- Total grants
- Total funders
- Total recipients
- Earliest award date
- 20 Nov 1998
- Latest award date
- 11 Feb 2019
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
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.
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.
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.
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.
Prosthetics and avatars can both be defined as forms of bodily extension - one mechanical, the other digital. Both are used widely in everyday life, yet research into their impact upon users’ lived experiences has been approached with different emphases. Medical research into prosthetic limbs has tended to focus on functionality, while research into avatar usage has embraced embodiment, social identity and interaction, legal ownership and rights. This project brings together researchers from rehabilitation medicine, law, digital performance and media to apply multiple perspectives to prosthetic and avatar bodily extensions. How do different forms of bodily extension impact on experiences of embodiment and being in the world? How do body image and social identity relate to the design and function of bodily extensions? How far are bodily extensions defined and acknowledged in medical, information technology and human rights law? The project has three major goals: To establish a new interdisciplinary research network in bodily extension, specifically in relation to prosthetics and avatars. To produce three interdisciplinary peer-reviewed articles for readerships in digital media and culture, rehabilitation medicine and innovation law. To develop a funding application for a Wellcome Trust Collaborative Award to further this research.
Gamma knife®(GK) is a stereotactic radiosurgery that can be used to treat trigeminal neuralgia(TN), without the need for pharmacological medication, and has been shown to result in patients being pain free without medication from as early as 6 months after surgery (Loescher et al, 2012). TN is a serious health issue that causes short, reoccurring sessions of intense, sharp facial pain, which has been compared to the feeling of an electric shock (Headache Classification Subcommittee of the International Headache Society, 2013). The cost effectiveness of GK has yet to be fully elucidated. Qualitative work has evaluated the effects of the drug of choice, Carbamazepine, used to treat TN, and found that patients report motor and cognitive difficulties (Zakrzewska et al, 2017). However, a more objective, quantitative investigation into the effects of Carbamazepine and GK treatment on patients with TN would allow for standardised assessment of risks and benefits and therefore make cost-effectiveness discussions more informed. This study will investigate the effects of different treatment regimens on manual dexterity tasks, where participants use a handheld stylus to interact with visual stimuli and postural stability tasks, where participants are exposed to a cognitive load and their gross motor control is measured.
Modern Cryo-Electron Microscopy with Direct Electron Detection at the University of Leeds. 11 Jun 2015
Funding is requested to buy a modern, cryo-capable, electron microscope to replace an outdated instrument at the end of its useful life. Data collection is currently slow and inefficient, and we cannot achieve the resolution that modern instruments allow. The new microscope will be more stable, automated, and equipped with a direct detector of the kind that is revolutionizing EM. We will also purchase the infrastructure to handle the enormous data flows that we will generate. This will transform electron microscopy in the Astbury Centre and support a wide range of biomedical projects in areas such as infection, degeneration and cancer. For 1M of Trust funds, and University investment of 1.7M, the new microscope will enable cutting-edge biological EM, including: 1) Pushing the structure determination of biological macromolecules (and their complexes) to the highest possible resolution, which in many cases will be close to atomic resolution (3-5 ). 2) Allowing us for the first time t o solve the structures of smaller macromolecules and complexes (>200-300 KDa) 3) Determining the structures of relatively lowly populated functional states in heterogeneous and/or dynamic systems 4) Performing tomography studies of unique biological events such as the entry of a virus into its host cell.