- Total grants
- Total funders
- Total recipients
- Earliest award date
- 25 Oct 2005
- Latest award date
- 30 Sep 2018
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
It is challenging to engage pregnant/early postnatal women with local maternity research, as pregnancy is a normal physiological process which is relatively short-term, and after which women find regular engagement challenging. As such, two different engagement approaches will be piloted by University-based researchers and Patient and Public Involvement advisers to engage local pregnant/early postnatal women in research development, recruitment and dissemination on a continuing and regular basis. Both approaches will involve local researchers coming to speak to women about the latest maternity research and opportunities for involvement. One approach will attach this activity to an existing class at a children’s centre, whilst the other will be attached to a new yoga and midwifery advice session developed as part of this project. Information provided during these sessions may be useful to women during their pregnancy or after they have had their babies, and the insights of women will help to ensure the research is relevant and has the best chance of success. Women will help researchers translate research findings into a format suitable for a range of audiences. The groups will be evaluated and, if successful, plans will be made to make the group self-sustaining.
Regulating healthcare through blockchain: Mapping the legal, ethical, technical and governance challenges 30 Nov 2017
Blockchain technologies have the potential to radically reshape many industries, including healthcare. These technologies create a distributed database across a network of computers, using cryptographic methods to verify the consistency of digital records and transactions. This could enable the secure, tamper-proof, transparent, and trustworthy management of health-related data. But some doubt whether blockchain can deliver on its promise. Others fear that it will deliver too much, providing efficiency and security without sufficient operational sensitivity to healthcare contexts. Blockchain is a form of ‘design-based’ regulation, entailing the hard-coding of regulatory norms into systems infrastructure and operation. For example, by creating a transparent and unalterable audit trail regarding data access and usage, or by building in privacy through data encryption. Hard-wiring norms (e.g. traceability and privacy) into healthcare systems might overcome shortcomings of conventional legal and ethical regulation, but is likely to face major implementation challenges. This project will identify, map, and examine the implications for utilising blockchain in healthcare. It will identify the legal ethical, technical, and governance opportunities, risks, and challenges. It will thereby begin to explore whether, and under what conditions, these technologies might be developed whilst remaining faithful to important ethical, democratic, and constitutional values.
MA Literature and Culture PT 30 Jun 2018
My research will use literary material to contextualise the reception of medical texts and diagrams in late medieval Europe. The research refers to medical diagrams found in western manuscripts produced between the 13thC and 15thC named homo signorum (zodiac man). The project argues that this image and the widely-known Galenic humoral theory influenced travel writers in their descriptions of non-European bodies. This medical information was not understood neutrally, and was received as referring to Western, European, male bodies. The research develops the work of Susan Conklin Akbari (2009) and Irina Metzler (1997), contributing towards the emerging recognition within Medieval Studies of prejudiced interpretations and applications of medical theory within medieval literary texts. A medical discourse was developing in the later Middle Ages which conceptualised race as biological. A 13thC scientific discourse claimed that non-European peoples partook in a ‘blood libel’, which involved restoring a natural flux of the melancholic humor through drinking the blood of male Christian children. Medieval understandings of physiology were conflated with literary representations of the deviant non-European body. This research aims to investigate the unbalanced, unhealthy bodies presented within travel narratives, which deviate from the Western-European normative ideal of health interpreted from medical texts and diagrams.
Determining The Intrathymic Mechanisms That Instruct Regulatory T-cell Production For Control Of Organ Specific Autoimmunity 30 Sep 2018
T-cells recognise and mount an immune response against pathogens however responses against self-tissue can occur, causing tissue damage and disease. In the thymus (a unique organ of T-cell development and education) autoreactive T-cells are removed but this isn’t 100% efficient, meaning a sub-population of T-cells termed regulatory T-cells (Tregs) is required to prevent self-reactivity. Our understanding of Treg development is incomplete and has been further challenged by findings of high heterogeneity in the thymic Treg population i.e. a large population of mature vs de novo Tregs. Furthermore possible Treg development outside the thymus by the most recent thymic emigrants (RTEs) remains unexplored. To accurately assess Treg development we use a novel mouse model with fluorescent markers that identify both a) Treg vs. non-Treg, and b) age. Distinguishing a cells identity along with its age allows us to investigate new and old Tregs in the thymus as well as Treg RTEs in the periphery using techniques such as flow cytometry, microscopy and qPCR to characterise thymic and extrathymic developmental stages. This work will provide new insight into how Tregs which regulate discreet tissue sites are generated, offering valuable new information on an essential regulator of self-reactivity and disease.
The role of inflammation in the formation of multi-drug resistant lineages of Escherichia coli 30 Sep 2018
Multi-drug resistant (MDR) Escherichia coli and Klebsiella pneumoniae are the new superbugs of the 21st century. Strains of these bacteria are now commonly being isolated which are resistant to all front line clinical antibiotics, as well as last line compounds such as colistin. In the absence of new effective antibiotics we must find new ways of combatting such infections. Data generated by our lab suggests that the main genetic difference between MDR E. coli and normal harmless E. coli is the presence of signatures of natural evolutionary selection in genes involved in anaerobic metabolism, which are utilised by E. coli in an inflamed environment. We will test the hypothesis that the ability to better live in inflamed intestinal environments led to the formation of MDR strains of E. coli, which can outcompete other bacteria and set up long term infections. We will further test if this can be countered using simple anti-inflammatory measures.
The neurophysiology of the human cerebellum is almost unstudied because the main non-invasive recording methods (fMRI, fNIRS, EEG and MEG) are all unsuitable and there is no clinical therapy requiring sub-dural recordings. This technical gap has significantly limited our ability to understand its role in areas such as cognition (1). A timely opportunity has now arisen with the development of a new form of MEG sensor ("room temperature" optically pumped magnetometers, OPMs) that promises to overcome this barrier (2). The key goal of this seed award is to develop the use of OPMs to record electrophysiological signals from the human cerebellum, confirm the sources of these signals, and pilot methods to record during the learning of new motor and cognitive skills. The latter, in particular, will open up an entirely new research field, allowing us for the first time to study not only when the cerebellum engages in cognition but how it is trained and what training signals it responds to, and thus to also understand what it learns. This work will advance our understanding of cerebellar physiology, with impact on many cerebellar disorders (developmental and degeneration disorders; stroke, tumour resection, trauma, alcoholism etc.).
Elucidating the mechanisms of host cell gene expression control by human papillomavirus (HPV) 31 May 2018
The Parish lab has demonstrated that the cellular protein CCCTC-binding factor (CTCF) associates with several sites within HPV genomes. The known cellular functions of CTCF include transcription insulation, epigenetic boundary formation and genetic imprinting, but why CTCF is specifically recruited to HPV genomes has not yet been established. The association of CTCF with its cellular target sequences changes upon cellular differentiation and this affects gene expression. ChIP-Seq experiments performed in the lab show that HPV infection results in a rapid and stable re-distribution of CTCF throughout the host cell genome. In addition, gene expression array analysis of HPV negative and HPV positive cells shows that expression of many genes is altered upon HPV infection. For example, CTCF recruitment to the cellular L3MBTL4 locus is significantly reduced following HPV infection, corresponding to a dramatic decrease in the expression of L3MBTL4 transcript encoding a methyltransferase thought to be important for the methylation of histones. The alteration of L3MBTL4 expression in this manner allows HPV to dramatically alter the cellular environment to support viral persistence. We hypothesise that HPV infection deregulates CTCF-dependent control of specific loci to facilitate efficient life cycle completion and maintain persistent infection.
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.
Animals must quickly respond to changes in their environment and internal physiological states to increase their chances of survival. Neuropeptide pathways are essential for generating behavioural flexibility, and their dysregulation has been implicated in mental and psychiatric disorders, such as anxiety and depression. Despite their significance and widespread occurrence, little is known about how neuropeptides work in the brain to modulate adaptive behaviours. This project aims to investigate the role of neuropeptides in behavioural choices in the fruit fly Drosophila. Leukokinin (Lk) is a neuropeptide involved in feeding behaviour in Drosophila. My preliminary data suggests that Lk+ neurons play an important role in regulating fly reproductive behaviours, and might adjust behaviour according to feeding needs. Using powerful genetic tools available in Drosophila, we will dissect the Lk neural pathway involved in controlling fly courtship behaviours, and test whether Lk acts as a physiological gating point for promoting appropriate behavioural selection, i.e. foraging vs. mating. Taking advantage of a genetically tractable model system, this research offers a unique opportunity to uncover principles of action-selection that might be conserved among species. This knowledge will ultimately help us better understand the function of the brain in health and disease.
Vacation Scholarships 2017 - University of Birmingham
The role of malignant B cells in Hodgkin lymphoma is unknow. Recent studies in Birmingham have provided preliminary evidence that non-malignant B cells frequently infiltrate the tissue of Hodgkin’s lymphoma. Furthermore, previous studies reported the clinical benefit of Rituximab, with CD20 negative tumour cells, which was unanticipated as it is a therapy targeted to CD20 positive cells. This suggested that non-tumour B cells promote tumour cell survival. Moreover, my supervisor's lab has recently optimised highly sensitive in situ hybridisation to detect in tissue sections the immunosuppressive cytokine IL-10, widely established as a marker of a subset of regulatory B cells. Taking these findings into consideration I am to: Characterise the non-tumour B cell population of Hodgkin’s lymphoma Determine the extent to which the phenotype of non-malignant B cells in Hodgkin’s lymphoma varies with tumour subtype and EBV status To determine the extent at which Hodgkin’s lymphoma xenografts recapitulate B cell infiltration in a humanised mouse model
The Role of MYBL2 in DNA damage response to etoposide in mouse embryonic stem cells (ESCs) 27 Apr 2017
Embryonic Stem cells (ESC) share common characteristics with cancer cells such as immortality and the ability to bypass the normal cell cycle checkpoints somatic cells have to pass through. This allows both cells to continuously proliferate without changing their cellular features. These similarities shared between both ESCs and cancer cells may relate to common patterns and mechanisms of regulating gene expression. In fact, as demonstrated by Yamanaka fully differentiated fibroblast could reverse their state of differentiation and be induced towards an embryonic stem cell-like state (induced-pluripotent stem cells (iPSCs)) by introducing four transcription factors expressed in a pluripotency state. These observations highlighted the importance of transcriptional factors in determining cell fate and their possible role in the induction of cancer. In this project, I will be working with mouse ESCs and will be looking at the role of MYBL2, a transcription factor highly expressed in ESC and iPSC, which is involved in cell proliferation and maturation, and try to better understand its role in the maintenance of genome integrity. I will be exploring how low levels of this gene affect the cell response to topoisomerase II inhibitor etoposide, a therapy currently used in to treat cancer.
The ability of platelet extracellular vesicles to promote adhesion of monocytes cells to endothelium 27 Apr 2017
There is an increasing realisation that haemostatic and inflammatory responses to tissue damage are linked by common mediators. Adhesive and signaling interactions between platelets and leukocytes have been well-described. Recently it has been realised that some of these interactions are actually mediated through extracellular vesicles (PEV) released by the platelets. Indeed, we find that PEV can bind to leukocytes and to endothelial cells, transducing signals and transferring adhesion receptors, and thus potentially amplifying inflammatory leukocyte recruitment. Here we aim to further expand our investigations by evaluating the specific ability of PEV once bound to endothelial cells, to support adhesion of monocytes. Building on our own previous observations where PEV were able to bind to endothelial cells and support adhesion of neutrophils, we will test the concentration and time dependence of PEV binding to the endothelial cells and how this modifies monocyte and lymphocyte adhesion. Based on their high avidity for PEV in suspension, we hypothesise that monocytes are particularly sensitive to interactions with PEV deposited on endothelial cells. This study will test whether this is correct, and supply further evidence as to whether PEV are potent players in the thrombo-inflammatory response, for example, linked with pathogenesis of atherosclerosis.
Effect of selective deletion of FAP expressing fibroblasts on the trafficking of T cells into the inflamed synovium. 27 Apr 2017
The main targets of rheumatoid arthritis (RA) treatments have previously been the leukocytes and cytokines they produce, however depleting these causes immunosuppression and infection by opportunistic disease. A mesenchymal cell marker, fibroblast activation protein (FAP) for constitutively active synovial fibroblasts in rheumatoid arthritis has been identified and found to be highly expressed in active disease with high levels correlated to a more aggressive disease presentation. Importantly in the inflammatory response, these cells are thought to be the key drivers of inflammation and joint damage in RA. It is possible that these cells regulate the recruitment of T cells into the joint and therefore their deletion prevents this accumulation, allowing resolution of inflammatory arthritis. This research has provided a promising target for new therapeutics. This project will analyse, by flow cytometry and immunofluorescence, the effect of deleting FAP+ fibroblasts within the inflamed joint. Specifically, the effect this has on the trafficking of T cells to the joint during experimental arthritis. The aim is to identify the differences in T cell types and populations that accumulate within the inflamed synovium between tissue samples. This will hopefully identify a possible mechanism of deleting RA synovial fibroblasts as a therapeutic target.
The emergence of bacteria that are resistant to available antibiotics represents a growing global threat requiring new strategies to combat infection. Multidrug-resistance is most serious for Gram-negative bacteria, with few antibiotics likely to be available in the near future. The understanding of the Gram-negative bacterial outer membrane (OM) is critical to developing new antimicrobial agents. Proteins present within this membrane play key roles in microbial pathogenesis Almost all proteins within this membrane utilise the Bam complex for correct folding into the outer membrane, as such it is a key target for the development of novel antimicrobials (Hagan et al. 2015). Unfortunately little is known about the molecular mechanisms of how it functions. It has been shown that one particular class of Bam substrate, the autotransporters, can be stalled in vivo by the simple addition of a large disulphide bonded loop within the passenger domain of these proteins (Renn and Clark 2011). The key goal of this study is to trap a disulphide bonded autotransporter within the Bam complex in vitro and to perform an initial characterisation of it. This will lead to providing fundamental information on how the Bam complex functions and potentially how it can be inhibited.
Polymorphisms in genes contribute about 50% of the risk for developing RA with the other half coming from factors such as diet, age, infection, traffic pollution and cigarette smoke. This may also be true of other chronic conditions such as Alzheimer's disease. In RA population studies show a potential interaction between cigarette smoke and PTPN 22, which has a polymorphic variant which increases susceptibility to RA and a broad range of other autoimmune chronic diseases. I will test the hypothesis that chemicals in cigarette smoke and traffic fumes (NO2) alter the function of PTPN 22 in leucocytes changing signalling through antigen receptors and perturbing the outcome of their activation to give rise to a pro-inflammatory phenotype which drives the development and perpetuation of RA. I will expose cell lines Jurkat (lymphocyte) and THP1 (macrophage) to cigarette smoke extract and to NO2. PTP's such as PTPN 22 are particularly susceptible to oxidative damage and I will assess the phosphatase activity of this enzyme, the phosphorylation of protein substrates it regulates and calcium signalling downstream. If time allows I will also expose primary neutrophils and T lymphocytes and investigate their functions in terms of reactive oxygen species generation and cytokine secretion.
The RNA Pol II complex is the RNA polymerase that transcribes the genes that codify for the proteins in our body, activity tightly controlled through interactions with transcription-regulatory factors. Although very much research is characterising the roles of these factors, very little, if anything, is known about how the multiple subunits of the RNA Pol II are important for the regulation of transcription. So far the RNA Pol II has been characterised as a whole complex of 12 proteins. However, our analysis of cancer genomic databases shows that single subunits can be upregulated, and this associates with aggressive tumours with poor survival in many different tumour types. We hypothesise that these single upregulations deplete transcription-regulatory factors from transcriptionally engaged RNA Pol II. This would lead to a defective transcription process associated with increased genome instability, as expected by much literature, including ours, and our cancer genomic database analysis. We propose to analyse therefore how the overexpression of single subunits affects RNA Pol II transcription, identifying which transcription processes and stages are particularly affected. Moreover, we intend analysing the genome instability, identifying the sites of DNA damage and correlating them with the transcription defects identified by our parallel analysis.
Nature-Inspired Contact Lenses for Continuous Glucose Monitoring in Type 1 Diabetic Children 08 Apr 2016
Over 3.9 million people suffer from diabetes in the UK and living with it is extremely hard; the diabetics need to regularly monitor their glucose concentrations in blood by pricking their fingers up to five times a day. This process is painful and it has low patient compliance, particularly among type 1 diabetic children. While researchers have tried creating biomaterials to detect glucose concentrations in body fluids such as tears, saliva and urine. We propose to develop contact lenses that change colour based on the variation in the concentrations of glucose in tears. This will be very useful for continuous monitoring of glucose concentrations by only visually observing the eye colour (via smart phone apps). The contact lenses will be developed using the functionalised biocompatible hydrogels, which change their index due to the changes in glucose concentrations. As these hydrogels are transparent, the colour changes will be produced by surface texturing them with arrays of nanostepped-pyramids. Such nanostepped-pyramids are inspired from 3D Christmas tree like structures, which account for the bright blue colours displayed by Morpho butterflies. This hybrid combination will provide a unique platform for producing contact lenses which reversibly sense analytes in tears for disease diagnosis and monitoring.
Structure-aided discovery of kinase inhibitors as targeted therapeutic agents for breast cancer 30 Jul 2016
Kinases are important targets for blocking cancer progression. However, many remain to be exploited. For example, no drugs are yet available to specifically inhibit any kinase which is switched on by a regulatory protein called calmodulin. Nonetheless, faulty expression of these “CaMK” enzymes is now thought to play a key role in breast cancer progression. The Wellcome Trust has funded the CAMSEED consortium to discover small molecule inhibitors for a CaMK protein involved in basal-like breast cancer. The three dimensional structure of this target has been solved by the Structural Genomics Consortium and Professor Stefan Knapp at the University of Oxford. Interactions with small molecules are being screened by Professor Michael Overduin’s lab at the University of Birmingham using superconducting magnets and high throughput robots at the national HWB-NMR facility. The design of improved inhibitors that can enter cells and selectively block the oncogenic state is being led by Professor Peter Fischer at the University of Nottingham, with Colin Kenyon at CSIR, Pretoria, designing deuterated analogs for enhanced activity. The result of the two year project is expected to be a set of lead molecules for development as potential therapeutic agents for breast cancer, and may yield a new approach for using nature’s own inhibitory mechanisms to block cancer-causing kinases.
ILC3 control of adaptive immune responses 02 Dec 2015
The emergence of the innate lymphoid cell (ILC) family has revolutionised our understanding of both the innate and adaptive immune systems. My research is focused on group 3 innate lymphoid cells (ILC3s), implicated as key regulators of adaptive immune responses. I intend to answer four related questions:1. What adaptive immune responses depend on ILC3s?2. Does ILC3 function depend on location?3. What are the mechanisms through which ILC3s control memory CD4 T cell responses?4. What are the pathways that control ILC3 function?