- 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
A failure to properly build and maintain cellular structures leads to cell-death or disease. Yet, the regulation and mechanisms of the machinery that coordinate such structures are generally poorly understood. The formation and maintenance of many cellular substructures is dependent on the receipt and retention of specific components, selected through tethering complexes. Of particular interest is the exocyst complex, whose role in polarized trafficking leads in part to the spatially and physically distinct cilia and tight junction membrane substructures. I hypothesize that membranes and combinations of their signaling proteins coordinate the mechanics of the polarized trafficking machinery through the exocyst. I will determine how this complex assembles and targets specific membranes through an innovative reconstitution combining biophysical and cell biological approaches. Through synergy with structural methods, the outcome of this approach will be information on the relationship between structure and functional mechanism on membranes, and the cellular consequence of exocyst spatiotemporal regulation. The imbalances of polarized trafficking in both aberrant development and cancers urge a program aimed at resolving the molecular mechanics of this pathway.
This project examines ‘Chronic Traumatic Encephalopathy’ (CTE), a form of dementia which arises from concussive and sub-concussive blows to the head. The majority of cases of CTE result from head impacts suffered during sporting activity. Given the large number of sports associated with a risk of CTE, there are increasing concerns about a ‘silent epidemic’ of dementias which may affect both amateur and professional athletes. These concerns have led to diverse calls for technological innovation, rule change, and legislation to ward against the disease. Drawing upon elite interviews and ethnography conducted with three sporting communities (American football; professional wrestling; age group rugby) this project will ask: How is CTE rendered intelligible within diverse sporting contexts? How do practitioners understand themselves, their brains, and their conduct in the context of the risk of CTE? Finally, how is knowledge of the brain and dementia entangled with classed, raced, and gendered sporting activities? This ambitious study will be amongst the first in Medical Sociology and Science and Technology Studies to consider CTE and will yield novel empirical and theoretical findings relating to the social shaping of this crucial, emerging diagnosis and its place within contemporary society.
An assay and tools for cell biological analysis of human neurogenesis
Obesity causes brain insulin resistance and prevents the brain from regulating metabolic responses, maintaining energy balance and controlling the nutritional status of an individual. Restoring the brain’s ability to modulate metabolic functions could be an important intervention to prevent the negative outcomes of obesity and diabetes. The Dorsal Vagal Complex (DVC) in the brainstem senses insulin to regulate glucose metabolism, food intake and body weight in rodents. Three days of high-fat diet feeding is sufficient to completely disrupt the insulin response in the DVC, thus causing an increase in blood glucose levels and excessive eating. Recently, I discovered that increased mitochondria fission and ER stress in the DVC can cause insulin resistance and affect the ability of the DVC to regulate blood glucose levels. I aim to understand whether increased mitochondria fission in the DVC can affect food intake and body weight in rats. Using in vivo and in vitro experiments, I aim to uncover the mechanism by which changes in mitochondria shape and size affect DVC insulin sensing and eating habits in rodents. This project could lead the way for the development of novel approaches that target the brain to regulate food intake and body weight in obese subjects.
The majority of small molecule drugs on the market only target a very small range of potential targets. They function by their binding event causing a direct modulation of their target protein’s function, however it is not clear that all proteins involved in disease can be targeted in such a manner. In this project, I aim to develop drug molecules with a different mechanism of action. One half of the molecule will be able to bind to a protein involved in a disease pathway and the second half of the drug would be capable of dragging the molecule to an enclosed cell compartment, known as the peroxisome. Such re-localisation will trap the disease pathway associate protein making it unable to carry out its function providing a new strategy for therapeutic intervention.
TRAF6 is essential for many biological processes, including those activated by interleukin-1 (IL-1) family members, Toll-Like-Receptor (TLR) ligands, and TNF superfamily (TNFSF) members. We have unexpectedly discovered that many of the essential roles of TRAF6 are independent of its E3 ubiquitin ligase activity and that, surprisingly, a key role of the TRAF6 E3 ligase is to restrict T cell activation and prevents autoimmunity. Building on these and other exciting findings we have made, the aim of the proposed reseach is to solve three major questions:- 1.What are the molecular mechanisms by which TRAF6 mediates signaling by the TNF superfamily members RANKL, CD40 and BAFF? 2. What are the molecular mechanisms by which the TRAF6 E3 ligase restricts T cell activation, and will they open up new opportunities to unleash the power of cytotoxic T cells to treat cancers and other diseases? 3. How does the TRAF6 E3 ligase activate a novel IL-1-dependent signaling pathway we have identified, which triggers activation of the "master" kinase TAK1 in the absence of its ubiquitin-binding subunits TAB2 and TAB3, and does this pathway have important roles in other TRAF6-dependent processes?
Investiagtion of protein-lipid interactions 01 Apr 2016
Until recently the lipid membrane was thought to be a passive or neutral environment in which the transmembrane proteins are located, but this has now been supplanted by a model in which lipid-protein interactions are important to the functioning of the cell. Proteins can locally deform membranes, modify and reorganise lipids, and regulate membrane charge, diffusion and lateral organisation. One method for investigating protein-lipid interaction is to measure the effect of proteins on the elusive "lipid rafts", which are hypothesised to exist in membranes possessing two co-existing liquid phases, as micro-domains of liquid ordered (Lo) phase in a sea of liquid disordered (Ld) phase. However, our recent work using a Wellcome Trust funded high speed Atomic Force Microscopy indicates that a more subtle mechanism fully explains the known properties of lipid rafts in cell membranes; that rafts are actually a highly dynamic fluctuation of a single liquid phase near a critical point of the lipid bilayer phase diagram, and that this fluctuation is then stabilised by the presence of a transmembrane protein, creating a stable nano-scale raft of
Exploring DNA origami nanotiles using atomic force microscopy as potential therapeutic delivery vehicles 01 Apr 2016
Production of DNA origami nanostructures is a promising approach for creating biocompatible nanomaterials to be used as drug delivery vehicles. The size and shape of these DNA nanostructures can be controlled by rationale design of the sequence of the DNA staple strands relative to the long template strand. We use atomic force microscopy (AFM) of two-dimensional nanotiles to investigate their self-assembly and final structure. Typically, nanotiles are not completely flat due to the helical nature of the DNA, which introduces supercoiling distributed across the nanotile. Certain drugs bind naturally to the DNA double helix, often either in the minor groove or as intercalators, inserting in between the base-pairs. The binding of drugs will affect the helical pitch of the DNA and change the curvature of the nanotiles. We can assess the curvature of the nanotiles by seeing which way up they bind to a model mica surface using the AFM. This project will investigate how binding of drugs into the DNA helix affects the DNA origami structure and shape. This is critical knowledge for rational design of nanotiles as drug delivery vehicles. Recent published studies show that nanotiles readily cross the cell membrane and are ideal candidates as therapeutic carriers.
Chemical inhibitors of Orai as possible therapeutics for treating colorectal cancer and associated liver metastases 01 Apr 2016
New drugs to treat colorectal and associated cancers are urgently required as Incidence of colorectal cancer alone is 75 thousand per year in the UK and there are no universally effective medications currently available. The project seeks to identify and develop new inhibitors of a protein (Orai3) as potential therapeutics for the treatment of these cancers and to support validation of these proteins as rational targets for future drug discovery. No chemical inhibitors of Orai3 have been discovered to date, however the group have recently identified a series of inhibitors of the homologue Orai1 with off-target activity at Orai3 which they hope to repurpose for Orai3 inhibition. The aim of the project is to develop a Structure and activity (SAR) for the inhibition of Orai3 channels thus allowing the control and inhibition of the Orai3 channel in cancerous cells. Chemical inhibitors identified within this project may offer potential starting points for development of commercially viable medicines and as tools to support the basic understanding of Orai related cancers leading to further research.
Aims To establish whether an unusual splicing event of CRMP2 contributes to tumourigenesis. Learn how to carry out scientific research and basic laboratory skills Approaches: I will learn how to culture tumour cells, fractionate sub-cellular components and identify expression of different variants of CRMP2 in each compartment. Further to this, I will learn how to clone different forms of CRMP2 and express these in cells. The project will then move to the generation of novel cell lines where the unusual splice variant of CRMP2 is removed from tumour cells that express it, and increased in cells that do not contain it. This will allow the investigation of the sufficiency and dependency of CRMP2 on tumour cell growth. All of the tools and techniques required are established in the host laboratory.
Investigation into the regulation of NICD stability and its role in determining the periodicity of the vertebrate segmentation clock 23 Jun 2014
Notch is one of the five major signalling pathways that regulate vertebrate and invertebrate development. Notch signalling relies on cell-cell contact as both ligand and receptor are transmembrane proteins. Upon ligand activation the intracellular domain of the receptor (NICD) is cleaved and translocates to the nucleus to activate gene transcription. NICD is extremely labile and phosphorylation allows this target to be recognised by the F-box protein Fbxw7 which then recruits the Skp1-Cui1-F-box protein (SCF) ubiquitin ligase complex that targets NICD for degradation. Thus, phosphorylation is a key event in NICD turnover but the details of this process remain obscure. Recent work in the lab has shown that a number of different small molecule kinase inhibitors, which delay the vertebrate segmentation clock, also lead to elevated NICD levels and prolonged NICD half-life. This research project aims to determine whether these inhibitors increase levels/half-life of NICD by changing NICD phosphorylation status and whether they affect the interaction of NICD with Fbxw7. We will employ a transgenic mouse that allows real time imaging of clock gene oscillations in tissue explant assays and will use CRISPR/Cas9 knock-in technology to generate NICD phospho-mutants to determine if this alters the periodicity of clock gene oscillations.
Determining the mechanism of β-barrel assembly machinery (BAM) in bacterial outer membranes 14 Jul 2014
Outer membrane proteins (OMPs) in Gram negative bacteria are critical for bacterial survival and virulence 1 . However how these beta-barrels fold in the membrane is not well understood. The in vivo folding of most substrate OMPs relies on the function of the beta -barrel assembly complex (BAM)2, of which the key component is BamA 3, itself a beta-barrel. Here we propose to use a panoply of structural and biophysical methods to dissect the functionality of BamA and the mechanism of OMP folding. Our key aims are: 1) To investigate the hypothesis that BamA functions by lateral gating. Using a combination of disulphide linking and FRET we will determine whether lateral gating is necessary for the folding of different OMPs, and how it may function. 2) To determine how BamA function is affected by liposome size and membrane crowding, by utilising a varied subset of lipid types and comparison of substrate OMPs in folding assays. 3) To determine the importance, and role of the beta -signal of OMPs in the interaction with BamA by dynamic force spectroscopy measurements. The question of how OMPs fold represents a fundamental gap in structural biology understanding. In addition, the OMPs of Gram negative bacteria are key to their pathogenicity, therefore understanding the mechanism of BAM may present new possibilities for drug targets.
Wellcome Trust Clinical PhD Programme at the University of Dundee: "Genomic investigation into evolution of Staphylococcus aureus and the micro-epidemiology of Staphylococcus aureus in atopic eczema." 14 Apr 2014
Across all continents Staphylococcus aureus is the commonest cause of skin and soft tissue infection. Surface displayed and secreted proteins are fundamental for the ability of this bacterium to colonise and infect human hosts. Such secreted factors confer this organism’s ability to adhere to host cells and evade the immune system. The Type VII protein secretion system (T7SS) in S. aureus is emerging as an important system that contributes to disease-causing mechanism for this human pathogen. It has previously been shown that inactivation of the Type VII system in S. aureus (or equivalent in Mycobacterium) reduces pathogenicity. As of yet the precise function of this secretory system is still not fully understood. The aim of this work is directed towards determining the role the T7SS plays in human skin colonisation and the potential role it has in infection. This will be achieved by studying both T7SS wild type and mutant strains in models of skin infection (murine) and colonisation (ex-vivo human tissue culture). Once the involvement of the T7SS in these models in confirmed we will examine the contribution of the secreted substrates with human cells.
Molecular mechanisms of O-GlcNAc signalling. 03 Dec 2013
Post-translational modification of eukaryotic protein serines/threonines with N-acetylglucosamine (O-GlcNAc) was discovered 20 years ago. Subsequent work has shown that O-GlcNAcylation is regulated by a tranferase (OGT) and a hydrolase (OGA), both single, essential genes, conserved from C. elegans to humans, and that a plethora of proteins in the nucleoplasm are O-GlcNAcylated. Excitingly, there are examples of O-GlcNAcylation having interplay with phosphorylation, including competition for the same serines/threonines, giving rise to the Yin-Yang hypothesis , that proposes O-GlcNAc as a global, glucose dependent, mechanism to control protein phosphorylation. I aim to use a multi-disciplinary approach to uncover the molecular mechanisms governing O-GlcNAcylation and its importance in a number of signal transduction pathways. Capitalising on a significant body or preliminary data, the aims are to: 1) Synthesize/discover OGA/OGT inhibitors and substrate analogues, including glycopeptide s. 2) Determine the structures of human OGA/OGT, including inhibitor/protein substrate complexes and probe mechanism/specificity with mutagenesis and in vitro assays. 3) Understand the effect of O-GlcNAc on phosporylation/activity on key signalling proteins in pathways involve in the insulin response, neuronal development and energy stasis. 4) Investigate whether orthologues of these enzymes in pathogenic bacteria are involved in prokaryotic O-GlcNAc and/or are virulence factors targetting ho st proteins.
'Scales of Life' is the ambitious inaugural exhibition at LifeSpace, an Art Science Research Gallery within the newly created Centre for Translational and Interdisciplinary Research at the College of Life Sciences, University of Dundee. The creation of this new research-driven gallery space, curated as a collaborative partnership with researchers from Duncan of Jordanstone College of Art and Design, enables an exciting opportunity for interdisciplinary art and science interactions. Scales of Lif e will reflect the key orders of biological organisation from molecules to cells to whole organisms. This mirrors the research expertise within the College, which encompasses biomedical, biological and chemical sciences, ranging from molecular structure and drug design to genetics and cellular control mechanisms of whole organisms. This project proposal requests support for the commission of artists Thomson & Craighead, in collaborative partnership with scientists at the University, to create a new installation, working title 'Stutterer', that utilises media technologies to reframe the way society perceives the visualisation of scientific data. The installation will exploit the human genome sequence as a molecular data source to produce a mutable artwork, delivering new observations on scientific visualisation. The commission, which reflects the molecular scale, will be the highlight of the Scales of Life exhibition that will celebrate the opening of the Centre by Sir Paul Nurse on the 1st October 2014.
In Memoriam. 10 Feb 2014
We propose a Public Event in Edinburgh on Saturday 8th March. This day to be about the importance of Body Donation to science in Scotland, but also to promote the benefits to society of a greater openness around the subject of death and dying. The event will include, and open with, a talk by Prof Sue Black of the University of Dundee on the subject of Body Donation, and will include workshops on story-telling and creative writing, on the body in art and sculpture, on the historical perspectives of death in Scotland, and will culminate in a lecture by Richard Holloway FRSE. It will be an all-day event with some events set up for the whole day, and some hour-long workshops. It is intended that we invite MSPs, relevant civil servants, and HM Inspector of Anatomy to attend, and the event will be open to the general public. The running of the workshops and installations will include the help of Prof Kirsty Gunn and Prof Calum Colvin, both joint winners of the Stephen Fry Award.