- Total grants
- Total funders
- Total recipients
- Earliest award date
- 20 Nov 1998
- Latest award date
- 25 Jan 2019
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
The role of protein tyrosine phosphatase 1B ( PTP1B ) in generation of tolergenic dendritic cells 31 May 2018
In homeostatic conditions dendritic cells are tolerogenic (Tol DC) and therefore, supress immune reactions, making them a key element in the maintenance of peripheral tolerance. Upon challenge, these Tol DC convert into mature, pro-inflammatory DC capable of initiating immune responses, this conversion is key in the induction of uveitis. It has been demonstrated that Tol DCs exhibit hyperphosphorylation of STAT3, a component of JAK/STAT signalling pathway, which is critical in controlling DC function. Previously, the lab has demonstrated that protein tyrosine phosphatase 1B is a key regulator of DC function via a STAT3 dependent mechanism. This project will investigate the role of PTP1B in intrinsic STAT3 regulation in DC by utilising a novel DC specific PTP1B knock out model (Zbtb46-PTP1B). I hypothesis that deletion of PTP1B in DC will result in hyperphosphorylation of STAT3, and preservation of Tol DC phenotype upon inflammatory challenge. Firstly, maturation status will be assessed through surface and intracellular flow cytometry for key DC activation markers (CD40, CD68, CD40, MHC class II) and cytokines (IL-12 and IL-10). Secondly, through assessment of key signalling pathways (JAK-STAT, PI3K-AKT, ERK1/2) involved in DC function, through western blotting, to allow mechanistic insight into the signalling pathways controlling Tol DC phenotype.
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.
Two-day international, multidisciplinary workshop on migration and health - particularly mental health - in historical and contemporary contexts, to be held at the University of Aberdeen, April 2014. 18 Nov 2013
The application is for support towards the costs of a two-day workshop, to be held at the University of Aberdeen from 10-11 April 2014. The primary theme of the workshop is Migration and Mental Health and it will explore in greater depth issues that were raised at a panel session on migration which was held during the annual Association for Medical Humanities conference in Aberdeen in July 2013. It will also build, more specifically, on a two-day symposium to be held in Halifax, Nova Scotia, in November 2013. The Canadian event, which is being co-organised by the applicant under the auspices of Saint Mary's University, Halifax, and the Gorsebrook Research Institute for Atlantic Canada Studies, is entitled Medicine and Migration: historical & contemporary dimensions. Canadian speakers will be joined by the applicant and another speaker from the UK. Aberdeen University is at the forefront of Medical Humanities in Scotland and the workshop will strengthen that profile. The applicant is e ngaged in collaborative interdisciplinary work with colleagues in Aberdeen, elsewhere in Scotland, the UK, and overseas. The workshop, which is expected to attract approximately 25 participants, will enhance and expand these networks and highlight a marginalised area of study.
Mode of delivery after caesarean section: An investigation of offspring risks and factors influencing women's attitudes towards delivery options. 21 Jun 2012
This project aims to address major issues associated with our ever increasing caesarean section (C/S) rate. Offspring risks of elective repeat caesarean section (ERCS) will be studied, including medical conditions potentially associated with a lack of exposure to labour and delivery. Factors which affect attitudes towards mode of delivery in a first pregnancy and following a C/S will be investigated, along with the effect of these factors on intended and eventual delivery mode. We plan to conduc t a retrospective cohort study comparing incidence of various medical conditions in offspring delivered by ERCS with those aiming for vaginal birth after C/S (VBAC) in Scotland. We will systematically review existing literature on factors affecting preferences for ERCS or VBAC. We will use these findings to inform a questionnaire study of psychological factors affecting preferred mode of delivery using a Theory of Planned Behaviour approach in; Group 1) women in their first pregnancy, who will r eceive the same questionnaire during mid-pregnancy and in the post-natal period, consisting of closed-ended questions; Group 2) Women in their second pregnancy after a previous C/S, who will receive an extended version of the questionnaire received by group 1, including open-ended questions.
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.
Grant to Norfolk Knitters and Stitchers 20 Mar 2015
as a staff grant towards the running costs of an organisation which brings people together to knit and sew for good causes
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.
The aim of this project is to develop a protocol whereby human embryonic stem cells (hESCs) can be induced to differentiate into insulin secreting Beta cells. The hESCs will be cultured in chemically defined media in the presence of growth factors that promote differentiation of endoderm. We will also generate hESC lines that have been stably transfected with DNA constructs in which fluorescent reporter proteins are expressed under the control of regulatory sequences of genes encoding transcrip tion factors that control beta cell differentiation. These lines will be used to optimise culture conditions for the differentiation of endoderm-enriched hESCs towards Beta cells. To assure differentiation towards a Beta cell like phenotype we propose to induce expression of transcription factors that are known to control islet development. We have constructed a novel plasmid in which a superactive form of the transcription factor PDX1, i.e. PDX1VP16 is fused to a 4 OH-tamoxifen responsive seq uence, ERT2. The plasmid is configured such a way that it should be possible to replace the PDX1 coding sequences with sequences for PAX4, BETA2, ngn3 or other factors that are known to control islet cell differentiation. The hESC-derived Beta cells will be characterised in vitro and in mouse diabetic models.
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.
Ion channels and transporters play major roles in cellular homeostasis, as exemplified by our work on mechanogated (MscS & MscK) and electrophile activated (KefC) channels. We have made considerable progress in understanding the gating of these two channel types including defining the open structure for MscS (submitted for publication) and the structure of the regulatory domain of KefC (in preparation). Our future programme will concentrate on developing these novel insights, but specifically to integrate into our research synthetic chemistry approaches that will provide the basis for interventions via deregulating the activity of these systems. I have identified collaborators at San Diego State University (SDSU) with whom we have undertaken preliminary studies of peptides that appear to interact with mechanosensisitve channels. In addition, our work on KefC gating has reached a crucial stage were more frequent interaction with the crystallographer (Roosild), who is based in Nevada , would be extremely valuable for the development of the structural analysis of gating, but also for defining objectives for synthetic chemistry approaches. Finally, there is a strong metagenomics group at SDSU and with them we will develop methods for analysing channel gene expression in bacterial communities.
MICL is an inhibitory C-type lectin-like receptor which we identified and have shown to be expressed predominantly on myeloid cells. Characterisation of this molecule, which has only been performed in primary human cells and transfected cell lines in vitro, has demonstrated that human MICL functions as an inhibitory receptor and can control myeloid cell activity. This receptor is conserved across species, and we have demonstrated that the murine homologue has similar functions and expression p atterns. As the targeted deletion of inhibitory receptors has revealed the physiological functions for many of these molecules, particularly in the control of inflammation and autoimmunity, we propose to generate and characterise a MICL deficient mouse. These mice will be examined for any defects in homeostasis, such as the development of autoimmunity, as well for defects in the control of inflammation following induced autoimmunity and infection, for example. We have also detected the presence of endogenous MICL ligand(s) in a variety of murine tissues, and propose here to identify and characterise the nature of these molecule(s).
Cataloguing the archives of the Aberdeen Medico-Chirurgical Society (1789 - 20th Century). 21 May 2008
Founded in 1789, Aberdeen Medico-Chirurgical Society (GB 0817) is acknowledgedamongst scholars in the field as holding a rich and unique collection of manuscripts relating to the provision of medical training, in particular surgery and midwifery; the championing of radical public health measures; as well as the provision of hospitals and their services within the community. These records, which date from the 18th to 20th centuries, survive alongside the papers of many internationally-renowned medics. Notwithstanding the significance of the archive for the history of medicine, it remains virtually unused by scholars. Intellectual access is hindered by a lack of a union catalogue or any application of international descriptive standards. The Society wishes to address these issues by listing its collections to international standards and by web-mounting the catalogue on the University ofAberdeen's CALM collection management system. This, along with targeted promotion, would for the first time bring the archives to the attention of thehistory of medicine community. We also wish to commission a professional conservation survey of this materialto report on its preservation (re-housing, environment) and conservation (treatment) needs. A significant proportion of the archive - the McGrigor Collection - was recently digitised and we wish to web-mount this as part of this project usingDigiTool resource discovery software, also hosted by the University. This willwiden access to a key collection with broad research appeal and serve as a further preservation measure. The web-mounted images will be linked to their relevant CALM catalogue entries.
Disease risk in Madagascar. 07 Apr 2011
The project will examine how environmental and social factors contribute to the risk from zoonoses in a developing country context, using rodents and rodent-borne disease in Madagascar as a model system. It will integrate analyses of archived data and samples from rodents, historic data on human plague incidence in Madagascar and new data on rodent and human infections in a diverse landscape. I will investigate how climate, habitat and landscape affect host-pathogen dynamics within the roden t populations, considering a range of pathogens with different transmission routes. In addition, I will explore how climate and landscape affect host and vector abundance and movement, key determinants of disease dynamics. Within humans, I will examine the relative importance of environmental and socio-economic factors for human exposure risk at different scales, determining whether relationships vary between pathogens. On the basis of the relationships detected, I will assess whether eff ective predictive risk models that exploit easily accessible data can be developed. I will produce maps of current risk and forecasts of risk under future climate change and deforestation rate scenarios. Results will be presented to health and environment sectors to raise awareness and explore potential disease reduction strategies
A major fungicidal mechanism employed by the immune system is the generation of ROS. However, the fungal pathogen Candida albicans is relatively resistant to ROS and can evade killing by macrophages. Indeed, responses to ROS are tightly linked with C. albicans virulence, yet little is known regarding the signalling mechanisms underlying such responses. Significantly, our pilot experiments revealed that the thioredoxin protein, Trx1, has vital signalling functions in C. albicans and regulates two major responses to ROS; activation of the Hog1 SAPK, and H2O2-induced filamentation. Furthermore, we find that trx1Δ cells display attenuated virulence in a mouse model of systemic candidiasis. No previous studies have identified mechanisms underlying ROS-induced filamentation, or have implicated thioredoxin in regulating a fungal SAPK pathway. Moreover, the virulence defect exhibited by trx1 cells highlights the potential importance of such processes in promoting C. albicans survival in the host. This project, which builds on a strong platform of data and combines the strengths of Newcastle and Aberdeen in C. albicans stress responses and virulence, has the following goals: to delineate the mechanisms of Trx1 regulation of the Hog1 SAPK and H2O2-induced morphogenesis and to explore which aspects of Trx1 function are important for virulence.