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Results

Exploring endosomal signalling of G protein coupled receptors (GPCRs) using luciferase complementation and luminosensing optogenetics 31 May 2018

Recently G protein coupled receptors (GPCRs) have been shown to signal from intracellular compartments such as endosomes, as well as the cell surface. There is increasing evidence that some synthetic drugs can activate such intracellular located GPCRs directly, but the functional consequences of this activation have been difficult to isolate. This project will study endosomal signalling from engineered optogenetic receptors (OptoXRs), activated by light and coupled to the Gq pathway linked to calcium mobilisation. I will deliver the light stimulus to OptoXR using bioluminescence from a luciferase enzyme, in a local manner to receptors either at the cell surface or within endosomes. This will be achieved using a complementation system, in which luciferase fragments are tagged to the OptoXR and cell surface or early endosomal markers respectively. Active luciferase will therefore only be reconstituted to deliver the light when the OptoXR is present in the same location as the expressed marker. I will then be able to compare the effect of adding the substrate on OptoXR calcium responses in which case, to determine whether calcium signals are produced from receptors in different locations. This will be backed up by confocal and luminescence microscopy to identify reeptor and luciferase locations.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Nottingham

DNA-clustering in yeast 31 May 2018

We propose to describe mathematically the processes by which telomeres form clusters in the nuclei of yeast cells. It is thought that this is due to the presence of proteins which bind to the telomeres. We wish to investigate the processes which determine cluster size through: 1. forming a mathematical model of the attachment processes through which proteins bind to telomeres. This may involve a site exclusion process, whereby the protein binding rate slows due to the declining number of vacant protein binding sites as the telomere `fills up'; 2. constructing a mathematical model of the aggregation of telomere-protein complexes into clusters, and determine which rate parameters are key to controlling cluster size; 3. investigating the rate of equilibration of these processes. The models we construct will have the form of systems of coupled ordinary differential equations. Through a judicious choice of rate constants, explicit equilibrium solutions will be obtainable, allowing available data to be fitted. Numerical simulations of the process will also be performed, to verify that the equilibrium solutions are accessible within biologically realistic time periods.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Nottingham

Synthesis, characterisation and biological evaluation of a novel library of iminosugar compounds as inhibitors of Galactofuranosyl Transferase 2 inhibitors in Mycobacterium Tuberculosis 30 Sep 2018

The increasing prevalence of antimicrobial resistance (AMR) represents one of the greatest existential to humanity. Of particular concern is the emergence of multi-drug and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB) infections which significantly diminish the treatment prospects for patients. This means that there is a distinct need for novel anti-TB drugs with unique targets which will allow them to circumvent the resistance to conventional drugs. One such target is the Galactofuranosyl Transferase 2 (GalfT2) enzyme. This enzyme plays a key role in the generation of the alternating beta-1,5 and beta-1,6 furanose linkages which make up a significant portion of TB’s complex cell wall. Knock-out studies have shown that this enzyme is vital to TB viability making it an attractive drug target. Previous work in the Thomas group identified iminosugars as a weak inhibitor of GalfT2. The aim of this project is to synthesise a library of these iminosugar compounds and explore their efficacy as GalfT2 inhibitors using both whole-cell and enzyme assays. Structural elaboration will be performed, principally driven by in silico drug design which will attempt to improve the inhibitory properties. The hope of the project is to identify novel iminosugar compounds which can act as effective anti-TB compounds.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Nottingham

Mathematical modelling of inflammation 31 May 2018

The proposed research seeks to build on existing mechanistic mathematical models for the inflammatory response by generalising them to structured-population frameworks able to capture, in particular, a continuum of macrophage states, motivated by a desire to shed light on the processes that regulate whether resolution or dysregulation of inflammation occurs. The level of the modelling assumptions and analysis will reflect what can realistically be achieved over the course of a Vacation Scholarship. Interactions of macrophages and neutrophils with bacterial biofilms will provide a concrete focus for the application of the general models, arising from discussions with (and enabling guidance from) microbiologists within the University. The key goals are: (i) Construction and extensive numerical simulation of a structured-population model that encompasses macrophage and neutrophil populations and builds directly on extant ordinary-differential-equation formulations. (ii) Generalisation of the model to include spatial effects, allowing the simulation of an idealised model for the interaction of inflammatory cells with a heterogeneous biofilm. (iii) Interpretation of results, providing the Scholar with experience of systems-biology research as applied to topics of direct relevance to healthcare.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Nottingham

Axonal miRNAs in the development and function of neuron connectivity: intra-axon and inter-neuronal actions 04 Dec 2017

Brain function depends on the correct formation, maintenance and constant changes of neuronal circuits. Among the multiple signaling pathways regulating these processes, microRNAs have emerged as crucial regulators of gene expression able to control the development and remodeling of neural connections. However, there is still a very limited understanding of their role in axon biology and inter-neuronal communication. Our central hypothesis is that specific miRNAs can be transported to the axon and regulate the development and function of neuronal connectivity via the control of local axonal translation (cis-action) and inter-neuronal (trans-action) mechanisms mediated by release of extracellular vesicles/exosomes. We will test this using a multidisciplinary approach with innovative cellular and molecular techniques based around compartmentalised microfluidic devices for the culture of mouse primary cortical neurons. The characterisation of axonal miRNAs and their capacity for intra- and inter- cellular action could transform our current understanding of the role of miRNAs in the development and function of neuronal networks. The impact of these findings will be many, both at the level of basic neuron connectivity, and in the understanding of neurodegenerative disease, where disruption of axonal projections and neuronal circuits has been intrinsically linked to progressive functional decline.

Amount: £99,730
Funder: The Wellcome Trust
Recipient: University of Nottingham

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £14,351
Funder: The Wellcome Trust
Recipient: University of Nottingham

Imaging Flow Cytometry 05 Jul 2018

We seek funding for an ImageStream X Mark II Imaging Flow Cytometer to be hosted by the University of Nottingham (UoN) Flow Cytometry Facility. This exciting technology combines the speed, statistical robustness and multi-parametric data of conventional flow cytometry with the detailed localisation information of microscopy. The machine has been specified following a trial demonstration and in consultation with our extensive user group and co-applicants. It includes five lasers, high magnification, extended depth of field and automated sampler options that would make it one of the most capable machines in its class in the UK. An imaging cytometer would significantly enhance research capability by offering unique high number and high content experiments. Novel applications include the ability to detect, enumerate and characterise rare cells; the ability to dissect cell signalling events through precise measurements of nuclear translocation events or co-localisation; the study of extracellular vesicles in both eukaryotic and prokaryotic systems; precise quantification of drug delivery/internalisation; and the study of cell death mechanisms. We have established mechanisms for access, charging and an extensive client list that have indicated keen interest in this technology, and have secured a 30% financial contribution from the University demonstrating the strategic importance of this equipment.

Amount: £335,298
Funder: The Wellcome Trust
Recipient: University of Nottingham

How do involuntary memories interfere with ongoing behaviour? 31 May 2018

This research will provide insights into how emotionally salient memories affect behaviour. In tasks where there is no requirement to remember, brain activity measures have shown that previously encountered positive and negative valence material is more likely to be retrieved than neutral material. It is important to extend this research to understand how this kind of involuntary retrieval influences behaviour. Participants will see negatively valenced as well as neutral pictures. In a subsequent task, participants will see these pictures again, interspersed with new (unstudied) pictures. There will be two blocks in this task. In one, participants will indicate whether the pictures are presented to the left/right of fixation. In the other, participants will indicate whether the picture depicts an event occurring indoors or outdoors. In both tasks, the key measure is reaction time. The critical questions are whether: (i) prior exposure increases reaction times, and (ii) this is more likely for negative valence pictures. Using two tasks permits an assessment of whether focusing on perceptual (block one) or semantic content (block two) influences when interference occurs. At issue is the influence that involuntary retrieval of emotional material has on behaviour.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Nottingham

Combating Gram Negative AMR Pathogens by Understanding the Envelope-Breaching Mechanisms of Predatory Bacteria 28 Nov 2017

We aim to determine the exact molecular mechanisms by which the bacterial predator Bdellovibrio invades Gram negative pathogen prey and whether components of its invasion machinery could be used in isolation as a new approach to the treatment of antimicrobially resistant (AMR) bacterial infections.Gram negative AMR pathogens are a major threat to healthcare. Their "extra" outer membrane is a barrier to effective drug delivery. We wish to learn from nature as Bdellovibrio is able to effortlessly pass through the envelope of pathogen, (but not host), cells and kill them from within. Whole-cell usage of live Bdellovibrio shows great therapeutic promise. However, a deeper understanding of the molecular mechanisms by which Bdellovibrio achieves invasion is essential to inform future therapeutic options. We will use our combined expertise (in microbial-genetics and microscopy, plus protein structure:function analysis of these unusual predators), and preparatory data including:- an RNAseq dataset from an invasion-stalled mutant -providing us with candidate proteins made during invasion; 3DSIM/fluorescence microscopy revealing a central pore, surrounding "collar" and a protein-tagged robust secretory vesicle at the predator-invasion site. Our end goal is to associate specific invasion protein function to these physical features of pore generation/entry, uncovering mechanisms used by nature to breach prey-envelopes.

Amount: £1,129,804
Funder: The Wellcome Trust
Recipient: University of Nottingham

Understanding the Mechanistic Link Between the Twin-Arginine Transport (Tat) System and Quorum Sensing in Pseudomonas aeruginosa in order to Design and Develop Novel Antivirulence/Adjuvant Drugs 30 Sep 2018

Pseudomonas aeruginosa is a common human pathogen that causes serious infections and is intrinsically resistant to many antibiotics. P. aeruginosa has multiple interlinked chemical messaging (quorum sensing) systems which control production of virulence factors, synchronisation of bacteria and formation of multidrug-resistant biofilms that lead to immune evasion and establishment of disease. One such system is 2-alkyl-4-quinolone (AQ) signalling and inactivation of this results in bacteria unable to cause infection. Perturbation of AQ signalling would therefore be an ideal target for new antimicrobial compounds. Inhibition of the Twin-arginine transport (Tat) system, the only pathway that secretes fully folded proteins in P. aeruginosa, perturbs AQ signalling yet the precise mechanism is not known. To identify which substrates of the Tat system influence AQs, a bioluminescent gene expression reporter that responds to AQs will be monitored in Tat substrate mutants, and AQs will be localised within bacteria. Novel Tat inhibitors will also be optimised and tested for antimicrobial potential. The aim is to understand the Tat-AQ signalling link alongside discovering and developing new antibiotics that target the Tat system, and therefore, virulence. Virulence is not an essential biological process, so antibiotic-resistance is less likely to develop due to a lower selective pressure.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Nottingham

Visual rehabilitation after stroke guided by anatomical and functional neuroimaging 31 May 2018

Approximately 60% of stroke survivors are left with significant visual impairment such as visual field loss. There are currently no effective rehabilitations for visual field loss, and perceptual retraining has only been shown to be effective for specific stimuli and visual field locations, rather than generalising to an overall improvement. However, functional imaging responses can reveal spared striate and extra striate cortex which opens up the possibility of retraining residual brain networks to detect and discriminate visual input in the visual field thought to be cortically blind. This project aims to assess the feasibility of combining diffusion weighted measurements with functional MRI data to establish maps of residual visual function and anatomical connectivity in stroke survivors with visual field loss. Furthermore, whether these spared areas support the generation of conscious visual perception in the damaged visual field. This will be perfomed on existing data from one stroke survivor, who will then return for behavioural experiments which present stimuli in areas that have been determined to be spared. With the knowledge gained in this project, we will be able to maximise the benefit of visual rehabilitation by targeting the training interventions to specific locations and kinds of stimuli.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Nottingham

Developing cardiac electrophysiology models for drug safety studies 17 Jul 2018

Simulations of the effect of multiple ion channel block on cardiac electrophysiology have become a key part of proposals to replace the ThoroughQT clinical study with more accurate preclinical tests. Success depends on having accurate mathematical models of both baseline cellular electrophysiology and drug-induced changes. Mathematical models include both ion channel kinetics (and drug effects on these) as well as action potential electrophysiology with appropriate expression levels of each ion channel type. We will extend and refine a new approach we have developed that uses shorter, more information-rich, experimental protocols for developing cell-specific mathematical models of ion channel and cellular electrophysiology, then predict drug responses with these models and validate against experiments. To make models that are ready for safety-critical use the problem of model selection (selecting the most appropriate set of equations) will also be addressed, as will model discrepancy – assessing, quantifying and predicting the difference between the model and reality. We will include uncertainty in our models and their inputs in a probabilistic framework, such that our predictions take the form of probability distributions. We will continue close collaboration with pharmaceutical companies and drug regulators to test and roll-out improved models.

Amount: £1,918,557
Funder: The Wellcome Trust
Recipient: University of Nottingham

Generation and evaluation of a range of nanoparticle formulations with the aim of targeting H. pylori 30 Sep 2018

Helicobacter pylori infects just over 50% of the world’s population and is the leading cause of peptic ulcers and gastric cancer. The current treatment, ‘triple therapy’, often does not completely clear the infection and usually causes unpleasant side-effects. Failure of treatment is mainly due to bacterial resistance to antibiotics, and inefficient access to the bacteria. The antibiotics act by entering the bloodstream and must cross the stomach lining to reach the bacteria in a thick layer of mucus. In this proposal, we aim to develop new drug delivery systems which penetrate this mucus layer and target antimicrobials directly to the H. pylori. Liposome and polymer-based nanoparticle formulations will be investigated. We hypothesise that delivery systems combining anti-bacterial fatty acids and antibiotics, as a dual approach, will be more effective and allow the administration of lower doses of antibiotics over a shorter period. The best-performing formulation from in vitro studies will be tested in vivo using a mouse model, and the bacterial clearance rates will be compared to the current triple therapy. Developing a new and improved therapeutic formulation will benefit patients by reducing suffering and saving lives, and it will also benefit the pharmaceutical industry and therefore the economy.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Nottingham

Cinema and Medicine in Early Soviet Russia 30 Nov 2017

Provision for Public Engagement

Amount: £22,042
Funder: The Wellcome Trust
Recipient: University of Nottingham

Governing AI safety in healthcare: developing a learning architecture for regulation, investigation and improvement 26 Jul 2018

Artificial intelligence has enormous potential to improve the safety of healthcare delivery, but it also has the potential to introduce a range of new risks to patient safety. To maximise the benefits of AI in healthcare, it is critical that the patient safety risks posed by AI are robustly analysed, regulated and governed. Due to the rapid pace of development in the technologies and applications of AI, it is also essential that systems of AI governance can themselves rapidly learn from experience. Accordingly, this seed award will support research, networking and planning activities to begin a programme of work systematically analysing the ‘learning architecture’ required to underpin the effective governance and regulation of AI in patient safety. Exploratory research will examine the scope of patient safety risks posed by AI, and characterise the key regulatory functions and learning mechanisms needed to effectively govern those risks, paying particular attention to the social, organisational and epistemic processes involved. A series of iterative design workshops with leading researchers, technologists, policymakers and patients will shape these emerging findings to develop a proposed governance framework, and a core group of collaborators will be established to develop detailed plans for a broad-based programme of future research.

Amount: £47,298
Funder: The Wellcome Trust
Recipient: University of Nottingham

Development of magnetic resonance imaging (MRI) at The University of Nottingham 17 May 2018

In 2003 Professor Sir Peter Mansfield (with Professor Paul Lauterbur) was awarded the Nobel Prize for Physiology or Medicine for discoveries concerning magnetic resonance imaging. This project will transform access to the papers of Peter Mansfield and other scientists associated with the development of MRI at the University of Nottingham: Professor Raymond Andrew and Professor Brian Worthington and associated records of the British Radiofrequency Spectroscopy Group; opening up the collections for teaching and research to tell the story of the pioneering work on MRI undertaken at Nottingham. The collections will be catalogued to ISAD(G) and repackaged in archival quality materials. Films, videos, audio tapes and 35 mm slides will be digitised for both preservation and access and to aid cataloguing. Photographs will be assessed for possible future digitisation. An interdisciplinary Advisory Group will be established to support the project and open up the collections to researchers. The collections will be promoted to both academics and the general public. It is hoped that this could lead to the discovery of further records relating to MRI at Nottingham and inspire other scientists to donate their records, so developing Manuscripts and Special Collections as a centre for research into the development of MRI.

Amount: £99,508
Funder: The Wellcome Trust
Recipient: University of Nottingham

The Animal Research Nexus: Changing Constitutions of Science, Health and Welfare 01 Feb 2017

This five-year collaborative programme will develop approaches for understanding laboratory animal research as a nexus, asking how reconceptualising connections and generating communication across different perspectives can contribute to improving the future of animal research. New research will draw attention to historical independencies between science, health and welfare; identify challenges emerging at the interfaces of animal research and create opportunities for informing policy and public engagement. We suggest collaborative approaches are essential for understanding how rapid transformations across science and society are changing the patterns of responsibility, trust and care which hold together, or constitute, this nexus. We will deliver new: integrated research across the social sciences and humanities, using historical research to inform understanding of present challenges and create new engagement opportunities for the future; interactive research projects, co-produced with researchers, animal suppliers, veterinarians, publics and patients, to investigate the contemporary dynamics of animal research; interfaces for generating cultures of communication with publics, policy-makers and practitioners across the animal research nexus. This programme brings together five leading researchers on the social and historical dimensions of animal research, uniting the strengths of five institutions, engaging creative practitioners, and advancing the work of five early career researchers and three PhD students.

Amount: £351,802
Funder: The Wellcome Trust
Recipient: University of Nottingham
Amount: £2,400,000
Funder: The Wellcome Trust
Recipient: University of Nottingham