably, laser power can be reduced substantially, thereby enabling long-term imaging of live cells expressing multiple fluorophores. This allows rapid, dynamic and complex processes to be acquired in super-resolution. The supplied ZEN2 software enables automation of many tasks. The equipment will be housed in our well-established Microscopy Core Facility in the College of Life Sciences and Medicine. The equipment will be maintained by core-funded staff with extensive expertise in state-of-the-art microscopy and decades of experience serving our research community, locally and further afield, using sustainable cost-recovery mechanisms. The equipment will primarily support our Welcome Trust funded researchers, but also other researchers working in the biomedical sciences, bringing considerable added value and new insights into these research programmes.
In vitro characterisation of neurons and glia derived from mouse ES cells having Y chromosome gene deficiencies 27 Apr 2017
The brain is a sexually dimorphic organ, which can explain why many psychiatric disorders are gender-biased. While it has been thought that fetal sex hormones play a crutial role in brain sexual differentiation, emerging evidence indicates that genetic and/or epigenetic factors encoded by sex chromosome genes are also involved. Here, we focus on several Y-linked genes expressed in the male brain, which may act in a dominant manner. Sry, Uty and Smcy genes, whose products can participate in histone modification, are of particular interest. However, their functions in the brain remain unknown mainly because of difficulties in conventional gene-targeting of Y loci in embryonic stem cells (ESCs). In this project, we will take advantage of Crispr/Cas genome-editing technology that allows us to modify Y-linked genes. Mutant alleles of these three genes in ESCs were created and then differentiation will be induced of neurons and glia from the mutant ES cells. Differential gene expression between wild-type and mutant cells will be analysed by RT-RCR and bisulfite PCR, and subsequently epigenetic status of these differential genes will be elucidated. The project will reveal influences of Y-linked genes on sex-specific epigenetic modification and lead to better understanding of gender-biased psychiatric disorders.
Biomphalaria glabrata: gene discovery, expression, profiling and interval mapping to elucidate mechanisms of resistance to Schistosoma mansoni. 14 Dec 2005
To promote an understanding of snail-schistosome interactions and development of novel intermediate host-based control strategies an EST gene discovery approach is proposed, to increase significantly the genomic database of B. glabrata, the intermediate host of Schistosoma mansoni, a major schistosome infecting man. There is international interest to commence genome sequencing of this important mollusc, and parasite resistance is the trait currently perceived as the most crucial. Isolation of transcripts by gene discovery approaches, and identification of those involved in resistance, by microarray analyses, will create the initial impetus for a genomic analysis of B. glabrata. Quantative trait loci (QTLs) will be identified through interval mapping, using preliminary linkage maps, incorporating genome-wide markers, using populations segregating for schistosome resistance. Combining microarrays with mapping will accurately identify candidates conferring resistance, separating causal from secondarily effected differentially expressed genes. The map position of each transcript will be improved progressively, and genes differentially expressed between resistant and susceptible snails and lying within a QTL will be further characterized. This work will provide the initial impetus for further genomic characterization of B. glabrata, allowing for future integration of parasite and intermediate host genomics to elucidate their co-evolution and suggest novel interventions.
Historical and conceptual links between Pierre Janet and Eugen Bleuler's (1911) concept of schizophrenia: A preliminary exploration. 26 Apr 2006
Historical and conceptual links between Pierre Janet and Eugen Bleuler's (1911) concept of schizophrenia: A preliminary exploration In the broadest terms, this project aims to explore the historical and conceptual roots of Eugen Bleuler's concept of schizophrenia, and its impact in Britain. The basic hypothesis is that the influence of Sigmund Freud on Bleuler's thinking has been overrated (including by Bleuler himself), with a corresponding devaluation of the extent to which Bleuler was influenced by Pierre Janet and his concepts, along with allied 'dissociationists' (such as Theodore Flournoy). The research attempts to trace the development not only of Bleuler's concept of schizophrenia, but also of the fundamental terms 'loosening' ('Lockerung') of associations, 'splitting' ('Spaltung') and complexes ('Komplex'). I am also seeking to trace Bleuler's contact with a variety of figures, and trace the significance of their influence on him, including Charcot, Forel, Wundt, Wernicke, Breuer, and, of course, Freud. Perhaps the most important is the influence of Carl Jung, Bleuler's colleague at the Burgholzi Hospital during the crucial years the concept of schizophrenia was being developed, and his 'second in command' for many years. The questions to address are: 1) When did Bleuler first formulate his ideas on 'loosening' of associations, and what influenced him in this regard? 2) Did Bleuler ever meet Janet? Did he have any direct contact with him? 3) How important an influence was Breuer and Freud's 'Preliminary Communication' in 1893 on Bleuler's developing ideas? 4) How much of an influence did Jung's ideas, particularly his 1907 book on Dementia Praecox have on Bleuler? 5) Why was Bleuler so enthusiastic about Freud? 6) How affected was Bleuler and the other Burgholzi physicians by Jung's sojourn with Janet in 1902-1903? 7) When was the term 'schizophrenia' first used around Burgholzi? 8) After Bleuler's book was published in 1911, did Freud read it? 9) Is there any historical record around Manfred Bleuler's invitation to Pierre Janet in 1946 to come to Zurich? Did he feel that Janet was an important influence on his father?
Student electives for Justine Downing, Jennifer Muir, Michelle Perera and Wendy Thomson. 19 Jul 2006
Interaction of Se, fatty acids and a polymorphism in GPX4 in modulation of vascular function. 15 Oct 2007
Incidence of vascular disease in humans can be influenced either beneficially or adversely by diet. Dietary fats can modulate vascular function and in particular, polyunsaturated fatty acids (PUFA), which have potentially beneficial effects, may have their function modulated by dietary selenium. This study aims to explore the molecular mechanisms through which selenium-containing proteins, and in particular, glutathione peroxidases can influence the metabolism of PUFA to promote formation of pro ducts in vascular cells that may be help prevent or decrease vascular disease. We propose that phospholipid hydroperoxide glutathione peroxidase (GPX4) has a critical role in eicosanoid metabolism and that this is influenced by a novel single nucleotide polymorphism (SNP) in GPX4. Thus, lipoxygenase activities and eicosanoid metabolism may be modulated by both dietary selenium through the peroxidases and through levels of PUFA in monocytes and endothelial cells. The effect of dietary releva nt levels of selenium and PUFA on endothelial-monocyte function/dysfunction will be assessed in genotyped cells and correlated with their effects on eicosanoid profiles and changes in gene and protein expression. Throughout this work we intend to gain insight not only into the interaction of dietary components with vascular health but crucially the role that genotype plays in this interaction.
Architecture of the genome: a genetic investigation of chromosome-positioning mechanisms. 16 May 2007
The intranuclear organization of chromosomes is critical for many aspects of genome function, affecting gene expression, DNA repair, and the organization of DNA replication. It is therefore imperative that we understand the mechanisms and cellular components that control chromosome architecture. We have pioneered a screening method that combines advanced imaging with yeast genetics to identify cellular components important for chromosome positioning, using a microscope system funded by a recent Wellcome Trust Equipment grant. Our pilot analysis has identified the chromatin assembly factor Asf1 and the Ctf18 ring-loading complex as crucial for correct positioning of the chromosome ends or telomeres. The first objective of this research programme is to use genetic, genomic, and proteomic approaches to understand the mechanisms by which Asf1 and Ctf18 affect telomere positioning. Second, we will undertake a genome-scale survey of the cellular components responsible for positioning and organizing telomeres. The information gained will contribute to the third part of the programme, in which we will analyse the localisation of non-telomeric chromosome domains, and identify the molecular components involved in global chromosome positioning. Overall, this research programme forms a cutting-edge investigation of the mechanisms controlling eukaryotic chromosome architecture.
Diet and autoimmunity: modulation of the myelin oligodendrocyte glycoprotein specific T cell repertoire by the milk protein butyrophilin. 08 Feb 2007
Sensitisation to the milk protein butyrophilin1A1 (BTN) initiates an immune response that cross-reacts with myelin oligodendrocyte glycoprotein (MOG), an important candidate autoantigen in multiple sclerosis (MS). This cross reactivity can be exploited to expand regulatory T cell populations that suppress the encephalitogenic potential of MOG-specific T cells in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. This project will exploit the availability of BTN deficient C57 BL/6 mice to test the hypothesis that epitopes derived from autologous BTN play a major role in shaping the composition/function of the endogenous MOG-reactive autoimmune T cell repertoire. Specifically, we will investigate: (1) The mechanism(s) by which immunological self-tolerance to autologous BTN is established. (2) How epitopes derived from autologous BTN influence the composition/function of the MOG-reactive T cell repertoire and susceptibility to MOG-induced EAE. (3) How sens itisation to autologous BTN may be exploited to suppress MOG-mediated autoaggression in adults.
In-vivo and In-vitro Control of Adult Neural Progenitor Differentiation in the Hippocampus by Retinoic Acid. 06 Feb 2007
All-trans retinoic acid (tRA) has been widely investigated as a regulator of the embryonic CNS , a topic we have extensively studied [2-10]. Much less is known however regarding its influence on the adult brain . We were the first to show that RA influences one aspect of hippocampal neuroplasticity neurogenesis [12, 13] and this proposal tests a new hypothesis that a precise equilibrium of tRA is essential to maintain this process. We will test this hypothesis by disrupting the bal ance of RA either by over-stimulation via treatment with 13-cis RA, used in the anti-acne drug Accutane  or under-stimulation using a retinol-binding protein null mutant mouse as a model for vitamin A deficiency. The effects of imbalance will be tested on three defined, quantifiable aspects of neurogenesis, determining: 1) the influence of varying RA concentrations on neuronal birth, 2) candidate cell cycle proteins influenced by RA and 3) RA s influence on neuronal maturation. New modulat ors of neurogenesis are currently sought because of their potential importance in CNS repair and psychiatric disease [15-17] and this proposal will characterize a new neurogenic modulator unique because of its ability to be adjusted by both dietary and genetic means.
Malaria accounts for 10% of the disease burden of Africa, where it has been estimated to kill a child every 30 seconds. Children in the early years of life are particularly vulnerable to the severe effects of malaria and most of the deaths each year result from P. falciparum infection in young children living in endemic areas. Malawi is one of those endemic areas, which is situated in South East Africa and has a population size of approx. 13 million with an estimated 2.4 million being under 5 years old. Severe malarial anaemia is an important clinical consequence of acute or recurrent malaria. However, other aetiological factors, principally malnutrition, also account for much of the anaemia seen in Africa. One study in neighbouring Kenya looking into the causes of anaemia in children, attributing 46% to Malaria, 25% to Malnutrition, the remainder principally ascribed to gastrointestinal infections such as hookworm. For my elective project, I will travel to the Mzuzu Central Hospital in the Northern Region of Malawi. The hospital serves a population of approximately 150,000. A thick and thin blood film and a haemoglobin level are routinely performed for every child who presents to this Hospital. These data are retained in the hospital case records. I will prospectively audit those results, coupled with the reason for initial presentation, for all children under 5 years admitted to the Hospital for the duration of my elective. This will provide results for approximately 150 children, approximately 35% of whom are likely to have P. falciparum parasitaemia.
Bio-traffic light systems; engineering toggle switches in yeast using translational control of gene expression. 29 Mar 2010
We will implement a translational control toggle switch using two proteins, Iron Response element binding Protein (IRP), and MS2-stem loop binding protein (MS2-BP); both proteins bind RNA stem loops in a sequence-specific manner. In the toggle switch circuit, the gene for IRP will contain an MS2 RNA stem in its 5' leader; a second gene will encode MS2-BP, with an iron response element in its 5' leader. Each RNA-binding protein can potentially inhibit the translation of the other (1, 2; Figure 1 ). The two RNA binding proteins will be fused to GFP and RFP respectively, to allow fluorescence monitoring of toggle switch position. By additionally regulating the transcription of each RNA-binding protein gene, using galactose- and copper-inducible promoters respectively, a re-set function is established, allowing red/green toggling. The project has scope for development if time allows; translational control of stop codon read through using suppressor tRNAs can be used to tag IRPGFP with a destabilising peptide tag, acting as a translationally controlled toggle reset. Mathematical modelling will be used to describe the expression of the circuit's genes, including both transcription and translation. Initially, we will use ordinary differential equations to predict the concentration of proteins in response to signal input. Later refinement will employ a stochastic model of translation that considers the traffic of ribosomes on the mRNAs, and links to the transcription process. The presence of a protein blocking the 5' leader of an mRNA will be modelled by reducing the probability with which ribosomes bind the mRNA. Stochastic simulations will moreover allow generalising predictions from single cells to populations of cells. The proposed model will be validated by comparing the predictions to experimental data. Overall, the project will test the hypothesis that synthetic toggle switches can be engineered using translational control. The project will additionally establish a translational control toolkit for eukaryote bioengineering. The specific objectives and anticipated outcomes of this project are as follows; 1. Development of deterministic and stochastic mathematical models of translational toggle switches to guide circuit design. 2. Construction of RNA binding protein BioBricks, fused to GFP and RFP, in yeast expression cassettes. 3. Testing of RNA-binding protein/fluorescent protein expression in yeast, at the single cell and population levels. 4. Iterative improvement of the model using experimental data, and test of new predictions generated by the model.
The Candida albicans ORFeome project. 30 Apr 2009
Candida albicans is the major agent of invasive fungal infections and a central model for studying fungal pathogenesis. This proposal aims to develop novel tools for functional genomics of C. albicans. It will generate 3 collections of clones and strains, providing a valuable resource to the international scientific community studying fungal virulence. The resource will set up genome-wide molecular tools and libraries of strains that can be used in an extensive range of applications including th e functional analysis of all the genes of C. albicans. The 3 main objectives are to generate: (1) a complete set of sequence-verified C. albicans genes cloned into an E. coli vector using Gateway technology. This will form the C. albicans ORFeome. (2) a complete set of C. albicans over-expression plasmids with each gene under the control of a strong inducible promoter within a signature-tagged vector enabling integration into the C. albicans chromosome at the RPS1 locus. (3) a library o f signature-tagged C. albicans over-expression strains by transforming each of the vectors generated in (2) into C. albicans. The clones and strains will then be made available to the research community. The company Open Biosystems have agreed to maintain and distribute the collection.
Overcoming nutritional immunity: micronutrient acquisition mechanisms of pathogenic fungi. 06 Nov 2013
During infection, mammalian hosts restrict the availability of key micronutrients in a process called nutritional immunity. Pathogens, therefore, must possess specialised, high affinity micronutrient acquisition systems to grow in the human body and cause disease. The first aim of this project is to characterise the molecular mechanisms of micronutrient uptake and intracellular mobilisation in pathogenic fungi. I will identify these components using a combination of bioinformatics, transcriptomi cs and high throughput screening of mutant libraries. The phenotypes of C. albicans mutants lacking micronutrient scavengers will be examined. The second aim will be to assess the contribution of these genes to resisting host enforced nutritional immunity. This will be achieved by testing C. albicans mutants in defined cell culture infection models, tailored to mimic specific aspects of nutritional immunity. The third aim is to define the impact of micronutrient exploitation on the outcome of in fection. I will use animal models to elucidate the contribution of selected C. albicans genes towards commensal colonisation and invasive infection. Furthermore, I will use the information gathered in C. albicans to investigate the function of conserved components in other pathogenic fungi. This will validate whether the identified pathways represent broad-spectrum therapeutic targets.
The 8-week scholarship will involve screening 15 Thalidomide analogs on both chicken and zebrafish embryos to test for whether they present teratogenic, antiangiogenic and/or anti-inflammatory effects. The chicken embryos will be used to analyse the effects of the analogues on embryogenesis. Two strains of zebrafish will be used; Fli-1EGFP strain has GFP-tagged endothelial cells and can be used to determine whether an analog is anti-angiogenic, and the MPO-GFP strain has GFP-tagged neutrophils and can be used to determine whether an analogue has anti-inflammatory effects. Further analysis can be performed using ELISA assays of TNFalpha to determine the potency of the analogs.
The Wellcome Trust has recently awarded the University of Aberdeen £600,000 in funding to support a range of strategic research activities that fall within the Wellcome Trust's remit. Projects must fall within the remit of the Wellcome Trust and be within the strategic remit of the Aberdeen ISSF including; Infection, Immunity and Inflammation, particularly Medical Mycology Understanding the molecular basis of obesity for the development of interventions Applied Health Sciences, particularly through our Chief Scientist Office-funded Health Economics Research Unit and Health Services Research Unit. The support strategy for the fund is to: Facilitate more interdisciplinary research across the schools and institutes Enhance research impact through its translation into practice and dissemination through public engagement Enhance our Career Development Support in biomedical research The ISSF Seed Corn Fund will invite proposals from researchers working in a priority area with the aim of supporting new interdisciplinary collaborations by: Providing access to core facilities for proof of concept, feasibility or other pilot work needed to strengthen full scale applications to the Wellcome Trust or other similarly prestigious funders; Applications are particularly encouraged utilising the Centre for Genome Enabled Genomics and Medicine to strengthen pilot data and informatics; Developing new commercialisation or knowledge exchange opportunities, especially for Wellcome Trust funded projects (e.g. through support to develop and implement drug development roadmaps, appointment of external consultants, access to clinical trial design/expertise/health economic advice). As part of our commitment to recruiting and retaining the highest calibre ECRs, we want to enhance our support for the preparation of fellowship applications within the Wellcome Trust’s remit within the context of our highly successful fellowship management scheme. The ISSF will provide up to 6 months of salary support for around 5-6 recipients who meet our criteria and who participate in the College of Life Sciences and Medicine (CLSM) fellowship traffic light scheme. We are launching a programme aimed at female academic staff returning from maternity leave or a career break, which enables them to apply for a period of protected research time. This support will position individuals for subsequent success in attainment of research grant or fellowship funding, or the publication of findings which support career development. You may apply for teaching and administrative replacement costs, but in addition you may also request costs for an RA for a limited period, and/ or some consumables. We wish to expand clinical scientist numbers through the Aberdeen Clinical Academic Training (ACAT) scheme. This is intended to allow clinical applicants to develop a research interest within one of our priority areas. As well as increasing the number of clinical scientists this approach creates new opportunities for translational and interdisciplinary research.
Verbal Autopsy with Participatory Action Research (VA-PAR): Developing a people-centred health systems research methodology. 25 Mar 2015
People-centred health systems (PCHS) is a recent progressive shift that has moved thinking beyond building-blocks models of health systems towards ones that centralise a human and relational nature. Despite the conceptual advance, empirical methods are lacking. The project seeks to develop methods for conducing and using Verbal Autopsy (VA) consistent with a PCHS approach by combining VA with Participatory Action Research (PAR) in a process connected to the health system at different levels. VA is a health surveillance technique that provides information on levels and causes of mortality in populations where deaths occur outside facilities and/or without registration. PAR is a process that aims to transform the roles of those participating from objects of research to active researchers and agents of change. It systematises local experience through collective analysis to generate valid forms of evidence on the relationships between health problems and their causes. Three phases of research are proposed. In Phase 1, we will conduct a secondary analysis of data gained through the application of the 2012 WHO VA standard in a Health and Demographic Surveillance Site (HDSS) in rural South Africa. Combing data on medical causes with new data on background characteristics of deaths, we will develop improved ways to classify causes in a method suitable for use at sub-district/district level. In Phase 2, local service users and providers will engage in a PAR process to review the results of Phase 1, set priorities for local services, and explore the potential for co-benefits related to empowerment and social inclusion. The final Phase 3 aims to consult at higher levels of the health system to consider how the method could be further applied and evaluated. The overall output is a practical and integrated methodology based on core standards that is contextually relevant and capable of affecting health gains by translating local priorities into actionable public health agendas.
Pattern recognition receptor co-stimulation and chronic fungal infection in chromoblastomycosis. 05 Oct 2010
Fonseca pedrosoi is a causative agent of chromoblastomycosis, a chronic disfiguring disease of the skin and subcutaneous tissues which is very difficult to treat. Virtually nothing is known about the immunology underlying this disease or why it causes chronic infections. Using murine models, we have discovered that the chronicity of the systemic disease is due to a defect in innate recognition. We found that although the pathogen was recognised by an unidentified Fc(gamma)-coupled receptor, it did not co-activate the Toll-like receptor pathway, which resulted in an insufficient pro-inflammatory response. Excitingly, infection could be cured in vivo by artificially co-stimulating the TLR-pathway, suggesting a possible route for treatment of this disease in humans. In this application, we wish to verify that this form of treatment would work without undesirable side-effects in a murine subcutaneous infection model, which would more closely resemble the human disease, and to explore the possibility of using topically applied TLR agonists as a form of treatment. We also propose to characterise the innate mechanisms involved in the recognition of F. pedrosoi, by identifying the pattern recognition receptor(s) involved and by characterising the cell wall of this organism.